MECHANISMS IN ENDOCRINOLOGY: The gut–brain axis: regulating energy balance independent of food intake

in European Journal of Endocrinology
Author:
Ruben NogueirasDepartment of Physiology, CIMUS, USC, CIBER Fisiopatología Obesidad y Nutrición (CiberOBN), Instituto Salud Carlos III, Galician Agency of Innovation, Xunta de Galicia, Santiago de Compostela, Spain

Search for other papers by Ruben Nogueiras in
Current site
Google Scholar
PubMedClose
View More View Less

Correspondence should be addressed to R Nogueiras; Email: ruben.nogueiras@usc.es
DOI:
https://doi.org/10.1530/EJE-21-0277
Volume/Issue:
Volume 185: Issue 3
Page Range:
R75–R91
Article Type:
Review Article
Online Publication Date:
03 Aug 2021
Copyright:
© The authors 2021
Open access

Obesity is a global pandemic with a large health and economic burden worldwide. Bodyweight is regulated by the ability of the CNS, and especially the hypothalamus, to orchestrate the function of peripheral organs that play a key role in metabolism. Gut hormones play a fundamental role in the regulation of energy balance, as they modulate not only feeding behavior but also energy expenditure and nutrient partitioning. This review examines the recent discoveries about hormones produced in the stomach and gut, which have been reported to regulate food intake and energy expenditure in preclinical models. Some of these hormones act on the hypothalamus to modulate thermogenesis and adiposity in a food intake-independent fashion. Finally, the association of these gut hormones to eating, energy expenditure, and weight loss after bariatric surgery in humans is discussed.

Abstract

Obesity is a global pandemic with a large health and economic burden worldwide. Bodyweight is regulated by the ability of the CNS, and especially the hypothalamus, to orchestrate the function of peripheral organs that play a key role in metabolism. Gut hormones play a fundamental role in the regulation of energy balance, as they modulate not only feeding behavior but also energy expenditure and nutrient partitioning. This review examines the recent discoveries about hormones produced in the stomach and gut, which have been reported to regulate food intake and energy expenditure in preclinical models. Some of these hormones act on the hypothalamus to modulate thermogenesis and adiposity in a food intake-independent fashion. Finally, the association of these gut hormones to eating, energy expenditure, and weight loss after bariatric surgery in humans is discussed.

Invited Author’s profile

Ruben Nogueiras is currently an Oportunius Research Professor and Associate Professor of the University of Santiago de Compostela (Spain). He coordinates the Molecular Metabolism Group in the CIMUS. The group is focused on the study of molecular mechanisms involved in obesity and its associated diseases such as type 2 diabetes and metabolic-associated fatty liver disease (MAFLD). More particularly, our two lines of research aim to increase our understanding of the crosstalk between the hypothalamus and peripheral organs and to find new molecules involved in both glucose and lipid metabolism in the liver. The translational value of our basic science research data can be determined by combining our preclinical results with clinical data.

Introduction

Obesity has already reached pandemic proportions worldwide, yet the percentage of people defined as obese appears to be still increasing (1, 2, 3, 4, 5). According to the World Health Organization, worldwide obesity has nearly tripled since 1975; in 2016, more than 1.9 billion adults were overweight, and more than 650 million, obese. In keeping with these numbers, 39% of all adults were overweight, and 13% were obese, worldwide. This rapid increase in obesity is likely due to multiple factors, such as social and environmental determinants and genetic predisposition. In the simplest terms, however, the underlying basis of obesity is a higher energy intake than energy expenditure (6, 7). In addition, obesity is commonly associated with several diseases, such as type-2 diabetes, fatty liver (1, 2, 4, 8, 9, 10), and different types of cancer (11), which overall constitute metabolic syndrome.

The CNS modulates energy balance by acting through both the brain and peripheral organs (12, 13, 14, 15); this was demonstrated several decades ago, based on the observation that animals with hypothalamic lesions have increased adiposity. In terms of energy homeostasis regulation, the hypothalamus is the most studied area of the CNS. The hypothalamus modulates the levels of the neurotransmitters and neuromodulators that control food intake and energy expenditure in response to changes in energy status (16, 17, 18, 19, 20). These peripheral metabolic signals (such as metabolites, nutrients, and hormones) reach hypothalamic neurons, where they regulate neuronal activity and/or the expression and synthesis of neuropeptides and neurotransmitters (16, 17, 18, 19, 20).

We now understand that the gut not only functions in digestion and assimilation of nutrients but also contains endocrine tissues that are involved in the regulation of energy balance. This gut regulation is carried out by different hormones secreted from endocrine cells in the gastrointestinal tract, as well as by several neural pathways that communicate information from the signals responsible for the regulation of food intake and energy expenditure. After receiving the information from peripheral tissues, the CNS processes these signals and sends orders to the controllers of energy homeostasis. Notably, hormones produced in the gastrointestinal tract include peptides secreted not only by the gut but also by the pancreas and liver. This review will focus on the effects that some of the peptide hormones (mainly those secreted by the stomach and gut) exert in energy homeostasis, which regulate body weight by mechanisms that affect not only food intake but also energy homeostasis and fat storage, among others.

Hypothalamus and energy balance

The hypothalamus lies just beneath the thalamus and above the pituitary gland, to which it is attached by a stalk. It modulates a broad spectrum of metabolic functions, including the function of endocrine axes and energy homeostasis. Structurally, the hypothalamus comprises several nuclei, which constitute interconnected neuronal circuits via axonal projections (16, 17, 18, 19, 20). The importance of the hypothalamus in the regulation of body weight was initially reported by lesion studies, which showed that damaging the ventromedial hypothalamus (VMH) causes hyperphagia and obesity while damaging the lateral hypothalamus (LH) leads to aphagia and even death by starvation.

The hypothalamus also contains other nuclei, including the arcuate nucleus (ARC), the dorsomedial nucleus (DMH), and the paraventricular nucleus (PVH), which also participate in the control of energy homeostasis. The ARC is a central region in controlling both food intake and energy expenditure. It integrates signals from the periphery based on its unique anatomical position and the relatively high permeability of the blood–brain barrier in this area. Here, different factors from the periphery are sensed by two main neuronal populations in the ARC: (i) neurons that express neuropeptides stimulate appetite, such as agouti-related protein (AgRP) and neuropeptide Y (NPY) and ii) neurons that express neuropeptides inhibit feeding, including proopiomelanocortin (POMC), the precursor of alpha-melanocyte-stimulating hormone (α-MSH), and the cocaine- and amphetamine-regulated transcript (CART) (21). Finally, the VMH is one of the hypothalamic areas that is most involved in the thermogenic activity of brown adipose tissue (BAT), involved in the sympathetic nervous system (SNS) outflow to BAT (22).

White, brown, and beige adipose tissues

White adipose tissue (WAT) comprises white adipocytes and the stromal vascular fraction of cells (preadipocytes, fibroblasts, endothelial cells, etc). While its main role is to store energy in the form of triglycerides, it is also an important endocrine organ. In contrast, BAT is responsible for energy and dissipation and is the most important organ for non-shivering thermogenesis. Brown adipocytes commonly contain multilocular lipid droplets and numerous, enlarged mitochondria and are abundantly innervated by sympathetic nerve efferent fibers that allow them to regulate thermogenesis. The physiological relevance of BAT in humans has only recently been elucidated. BAT is especially abundant in newborns and in hibernating mammals, so it was classically assumed that this tissue only plays an important thermogenic function in these situations (23, 24, 25, 26). However, metabolically active BAT is also present in cervical, supraclavicular, and paravertebral regions in healthy adults (24, 27, 28, 29, 30). A third class of adipose tissue, named beige/brite adipose tissue, has now also been identified (31, 32, 33). Beige adipocytes have similar morphologic features to brown adipocytes (e.g. have central nuclei, multilocular lipid droplets, and numerous mitochondria and are responsive to thermogenic stimuli). WAT can convert (to a degree) into brown adipocyte-like cells (beige, or similar) upon sustained cold exposure or direct β-adrenergic activation, in a process termed 'browning'. However, in contrast to brown adipocytes, beige adipocytes are located within the WAT depots. It is now accepted that both BAT and brite/beige adipocytes coexist in adults (34, 35).

Ghrelin

Ghrelin is a 28-amino acid (aa) peptide originally discovered as the endogenous ligand for the 'orphan' growth hormone secretagogue receptor (GHSR) (36). Ghrelin is produced mainly by the stomach (36) but also by other tissues, such as the duodenum (37); its production is regulated by nutritional factors as well as different hormone factors. Fasting leads to increased ghrelin expression in the stomach as well as increased ghrelin plasma concentrations (38); its levels are reduced immediately after food intake. Postprandial ghrelin reduction was initially reported to be proportional to the ingested calorie load (39). Although the postprandial ghrelin response to macronutrient composition in people with obesity is not very clear (40, 41, 42), it is macronutrient-specific in people in the normal-weight range, with isoenergetic meals of different macronutrient content differentially affecting ghrelin levels. In general, carbohydrate intake leads to the most rapid ghrelin reduction; protein intake induces prolonged ghrelin suppression, and fat intake only minimally affects ghrelin levels (41, 43). Ghrelin levels change throughout the day, reaching high levels before food intake and during the night, suggesting that ghrelin is an important factor in meal initiation (44). Circulating ghrelin levels are decreased in human and rodent obesity (45, 46, 47) and are known to be elevated in people with anorexia nervosa and in states of cachexia (48, 49). Ghrelin is the only known peptide hormone secreted by the gastrointestinal tract that induces food intake and adiposity (50). Evaluation of the relationship between ghrelin and energy expenditure in humans shows an inverse relationship between ghrelin and the resting metabolic rate in lean, obese, and hyperthyroid subjects (51, 52). In addition, there is also an inverse relationship between ghrelin in the resting and postprandial energy expenditure, which (in healthy, young women) seems to be independent of variations in body composition, insulin levels, and daily energy intake (53). This relationship between active ghrelin levels and energy expenditure appears to be important in human obesity (51). Bariatric surgery, currently the most efficient treatment for obesity, enhances glucose homeostasis and enhances gut hormone secretion immediately after surgery, but its effects on the serum ghrelin levels following bariatric surgery remain controversial. Different studies have reported serum ghrelin levels to be increased, decreases, or not changed, following bariatric surgery (for specific reviews on this topic, see (54, 55, 56)). Overall, a comparison between the studies is difficult, given the different anthropometric characteristics of the patients, the distinct types of surgery, and the different ghrelin assays used. Therefore, it remains unclear whether changes in ghrelin levels have any impact on weight loss after bariatric surgery (Table 1).

Table 1

Structure, site of production, main functions, and levels following bariatric surgery of different gut hormones.
Hormone Structure Site of production Main functions Levels post bariatric surgery
Ghrelin 28 aa Stomach Stimulates food intake and adiposity,

increases gastric emptying		 Controversial
GLP1 31 aa Intestinal L cells Stimulates insulin, inhibits food intake, reduces gastric emptying ↑
GLP2 33 aa Intestinal L cells In humans, no effect on food intake or gastric emptying ↑
Oxyntomodulin 37 aa Intestinal L cells Inhibits food intake, reduces gastric emptying ↑
GIP 42 aa Intestinal K cells Stimulates insulin, inhibits food intake ↑
PYY 36 aa L cells in the ileum and colon Inhibits food intake, reduces gastric emptying ↑
CCK 115 aa L cells in colon Inhibits food intake, slows gastric emptying, pancreatic enzyme secretion ↑
Uroguanylin 16 aa Intestinal epithelial cells

Increases secretion of Na, Cl, and HCO3		 Inhibits food intake, increases gastric motility ↑
FGF15/19 216 aa Ileum Inhibits food intake, increases gastric motility ↑

Even though the potent anabolic action of ghrelin is very clear, preclinical studies show that manipulating the ghrelin/GHSR system in genetically modified mice has only a mild phenotype. Specifically, mice with a genetic knockdown (KO) of the ghrelin gene (Ghrl−/−) do not differ in food intake, body weight, body size, growth rate, body composition, reproduction, bone density, or organ weights, as compared to WT mice (57, 58). However, chronically exposing the Ghrl−/− mice (with a mixed genetic background) to a high-fat diet (HFD) shows a clear metabolic benefit from being ghrelin-deficient, especially if the HFD starts at an early age (note that this benefit is not evident in mature, congenic KO mice with a pure C57BL/6J background (59)). Namely, Ghrl−/− mice (with a genetically mixed background) fed a HFD have a reduced respiratory quotient and increased fat oxidation, indicating a shift in the metabolic fuel preference toward higher lipid utilization (58). Further, these Ghrl−/− mice have lower body weights and less fat mass despite similar food intake as the WT mice, which might be attributed to increased energy expenditure and locomotor activity (60). Overall, these results indicate that ghrelin can play a role in the preference of nutrients using metabolic fuels other than fat.

Ghsr1a−/− mice exhibit similar growth curves and food intake as their WT littermates (61) but have a modest reduction of bodyweight in adulthood (despite similar food intake, bone density, body composition, and metabolic rates) and lower levels of insulin growth factor-1 (IGF1) (61). Interestingly, Ghsr1a−/− mice are not able to maintain glucose levels to the same extent as WT animals when they are fasted or challenged by calorie restriction, indicating that GHSR1A is essential for maintaining glucose metabolism under conditions of negative energy balance (59). The age of the animals seems to be a crucial factor controlling the endogenous role of GHSR1a. For instance, 4-month-old Ghsr1a−/− mice show a slight reduction of body weight, which increases with age (to a modest reduction) (62). Age-induced obesity is mainly produced by an increase of adipogenesis in WAT and a decline in the thermogenic capacity of BAT. Surprisingly, however, older Ghsr1a−/− mice exhibit a lean phenotype with increased insulin sensitivity, reduced fat mass, and a healthier lipid profile (62). The reason for reduced adiposity is that old Ghsr1a−/− mice exhibit elevated energy expenditure, increased resting metabolic rate, and increased expression of thermogenic genes in BAT (62). Notably, double-KO mice lacking both ghrelin and GHSR1a have metabolic improvements, defined as lower body weight, reduced body fat, and lower plasma cholesterol, than WT mice when fed a standard chow diet (63). In other words, the lack of both ghrelin and GHSR1a increases energy expenditure, body core temperature, and locomotor activity despite normal food intake (63).

It is worth mentioning again that ghrelin is the only circulating gut hormone that, upon systemic and central administration, potently increases not only adiposity and food intake (50) but also other parameters, such as energy expenditure and nutrient partitioning (64, 65), that are relevant for its anabolic effect (Fig. 1). To exert these broad biological actions, ghrelin requires neuronal circuits located in different brain areas, and especially in the hypothalamus (66). Ghrelin increases the activity of Npy- and Agrp-expressing neurons and inhibits the activities of Pomc-expressing neurons (64). NPY and AgRP are crucial for ghrelin’s effects (67). Thus, ghrelin’s effects on adiposity are achieved through both centrally and peripherally mediated signaling mechanisms that modulate (i) the hypothalamic melanocortin system, and (ii) peripheral lipid metabolism, in a manner that is independent of both food intake and growth hormone (68, 69, 70). Central administration of ghrelin induces increased adiposity by stimulating key enzymes that promote fatty acid storage as well as by decreasing the expression of genes that control the rate-limiting step in fat oxidation (69, 71). The actions of the brain ghrelin system on adipose tissue are mediated by the SNS and are independent of food intake or energy expenditure (69).

Figure 1
Figure 1

Schematic representation of the metabolic effects of (i) catabolic hormones, including glucagon-like peptide-1 (GLP1), oxyntomodulin, gastric inhibitory polypeptide (GIP), and uroguanylin), and (ii) anabolic hormones, such as ghrelin. These hormones act at the central level: receptors of each hormone are expressed in different brain areas (of which the hypothalamus is the most studied) and can directly modify the metabolism of different organs via the sympathetic nervous system (SNS).

Citation: European Journal of Endocrinology 185, 3; 10.1530/EJE-21-0277

Proglucagon-derived hormones

The proglucagon gene is expressed by the pancreatic islet α-cells, which are specific enteroendocrine cells (L-cells) of the intestinal mucosa, and by a discrete set of neurons within the nucleus of the solitary tract. The proglucagon gene encodes structurally related proglucagon-derived peptides, including glucagon, glucagon-like peptide-1 (GLP1), glucagon-like peptide-2 (GLP2), glicentin, and oxyntomodulin (Oxm). The relative amounts and forms of these peptides in different cell types depend on tissue-specific posttranslational modifications by prohormone convertases. For instance, in pancreatic α-cells, prohormone convertase 2 produces predominantly glucagon, while in the intestinal L-cells and neurons of the nucleus of the solitary tract, prohormone convertases 1/3 produce GLP1, oxyntomodulin, and GLP2 (72, 73, 74, 75) (for a detailed review on this topic, see (76)).

GLP1

GLP1 is a 31-aa long (7-37) peptide hormone produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem. Further processing by a prohormone convertase results in peptides of 36 and 30 amino acids, GLP1(1-36)amide and GLP1(7-36)amide (77). GLP1 regulates blood glucose levels through its combined actions on the stimulation of glucose-dependent insulin secretion and the inhibition of glucagon secretion, gastric emptying, and food intake (78). The major stimulus for GLP1 secretion is the ingestion of nutrients, including glucose and fatty acids. GLP1 also inhibits food intake and promotes satiety in normal, obese, and diabetic humans (79). In addition to its clear effects on feeding, some reports have shown that GLP1R analogs (like liraglutide) can also increase energy expenditure (80, 81, 82, 83, 84); in contrast, however, another study showed that 12-week treatment with liraglutide can reduce energy expenditure, with a tendency to be decreased that persisted after 26 weeks, without affecting the fat fraction in the supraclavicular BAT depot (85). While still controversial, these findings suggest that liraglutide-induced weight loss is based on a reduction in energy intake rather than an increase in energy expenditure. Concerning bariatric surgery, different studies have shown that GLP1 plays an important role in the weight loss-independent glycemic effects of bariatric surgery (in particular, for Roux-en-Y gastric bypass and sleeve gastrectomy). In general, there is a marked postprandial rise in GLP1 levels after bariatric surgery, both in animal models and humans. This is a consequence of rapid nutrient delivery in the gastrointestinal tract, where the majority of L-cells are located. However, it is not clear that the high postprandial GLP1 after surgery is responsible for postoperative metabolic improvements (for a review on this topic, see (86, 87)) (Table 1).

In rodents, central or peripheral administration of GLP1R agonists inhibits food intake and leads to a reduction in body weight (88, 89). There are abundant reports showing that GLP1R analogs stimulate energy expenditure in a feeding-independent manner. For instance, the direct stimulation of the brain GLP1 signaling pathway by GLP1 or liraglutide reduces body weight and increases the thermogenic activity of BAT and the browning of WAT in a food intake-independent manner (82, 90). Indeed, this stimulation of the thermogenic activity was also reflected by the augmented levels of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1A) and uncoupling protein-1 (UCP1), two surrogate markers of thermogenesis, in the BAT of animals receiving GLP1 receptor agonists (90). This response was abrogated in GLP1 receptor null mice, indicating the specificity of the GLP1/GLP1 receptor system in the regulation of the thermogenic function. The stimulatory effect of brain GLP-1 on BAT activity is mediated by the SNS, and the brain administration of GLP1 receptor agonists enhances the electrophysiological activity of the sympathetic fibers that innervate the interscapular BAT (90) (Fig. 1).

GLP1R is widely expressed in different neuronal subsets within the CNS, coexisting with neuronal populations that play a key role in regulating energy homeostasis (91, 92). Injection of liraglutide into the ventromedial nucleus (VMH) recapitulates the effects found after ICV injection of liraglutide as well as the thermogenic program in WAT (82). On the other hand, when GLP1 is administered into the CNS over several days, it also decreases lipid deposition in adipocytes of lean mice. These actions seem to be partially modulated through effects on the sympathetic outflow, leading to an efficient shift in substrate metabolism and reduced energy storage and adiposity (93). However, in conditions of obesity, there seems to be a selective central GLP1–resistance; even though the brain GLP1 system is efficiently regulating food intake, body weight, and glucose homeostasis (94), it has no capacity to exert its actions on adipocyte metabolism. Indeed, the potential clinical relevance of the molecular mechanism described in rodents remains unknown, and the importance of the brain GLP1R signaling for the weight loss and antidiabetic effects of GLP1 receptor agonists remains to be established.

GLP2

GLP2 is a 33-aa peptide released from the mucosal enteroendocrine L-cells of the intestine by cleavage with the proglucagon prohormone convertase 1/3. It is secreted following nutrient ingestion, and reduces gastric emptying, enhances digestion and absorption, and is involved in the maintaining of glucose homeostasis (95, 96). Peripheral administration of GLP2 reduces short-term food intake in mice (97), and this action may be mediated by both peripheral and central mechanisms. On one hand, the action of GLP2 on gastric distension inhibits feeding via vagal afferent neurons; indeed, the GLP2 receptor is found in the cell bodies of vagal afferents in the nodose ganglion (98). On the other hand, the GLP2 receptor is also located in POMC neurons, where its activation suppresses feeding (99) and also enhances hepatic insulin sensitivity (95). This anorexigenic effect of GLP2 does not occur in diet-induced obese mice, indicating a GLP2 resistance in obesity (97).

Even though the effects of GLP2 are clear in rodents, peripheral administration of GLP2 in humans has no effect on gastric emptying, satiety, or energy intake (100, 101). However, in humans, GLP2 can inhibit both pentagastrin-stimulated and sham feeding-stimulated gastric acid secretion (102, 103), and it can also stimulate glucagon secretion and enhance lipid absorption (103). Similar to GLP1, GLP2 levels rise and are correlated with satiety after bariatric surgery (104, 105, 106). However, another study in obese adolescents failed to show any effects of bariatric surgery son GLP2 (107) (Table 1).

Oxyntomodulin (Oxm)

Oxm is a 37-aa peptide hormone found in the colon that is produced by the oxyntic cells of the oxyntic mucosa. Similar to GLP1, Oxm is rapidly released after food ingestion from the L-cells of the distal small intestine, in proportion to meal calorie intake (72, 73, 74). Oxm is reported to be a full agonist of GLP1R and the glucagon receptor, although it has a reduced affinity as compared to GLP1 or glucagon (108, 109, 110, 111, 112). Oxm causes weight loss in humans (113, 114) and rodents (110, 115). Overweight and obese people who receive s.c. administration over a 4-week period showed an average weight loss of 2.3 kg (114). A randomized controlled trial showed that the s.c. administration of pre-prandial oxyntomodulin increases energy expenditure, and reduces energy intake, in overweight and obese humans (116). Oxm levels remained unchanged between a group of obese women after bariatric surgery or women losing weight by diet, but its levels were elevated in response to oral glucose after surgery but not after diet (117). In addition, an increase in postprandial levels of Oxm following bariatric surgery has been suggested as a predictor of weight loss after surgery (118, 119) (Table 1).

In mice, Oxm lowers food intake, reduces body weight, and increases core temperature as compared to control animals that received equivalent amounts of food; this weight loss is associated with increased energy expenditure (110, 115). Therefore, the bodyweight-lowering effects of Oxm are likely involved in suppressed food intake and increased energy expenditure (Fig. 1).

Gastric inhibitory polypeptide (GIP)

GIP is a 42-aa peptide produced in, and secreted from, intestinal K cells of the proximal small intestine (duodenum and jejunum) in response to eating (120). The GIP receptor is abundantly expressed in pancreatic β cells, where its activation provokes an insulin response (121). In humans, an infusion of GIP does not cause any significant effect on appetite, energy intake, or energy expenditure (122, 123). Likewise, based on rodent preclinical work (see below), studies investigating the effects of a co-infusion of GIP and GLP1 in humans found that GIP does not potentiate the effects of GLP1 on lowering energy intake (123, 124) (Table 1).

In rodents, chronic exposure to a high-fat diet (HFD) increases intestinal expression of GIP (125), induces K cell hyperplasia (126), and increases the presence of GIP in circulation (126). Further, human obesity correlates with hypersecretion of GIP (127). The physiological role of GIP in metabolic control beyond that of an endogenous incretin is controversial. Studies report opposite effects on the maintenance of body weight in various loss- or gain-of-function models (see review (128)). The use of genetic animal models has suggested that GIP promotes obesity. For instance, Gipr–/– mice are protected from obesity (either diet-induced or leptin deficiency-induced), maintain proper insulin sensitivity, and use more fat as an energy substrate than WT controls, despite exhibiting no differences in food intake (129). Other studies suggest a role for GIPR agonism in promoting fat storage. GIP induces the expression of the lipogenic machinery (130), stimulates the adipose tissue lipoprotein lipase activity (131), and enhances the uptake of glucose and free fatty acids (132). In addition, knock-in of a biologically inactive GIP impairs oral glucose tolerance and protects from diet-induced obesity and insulin resistance in mice (133). Similarly, mice lacking GIP-producing cells present attenuated weight gain with a HFD and consume more energy than WT controls, recapitulating many of the phenotypic observations of Gipr–/– mice (134). In contrast to studies indicating that GIP favors anabolic action, several recent studies have suggested that GIP exerts a beneficial effect on adipose tissue and promotes weight loss. For instance, transgenic Gip overexpression protects mice against diet-induced obesity; their weight loss is caused by reduced food intake while energy expenditure remains unaffected (135). This was associated to an upregulation of the Gip gene expression in the VMH (135). The relevance of the hypothalamic neuronal circuits in mediating the effects of GIP was corroborated in a pharmacological report, in which GIP was administered directly to the brain; in this case, there was no association to differences in food intake, yet the GIP-treated mice showed a decreased body weight as compared to controls (136). These findings thereby suggest that GIP stimulates energy expenditure (Fig. 1). Notably, the feeding intake differs depending on whether if GIP is administrated to the brain or is specifically injected in the VMH, suggesting that there are hypothalamic nuclei-specific mechanisms that regulate specific effects of GIP in energy balance.

Peptide YY3-36 (PYY)

PYY, also known as peptide tyrosine tyrosine, is a 36-aa peptide released from cells in the ileum and colon. PYY is part of a larger family of proteins that also includes NPY and pancreatic polypeptide. All three peptides contain a hairpin turn within the amino acid backbone and hence are known as pancreatic polypeptide-fold proteins. PYY3–36 is a major form of PYY in both the gut mucosal endocrine cells and in circulation (137). PYY is secreted in response to feeding in proportion to meal energy content (138). Peripheral administration of PYY3-36 inhibits food intake for several hours in both rodents and humans (139, 140, 141). It also causes weight loss in obese models, such as leptin-deficient mice, diet-induced obese mice, and non-diabetic fatty Zucker rats (139, 142). The inhibitory effect of PYY on feeding involves mechanisms regulating appetite within the CNS, as PYY3-36 modulates brain activity in appetite centers in humans (143). Interestingly, the co-infusion of PYY3-36 and GLP1 has a synergistic action in reducing energy intake in overweight men, as this reduction was higher than the injection of each peptide separately (144).

In addition to its relevant action in feeding, PYY3–36 has also been reported to affect energy expenditure, but the different studies show controversial data. For instance, infusions of PYY3–36 were shown to increase energy expenditure and fat oxidation in both obese and lean humans (145), but this effect was not reproduced in another study in obese humans, as s.c. infusion of PYY did not affect resting energy expenditure (146). Also, another report failed to detect changes in energy expenditure after the administration of PYY3–36 in overweight men (144). In healthy women, total PYY was significantly correlated to postprandial energy expenditure at 60, 90, 120, and 150 min post-treatment (147); these results are supported by an independent work in normal-weight premenopausal women, which showed a significant association between PYY and the resting metabolic rate (148), which is an important contributor to energy expenditure. In summary, although some studies suggest a potential role for PYY in the regulation of energy expenditure in humans, it seems that this action may be dependent on the characteristics of the cohort; clarifying this deserves further research. On the other hand, PYY levels have been reported to increase following bariatric surgery. Both fasting and postprandial PYY levels increase significantly within just 1 week of surgery in obese patients and remain elevated after 1 year (149, 150, 151, 152) (Table 1).

Cholecystokinin (CCK)

CCK is synthesized and secreted by enteroendocrine cells in the duodenum mainly in the presence of digestion products of fats and proteins. Human CCK preproprotein contains 115 aa, but posttranslational processing can result in the different molecular forms identified in tissue and blood, which range in size from 4 to 83 aa. CCK8 is the most abundant form of CCK in the human brain, while CCK8, CCK22, CCK33, and CCK58 are present in the human intestine and circulation in significant amounts (whereby CCK22 and CCK33 are the most abundant in circulation) (153). The presence of CCK causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively and also acts as a hunger suppressant (154). Administration of CCK inhibits food intake in humans as well other animals. CC suppresses energy intake in a dose-dependent manner in rats (155), and CCK8 reduces both the size and duration of a meal (156). In humans, i.v. infusion of CCK8 and CCK33 increases the perception of fullness, decreases hunger, and reduces energy intake (157, 158, 159, 160). However, the response of CCK in humans following bariatric surgery has been reported differently according to the studies; while one report found that CCK levels are not altered after a glucose or protein meal after surgery (161), another one that compared patients before and after bariatric surgery with healthy lean volunteer controls found that post-surgery patients have higher levels of postprandial CCK (162) (Table 1).

Although there is no clear evidence for the role of CCK in the modulation of energy expenditure in humans, animal models suggest an inhibitory effect of CCK on this parameter. CCK- and CCK2R-deficient mice display increased energy expenditure (163, 164). CCK2R knockout mice have a higher energy expenditure, which seems to be linked to increased physical activity (164); in contrast, CCK-deficient mice are resistant to HFD-induced obesity by mechanisms independent of energy intake and physical activity, which remained unchanged (163). This resistance against diet-induced obesity is also associated to defects in fat absorption, especially of long-chain saturated fatty acids (163). Further work is necessary to clarify the physiological mechanisms and nutrient conditions by which CCK may affect energy expenditure in rodents and to address whether these preclinical data may have some clinical implications for humans.

Uroguanylin

Uroguanylin (UGN) is a 16-aa peptide encoded by the precursor pro-UGN, which is secreted by duodenal epithelial cells into the lumen, where it is processed and converted into its active form. UGN binds to the transmembrane receptor guanylyl cyclase 2C (GUCY2C), triggering intracellular levels of cyclic GMP (cGMP) (165, 166). Guanylin is a 15-aa peptide also derived from the prohormone pro-UGN, secreted by epithelial cells from the colon, that binds to GUCY2C (167, 168). The activation of GUCY2C increases intestinal secretions of the electrolytes sodium, chloride, and bicarbonate (169, 170). Excessive synthesis of UGN or guanylin causes diarrhea; indeed, staphylococcal enterotoxins (STs) are bacterial proteins linked to significant human diseases (e.g. food poisoning and toxic shock syndrome) that bind to and functionally activate the GUCY2C receptor (167, 171).

UGN expression in the intestine is modulated by the availability of nutrients and correlates positively with circulating UGN levels (172). In mice, circulating levels of pro-UGN are higher in response to the ingestion of nutrients (165). In agreement with a postprandial release of UGN, nutrient deprivation of mice reduces the expression of UGN in the duodenum as well as the circulating levels of UGN (173). According to this, the refeeding of pre-fasted mice returns the levels of UGN in the intestine and blood to baseline conditions. The nutrient-dependent adjustment of UGN levels is mediated by leptin, an adipose tissue-derived hormone whose expression is positively correlated with the volume of fat mass. In mice, leptin levels decreased in fasting states and are restored after re-feeding (173).

UGN has been also suggested to reduce food intake and body weight in rodents, after circulating UGN reaches the hypothalamus and binds to the GUCY2C receptor (165). The systemic and central injection of UGN or compounds activating the GUCY2C receptor inhibits food intake in WT mice but have no effect in mice lacking GUCY2C (165). Despite these initial findings, results from subsequent studies have been controversial. While the initial report showed that GUCY2C receptor (Gucy2c–/–) deficient mice have increased adiposity due to hyperphagia (165), a later report was not able to reproduce those results and found that Gucy2c–/– mice did not differ from control mice in their body weight, fat mass, or glucose homeostasis (174). Thus, the endogenous relevance of the UGN–GUCY2C system for regulating energy balance has yet to be determined. The chronic central infusion of UGN in diet-induced obese mice over several days causes a food intake-independent reduction in weight gain and adiposity (175). The resistance against HFD-induced obesity could be explained by a higher energy expenditure, which is consistent with the stimulated activity of the BAT, as shown by augmented expression of genes necessary for thermogenesis (uncoupling protein 1, uncoupling protein 3, PR/SET domain 16, and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha) in the BAT of UGN-treated obese mice (175). Furthermore, central administration of UGN not only induces browning but also stimulates lipid mobilization in s.c. adipose tissue, as shown by the increased levels of phosphorylated hormone-sensitive lipase (pHSL) (175) (Fig. 1). To exert its actions in WAT and BAT, UGN requires an intact SNS, as the lack or pharmacological blockade of beta-adrenoreceptors abolishes the catabolic effect of brain UGN in diet-induced obese mice. However, the effects of centrally administered UGN to mice are not only mediated by the sympathetic activity of fibers innervating adipose tissue but also via gastrointestinal effects. For instance, UGN stimulates gastric motility. The gastrointestinal action of UGN is mediated by the parasympathetic nervous system, and more precisely, by the vagus nerve that connects the gut with brain areas (176). Indeed, the UGN-induced gastric motility is blunted in vagotomized mice; however, in these mice, the excitatory action of UGN on the sympathetic nervous system persists, and therefore, they still show increased BAT thermogenic activity and browning of WAT (175). Overall, these results suggest that the chronic effects of UGN on metabolism occur via both branches of the autonomic nervous system.

Fibroblast growth factor 15/19 (FGF15/19)

FGF15 in mice (or its human orthologue FGF19) is a 216-aa peptide hormone secreted in the absorptive cells of the mouse ileum that plays an important role in feedback inhibition of hepatic bile acid synthesis (177, 178). It is released from the gut after food intake and controls the homeostasis of bile acids and glucose during the transition from a fed to a fasted state (178, 179). Different reports have described that FGF15 acts in the brain of rodent models of obesity and enhances insulin sensitivity, improves glucose tolerance, decreases food intake and body weight, and increases energy expenditure (180, 181, 182, 183). Similar to other hormones produced in the gut, FGF15/19 levels are elevated after bariatric surgical procedures (184, 185, 186, 187, 188, 189, 190), and whilst most reports suggest an important role of this hormone in the metabolic benefits of bariatric surgery, one did not, as the increase of FGF19 did not parallel the improvement of glucose tolerance (189).

Although the pharmacological effects of FGF19 are well recognized in preclinical models, the physiological roles of FGF19 in humans remain to be clarified. In people with impaired fasting glucose, fasting FGF19 levels are decreased and are negatively correlated with fasting plasma glucose, but not associated with insulin secretion and sensitivity (191). A subsequent study described that FGF19 positively correlates with glucose effectiveness and is negatively associated with fasting plasma glucose and hepatic glucose production (192). FGF19 levels have been also described to be higher after bariatric surgery. Vertical sleeve gastrectomy, duodenal-jejunal bypass liner, and Roux-en-Y gastric bypass, but not gastric banding, significantly raises blood FGF19 levels, with an inverse association between FGF19 and BMI reduction post-surgery (193). Whether FGF19 can modify eating patterns in humans, and whether it is linked to energy expenditure, have not yet been assessed (Table 1).

Concluding remarks

We now know that the gut acts as a nutrient sensor that can signal the release of several hormones. These signals about hunger or satiety produced long-term and/or short-term responses to control feeding behavior, acting through different peripheral and central mechanisms. Thus, energy intake, energy expenditure, and (as a result) body weight are tightly regulated. So far, several lifestyle interventions, bariatric surgery, and some drugs are currently used to treat obesity, but all have associated problems, and most – if not all – pharmacological agents have limited effectiveness.

The continued research on the broad spectrum of mechanisms regulating energy balance, including the gut–brain axis, underscores the difficulties faced by an obese person who is trying to lose weight. For instance, because ghrelin stimulates appetite in rodents and humans, it was expected that ghrelin antagonists could exert beneficial effects against obesity; however, this strategy has failed (194, 195). Also, different approaches with drugs that individually activate the receptors for different catabolic gut hormones have not provided the expected beneficial results, and the GLP1 analog liraglutide has been the only one to be approved by the US Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) for the treatment of obesity. In the past few years, much effort has been put into developing combinatorial approaches that target food intake and energy expenditure pathways (including those directed toward insulin sensitivity), which have shown very promising results (196, 197). Some of these approaches combine gut peptide agonism to treat obesity and its associated disorders and have been demonstrated to be effective at reducing weight, improving glucose homeostasis, and ameliorating the content of fatty acids in the liver of diet-induced obese mice (198, 199, 200). Some of the gut peptide-based multi-agonists initially investigated in preclinical models of obesity are currently under phase I or II clinical trials (see review (196)), which will likely produce the main next-generation pharmacological agents to be used. These new drugs include semaglutide, a second-generation GLP1 agonist, and tirzepatide, a dual agonist for GLP1 receptor and GIP receptor (201, 202); both of these seem to improve the weight loss effect as compared to the currently approved drugs, which produce an average weight loss of 5% to 7%. Whether these drugs act on the brain of people with obesity has not been assessed; however, given that receptors for most (if not all) gastrointestinal hormones are located in different brain areas, including the hypothalamus, it is likely that their metabolic effects are mediated by central mechanisms (at least partially).

In summary, the research community has greatly advanced our understanding of how the gut–brain axis works, based on results from physiologically relevant aspects discovered more than 4 decades ago (203) to the newest results from chemically developed multi-agonists drugs. These advances now make it possible to envision a realistic treatment against the metabolic syndrome pandemic.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by grants from FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (RTI2018-099413-B-I00 and RED2018-102379-T), Xunta de Galicia (2016-PG057 and ED431C 2020/12), Fundación BBVA, Fundación Atresmedia, European Foundation for the Study of Diabetes, Fundación La Caixa, the European Community’s H2020 Framework program under the following grant: ERC Synergy Grant-2019-WATCH- 810331. Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds.

References

  • 1↑

    Farooqi IS, O’Rahilly S. Monogenic obesity in humans. Annual Review of Medicine 2005 56 443–458. (https://doi.org/10.1146/annurev.med.56.062904.144924)

    • Search Google Scholar
    • Export Citation
  • 2↑

    Flier JS Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004 116 337–350. (https://doi.org/10.1016/s0092-8674(0301081-x)

    • Search Google Scholar
    • Export Citation
  • 3↑

    Friedman JM A war on obesity, not the obese. Science 2003 299 856–858. (https://doi.org/10.1126/science.1079856)

  • 4↑

    Medina-Gomez G, Vidal-Puig A. Gateway to the metabolic syndrome. Nature Medicine 2005 11 602–603. (https://doi.org/10.1038/nm0605-602)

  • 5↑

    Tobias D, Pan A, Hu FB. BMI and mortality among adults with incident type 2 diabetes. New England Journal of Medicine 2014 370 1363–1364. (https://doi.org/10.1056/NEJMc1401876)

    • Search Google Scholar
    • Export Citation
  • 6↑

    Popkin BM, Gordon-Larsen P. The nutrition transition: worldwide obesity dynamics and their determinants. International Journal of Obesity and Related Metabolic Disorders 2004 28 (Supplement 3) S2–S 9. (https://doi.org/10.1038/sj.ijo.0802804)

    • Search Google Scholar
    • Export Citation
  • 7↑

    Simopoulos AP Essential fatty acids in health and chronic disease. American Journal of Clinical Nutrition 1999 70 (Supplement) 560S–569S. (https://doi.org/10.1093/ajcn/70.3.560s)

    • Search Google Scholar
    • Export Citation
  • 8↑

    Cota D, Proulx K, Seeley RJ. The role of CNS fuel sensing in energy and glucose regulation. Gastroenterology 2007 132 2158–2168. (https://doi.org/10.1053/j.gastro.2007.03.049)

    • Search Google Scholar
    • Export Citation
  • 9↑

    Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. Journal of Clinical Investigation 2006 116 1761–1766. (https://doi.org/10.1172/JCI29063)

    • Search Google Scholar
    • Export Citation
  • 10↑

    Sarafidis PA, Nilsson PM. The metabolic syndrome: a glance at its history. Journal of Hypertension 2006 24 621–626. (https://doi.org/10.1097/01.hjh.0000217840.26971.b6)

    • Search Google Scholar
    • Export Citation
  • 11↑

    Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Reviews: Cancer 2004 4 579–591. (https://doi.org/10.1038/nrc1408)

    • Search Google Scholar
    • Export Citation
  • 12↑

    Carling D, Sanders MJ, Woods A. The regulation of AMP-activated protein kinase by upstream kinases. International Journal of Obesity 2008 32 (Supplement 4) S55–S 59. (https://doi.org/10.1038/ijo.2008.124)

    • Search Google Scholar
    • Export Citation
  • 13↑

    Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism 2005 1 15–25. (https://doi.org/10.1016/j.cmet.2004.12.003)

    • Search Google Scholar
    • Export Citation
  • 14↑

    Lage R, Diéguez C, Vidal-Puig A, López M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends in Molecular Medicine 2008 14 539–549. (https://doi.org/10.1016/j.molmed.2008.09.007)

    • Search Google Scholar
    • Export Citation
  • 15↑

    Ruderman NB, Saha AK, Kraegen EW. Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 2003 144 5166–5171. (https://doi.org/10.1210/en.2003-0849)

    • Search Google Scholar
    • Export Citation
  • 16↑

    Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. Journal of Comparative Neurology 2005 493 63–71. (https://doi.org/10.1002/cne.20786)

    • Search Google Scholar
    • Export Citation
  • 17↑

    Gao Q, Horvath TL. Neurobiology of feeding and energy expenditure. Annual Review of Neuroscience 2007 30 367–398. (https://doi.org/10.1146/annurev.neuro.30.051606.094324)

    • Search Google Scholar
    • Export Citation
  • 18↑

    Lopez M, Lelliott CJ, Vidal-Puig A. Hypothalamic fatty acid metabolism: a housekeeping pathway that regulates food intake. BioEssays 2007 29 248–261. (https://doi.org/10.1002/bies.20539)

    • Search Google Scholar
    • Export Citation
  • 19↑

    Lopez M, Tovar S, Vazquez MJ, Williams LM, Dieguez C. Peripheral tissue-brain interactions in the regulation of food intake. Proceedings of the Nutrition Society 2007 66 131–155. (https://doi.org/10.1017/S0029665107005368)

    • Search Google Scholar
    • Export Citation
  • 20↑

    Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature 2006 443 289–295. (https://doi.org/10.1038/nature05026)

    • Search Google Scholar
    • Export Citation
  • 21↑

    Willesen MG, Kristensen P, Romer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 1999 70 306–316. (https://doi.org/10.1159/000054491)

    • Search Google Scholar
    • Export Citation
  • 22↑

    Bamshad M, Song CK, Bartness TJ. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. American Journal of Physiology 1999 276 R1569–R 1578. (https://doi.org/10.1152/ajpregu.1999.276.6.R1569)

    • Search Google Scholar
    • Export Citation
  • 23↑

    Lowell BB, Spiegelman BM. Towards a molecular understanding of adaptive thermogenesis. Nature 2000 404 652–660. (https://doi.org/10.1038/35007527)

    • Search Google Scholar
    • Export Citation
  • 24↑

    van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. New England Journal of Medicine 2009 360 1500–1508. (https://doi.org/10.1056/NEJMoa0808718)

    • Search Google Scholar
    • Export Citation
  • 25↑

    Tran TT, Kahn CR. Transplantation of adipose tissue and stem cells: role in metabolism and disease. Nature Reviews: Endocrinology 2010 6 195–213. (https://doi.org/10.1038/nrendo.2010.20)

    • Search Google Scholar
    • Export Citation
  • 26↑

    Whittle AJ, Lopez M, Vidal-Puig A. Using brown adipose tissue to treat obesity - the central issue. Trends in Molecular Medicine 2011 17 405–411. (https://doi.org/10.1016/j.molmed.2011.04.001)

    • Search Google Scholar
    • Export Citation
  • 27↑

    Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB Journal 2009 23 3113–3120. (https://doi.org/10.1096/fj.09-133546)

    • Search Google Scholar
    • Export Citation
  • 28↑

    Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. American Journal of Physiology: Endocrinology and Metabolism 2007 293 E444–E452. (https://doi.org/10.1152/ajpendo.00691.2006)

    • Search Google Scholar
    • Export Citation
  • 29↑

    Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH & Doria A et al.Identification and importance of brown adipose tissue in adult humans. New England Journal of Medicine 2009 360 1509–1517. (https://doi.org/10.1056/NEJMoa0810780)

    • Search Google Scholar
    • Export Citation
  • 30↑

    Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ & Enerback S et al.Functional brown adipose tissue in healthy adults. New England Journal of Medicine 2009 360 1518–1525. (https://doi.org/10.1056/NEJMoa0808949)

    • Search Google Scholar
    • Export Citation
  • 31↑

    Walden TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, ‘brite,’ and white adipose tissues. American Journal of Physiology: Endocrinology and Metabolism 2012 302 E19–E31. (https://doi.org/10.1152/ajpendo.00249.2011)

    • Search Google Scholar
    • Export Citation
  • 32↑

    Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes and Development 2013 27 234–250. (https://doi.org/10.1101/gad.211649.112)

    • Search Google Scholar
    • Export Citation
  • 33↑

    Giralt M, Villarroya F. White, brown, beige/Brite: different adipose cells for different functions? Endocrinology 2013 154 2992–3000. (https://doi.org/10.1210/en.2013-1403)

    • Search Google Scholar
    • Export Citation
  • 34↑

    Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P & Schaart G et al.Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012 150 366–376. (https://doi.org/10.1016/j.cell.2012.05.016)

    • Search Google Scholar
    • Export Citation
  • 35↑

    Jespersen NZ, Larsen TJ, Peijs L, Daugaard S, Homoe P, Loft A, de Jong J, Mathur N, Cannon B & Nedergaard J et al.A classical brown adipose tissue mRNA signature partly overlaps with Brite in the supraclavicular region of adult humans. Cell Metabolism 2013 17 798–805. (https://doi.org/10.1016/j.cmet.2013.04.011)

    • Search Google Scholar
    • Export Citation
  • 36↑

    Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999 402 656–660. (https://doi.org/10.1038/45230)

    • Search Google Scholar
    • Export Citation
  • 37↑

    Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochemical and Biophysical Research Communications 2000 279 909–913. (https://doi.org/10.1006/bbrc.2000.4039)

    • Search Google Scholar
    • Export Citation
  • 38↑

    Toshinai K, Mondal MS, Nakazato M, Date Y, Murakami N, Kojima M, Kangawa K, Matsukura S. Upregulation of ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochemical and Biophysical Research Communications 2001 281 1220–1225. (https://doi.org/10.1006/bbrc.2001.4518)

    • Search Google Scholar
    • Export Citation
  • 39↑

    Callahan HS, Cummings DE, Pepe MS, Breen PA, Matthys CC, Weigle DS. Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict intermeal interval in humans. Journal of Clinical Endocrinology and Metabolism 2004 89 1319–1324. (https://doi.org/10.1210/jc.2003-031267)

    • Search Google Scholar
    • Export Citation
  • 40↑

    Jakubowicz D, Froy O, Wainstein J, Boaz M. Meal timing and composition influence ghrelin levels, appetite scores and weight loss maintenance in overweight and obese adults. Steroids 2012 77 323–331. (https://doi.org/10.1016/j.steroids.2011.12.006)

    • Search Google Scholar
    • Export Citation
  • 41↑

    Koliaki C, Kokkinos A, Tentolouris N, Katsilambros N. The effect of ingested macronutrients on postprandial ghrelin response: a critical review of existing literature data. International Journal of Peptides 2010 2010 710852. (https://doi.org/10.1155/2010/710852)

    • Search Google Scholar
    • Export Citation
  • 42↑

    le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. Journal of Clinical Endocrinology and Metabolism 2005 90 1068–1071. (https://doi.org/10.1210/jc.2004-1216)

    • Search Google Scholar
    • Export Citation
  • 43↑

    Foster-Schubert KE, Overduin J, Prudom CE, Liu J, Callahan HS, Gaylinn BD, Thorner MO, Cummings DE. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. Journal of Clinical Endocrinology and Metabolism 2008 93 1971–1979. (https://doi.org/10.1210/jc.2007-2289)

    • Search Google Scholar
    • Export Citation
  • 44↑

    Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001 50 1714–1719. (https://doi.org/10.2337/diabetes.50.8.1714)

    • Search Google Scholar
    • Export Citation
  • 45↑

    Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001 50 707–709. (https://doi.org/10.2337/diabetes.50.4.707)

    • Search Google Scholar
    • Export Citation
  • 46↑

    Ariyasu H, Takaya K, Hosoda H, Iwakura H, Ebihara K, Mori K, Ogawa Y, Hosoda K, Akamizu T & Kojima M et al.Delayed short-term secretory regulation of ghrelin in obese animals: evidenced by a specific RIA for the active form of ghrelin. Endocrinology 2002 143 3341–3350. (https://doi.org/10.1210/en.2002-220225)

    • Search Google Scholar
    • Export Citation
  • 47↑

    Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. Journal of Clinical Endocrinology and Metabolism 2002 87 240–244. (https://doi.org/10.1210/jcem.87.1.8129)

    • Search Google Scholar
    • Export Citation
  • 48↑

    Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M, Tschop M. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. European Journal of Endocrinology 2001 145 669–673. (https://doi.org/10.1530/EJE-1450669)

    • Search Google Scholar
    • Export Citation
  • 49↑

    Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, Hosoda H, Shimizu W, Yamagishi M & Oya H et al.Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation 2001 104 2034–2038. (https://doi.org/10.1161/hc4201.097836)

    • Search Google Scholar
    • Export Citation
  • 50↑

    Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000 407 908–913. (https://doi.org/10.1038/35038090)

  • 51↑

    Marzullo P, Verti B, Savia G, Walker GE, Guzzaloni G, Tagliaferri M, Di Blasio A, Liuzzi A. The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure. Journal of Clinical Endocrinology and Metabolism 2004 89 936–939. (https://doi.org/10.1210/jc.2003-031328)

    • Search Google Scholar
    • Export Citation
  • 52↑

    Riis AL, Hansen TK, Moller N, Weeke J, Jorgensen JO. Hyperthyroidism is associated with suppressed circulating ghrelin levels. Journal of Clinical Endocrinology and Metabolism 2003 88 853–857. (https://doi.org/10.1210/jc.2002-021302)

    • Search Google Scholar
    • Export Citation
  • 53↑

    St-Pierre DH, Karelis AD, Cianflone K, Conus F, Mignault D, Rabasa-Lhoret R, St-Onge M, Tremblay-Lebeau A, Poehlman ET. Relationship between ghrelin and energy expenditure in healthy young women. Journal of Clinical Endocrinology and Metabolism 2004 89 5993–5997. (https://doi.org/10.1210/jc.2004-0613)

    • Search Google Scholar
    • Export Citation
  • 54↑

    Tymitz K, Engel A, McDonough S, Hendy MP, Kerlakian G. Changes in ghrelin levels following bariatric surgery: review of the literature. Obesity Surgery 2011 21 125–130. (https://doi.org/10.1007/s11695-010-0311-z)

    • Search Google Scholar
    • Export Citation
  • 55↑

    Lee H, Te C, Koshy S, Teixeira JA, Pi-Sunyer FX, Laferrere B. Does ghrelin really matter after bariatric surgery? Surgery for Obesity and Related Diseases 2006 2 538–548. (https://doi.org/10.1016/j.soard.2006.06.002)

    • Search Google Scholar
    • Export Citation
  • 56↑

    Xu HC, Pang YC, Chen JW, Cao JY, Sheng Z, Yuan JH, Wang R, Zhang CS, Wang LX, Dong J. Systematic review and meta-analysis of the change in ghrelin levels after Roux-en-Y gastric bypass. Obesity Surgery 2019 29 1343–1351. (https://doi.org/10.1007/s11695-018-03686-3)

    • Search Google Scholar
    • Export Citation
  • 57↑

    Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neither growth nor appetite. Molecular and Cellular Biology 2003 23 7973–7981. (https://doi.org/10.1128/MCB.23.22.7973-7981.2003)

    • Search Google Scholar
    • Export Citation
  • 58↑

    Wortley KE, Anderson KD, Garcia K, Murray JD, Malinova L, Liu R, Moncrieffe M, Thabet K, Cox HJ & Yancopoulos GD et al.Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. PNAS 2004 101 8227–8232. (https://doi.org/10.1073/pnas.0402763101)

    • Search Google Scholar
    • Export Citation
  • 59↑

    Sun Y, Butte NF, Garcia JM, Smith RG. Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. Endocrinology 2008 149 843–850. (https://doi.org/10.1210/en.2007-0271)

    • Search Google Scholar
    • Export Citation
  • 60↑

    Wortley KE, del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO, Sleeman MW. Absence of ghrelin protects against early-onset obesity. Journal of Clinical Investigation 2005 115 3573–3578. (https://doi.org/10.1172/JCI26003)

    • Search Google Scholar
    • Export Citation
  • 61↑

    Sun Y, Wang P, Zheng H, Smith RG. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. PNAS 2004 101 4679–4684. (https://doi.org/10.1073/pnas.0305930101)

    • Search Google Scholar
    • Export Citation
  • 62↑

    Lin L, Saha PK, Ma X, Henshaw IO, Shao L, Chang BH, Buras ED, Tong Q, Chan L & McGuinness OP et al.Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell 2011 10 996–1010. (https://doi.org/10.1111/j.1474-9726.2011.00740.x)

    • Search Google Scholar
    • Export Citation
  • 63↑

    Pfluger PT, Kirchner H, Gunnel S, Schrott B, Perez-Tilve D, Fu S, Benoit SC, Horvath T, Joost HG & Wortley KE et al.Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. American Journal of Physiology: Gastrointestinal and Liver Physiology 2008 294 G610–G 618. (https://doi.org/10.1152/ajpgi.00321.2007)

    • Search Google Scholar
    • Export Citation
  • 64↑

    Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M & Heiman ML et al.The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003 37 649–661. (https://doi.org/10.1016/s0896-6273(0300063-1)

    • Search Google Scholar
    • Export Citation
  • 65↑

    Muller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, Batterham RL, Benoit SC, Bowers CY & Broglio F et al.Ghrelin. Molecular Metabolism 2015 4 437–460. (https://doi.org/10.1016/j.molmet.2015.03.005)

    • Search Google Scholar
    • Export Citation
  • 66↑

    Al Massadi O, Lopez M, Tschop M, Dieguez C, Nogueiras R. Current understanding of the hypothalamic ghrelin pathways inducing appetite and adiposity. Trends in Neurosciences 2017 40 167–180. (https://doi.org/10.1016/j.tins.2016.12.003)

    • Search Google Scholar
    • Export Citation
  • 67↑

    Wang Q, Liu C, Uchida A, Chuang JC, Walker A, Liu T, Osborne-Lawrence S, Mason BL, Mosher C & Berglund ED et al.Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin. Molecular Metabolism 2014 3 64–72. (https://doi.org/10.1016/j.molmet.2013.10.001)

    • Search Google Scholar
    • Export Citation
  • 68↑

    Perez-Tilve D, Heppner K, Kirchner H, Lockie SH, Woods SC, Smiley DL, Tschop M, Pfluger P. Ghrelin-induced adiposity is independent of orexigenic effects. FASEB Journal 2011 25 2814–2822. (https://doi.org/10.1096/fj.11-183632)

    • Search Google Scholar
    • Export Citation
  • 69↑

    Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, Castaneda TR, Muzzin P, Schurmann A & Szanto I et al.Ghrelin action in the brain controls adipocyte metabolism. Journal of Clinical Investigation 2006 116 1983–1993. (https://doi.org/10.1172/JCI25811)

    • Search Google Scholar
    • Export Citation
  • 70↑

    Porteiro B, Diaz-Ruiz A, Martinez G, Senra A, Vidal A, Serrano M, Gualillo O, Lopez M, Malagon MM & Dieguez C et al.Ghrelin requires p53 to stimulate lipid storage in fat and liver. Endocrinology 2013 154 3671–3679. (https://doi.org/10.1210/en.2013-1176)

    • Search Google Scholar
    • Export Citation
  • 71↑

    Sangiao-Alvarellos S, Vazquez MJ, Varela L, Nogueiras R, Saha AK, Cordido F, Lopez M, Dieguez C. Central ghrelin regulates peripheral lipid metabolism in a growth hormone-independent fashion. Endocrinology 2009 150 4562–4574. (https://doi.org/10.1210/en.2009-0482)

    • Search Google Scholar
    • Export Citation
  • 72↑

    Ghatei MA, Uttenthal LO, Christofides ND, Bryant MG, Bloom SR. Molecular forms of human enteroglucagon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract. Journal of Clinical Endocrinology and Metabolism 1983 57 488–495. (https://doi.org/10.1210/jcem-57-3-488)

    • Search Google Scholar
    • Export Citation
  • 73↑

    Rouille Y, Westermark G, Martin SK, Steiner DF. Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC1-6 cells. PNAS 1994 91 3242–3246. (https://doi.org/10.1073/pnas.91.8.3242)

    • Search Google Scholar
    • Export Citation
  • 74↑

    Pocai A Action and therapeutic potential of oxyntomodulin. Molecular Metabolism 2014 3 241–251. (https://doi.org/10.1016/j.molmet.2013.12.001)

    • Search Google Scholar
    • Export Citation
  • 75↑

    Holst JJ Enteroglucagon. Annual Review of Physiology 1997 59 257–271. (https://doi.org/10.1146/annurev.physiol.59.1.257)

  • 76↑

    Sandoval DA, D’Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiological Reviews 2015 95 513–548. (https://doi.org/10.1152/physrev.00013.2014)

    • Search Google Scholar
    • Export Citation
  • 77↑

    Drucker DJ, Habener JF, Holst JJ. Discovery, characterization, and clinical development of the glucagon-like peptides. Journal of Clinical Investigation 2017 127 4217–4227. (https://doi.org/10.1172/JCI97233)

    • Search Google Scholar
    • Export Citation
  • 78↑

    Muller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, Flatt PR, Fritsche A, Gribble F, Grill HJ & Habener JF et al.Glucagon-like peptide 1 (GLP-1). Molecular Metabolism 2019 30 72–130. (https://doi.org/10.1016/j.molmet.2019.09.010)

    • Search Google Scholar
    • Export Citation
  • 79↑

    Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. Journal of Clinical Investigation 1998 101 515–520. (https://doi.org/10.1172/JCI990)

    • Search Google Scholar
    • Export Citation
  • 80↑

    van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. International Journal of Obesity 2014 38 784–793. (https://doi.org/10.1038/ijo.2013.162)

    • Search Google Scholar
    • Export Citation
  • 81↑

    Harder H, Nielsen L, Tu DT, Astrup A. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care 2004 27 1915–1921. (https://doi.org/10.2337/diacare.27.8.1915)

    • Search Google Scholar
    • Export Citation
  • 82↑

    Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, Serrano M, Ferno J, Salvador J & Escalada J et al.GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 2014 63 3346–3358. (https://doi.org/10.2337/db14-0302)

    • Search Google Scholar
    • Export Citation
  • 83↑

    Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, Zdravkovic M, Le Thi TD, Colagiuri S & LEAD-1 SU Study Group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabetic Medicine 2009 26 268–278. (https://doi.org/10.1111/j.1464-5491.2009.02666.x)

    • Search Google Scholar
    • Export Citation
  • 84↑

    Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, Madsen J, Rasmussen MF, Lean ME & NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009 374 1606–1616. (https://doi.org/10.1016/S0140-6736(0961375-1)

    • Search Google Scholar
    • Export Citation
  • 85↑

    van Eyk HJ, Paiman EHM, Bizino MB, IJzermans SL, Kleiburg F, Boers TGW, Rappel EJ, Burakiewicz J, Kan HE & Smit JWA et al.Liraglutide decreases energy expenditure and does not affect the fat fraction of supraclavicular brown adipose tissue in patients with type 2 diabetes. Nutrition, Metabolism, and Cardiovascular Diseases 2020 30 616–624. (https://doi.org/10.1016/j.numecd.2019.12.005)

    • Search Google Scholar
    • Export Citation
  • 86↑

    Hutch CR, Sandoval D. The role of GLP-1 in the metabolic success of bariatric surgery. Endocrinology 2017 158 4139–4151. (https://doi.org/10.1210/en.2017-00564)

    • Search Google Scholar
    • Export Citation
  • 87↑

    Hindso M, Svane MS, Hedback N, Holst JJ, Madsbad S, Bojsen-Moller KN. The role of GLP-1 in postprandial glucose metabolism after bariatric surgery: a narrative review of human GLP-1 receptor antagonist studies. Surgery for Obesity and Related Diseases 2021 17 1383–1391. (https://doi.org/10.1016/j.soard.2021.01.041)

    • Search Google Scholar
    • Export Citation
  • 88↑

    Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM & Lambert PD et al.A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996 379 69–72. (https://doi.org/10.1038/379069a0)

    • Search Google Scholar
    • Export Citation
  • 89↑

    Meeran K, O’Shea D, Edwards CM, Turton MD, Heath MM, Gunn I, Abusnana S, Rossi M, Small CJ & Goldstone AP et al.Repeated intracerebroventricular administration of glucagon-like peptide-1-(7–36) amide or exendin-(9–39) alters body weight in the rat. Endocrinology 1999 140 244–250. (https://doi.org/10.1210/endo.140.1.6421)

    • Search Google Scholar
    • Export Citation
  • 90↑

    Lockie SH, Heppner KM, Chaudhary N, Chabenne JR, Morgan DA, Veyrat-Durebex C, Ananthakrishnan G, Rohner-Jeanrenaud F, Drucker DJ & DiMarchi R et al.Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 2012 61 2753–2762. (https://doi.org/10.2337/db11-1556)

    • Search Google Scholar
    • Export Citation
  • 91↑

    Shimizu I, Hirota M, Ohboshi C, Shima K. Identification and localization of glucagon-like peptide-1 and its receptor in rat brain. Endocrinology 1987 121 1076–1082. (https://doi.org/10.1210/endo-121-3-1076)

    • Search Google Scholar
    • Export Citation
  • 92↑

    Richards P, Parker HE, Adriaenssens AE, Hodgson JM, Cork SC, Trapp S, Gribble FM, Reimann F. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 2014 63 1224–1233. (https://doi.org/10.2337/db13-1440)

    • Search Google Scholar
    • Export Citation
  • 93↑

    Nogueiras R, Perez-Tilve D, Veyrat-Durebex C, Morgan DA, Varela L, Haynes WG, Patterson JT, Disse E, Pfluger PT & Lopez M et al.Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity. Journal of Neuroscience 2009 29 5916–5925. (https://doi.org/10.1523/JNEUROSCI.5977-08.2009)

    • Search Google Scholar
    • Export Citation
  • 94↑

    Knauf C, Cani PD, Ait-Belgnaoui A, Benani A, Dray C, Cabou C, Colom A, Uldry M, Rastrelli S & Sabatier E et al.Brain glucagon-like peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance and reduces energy expenditure. Endocrinology 2008 149 4768–4777. (https://doi.org/10.1210/en.2008-0180)

    • Search Google Scholar
    • Export Citation
  • 95↑

    Shi X, Zhou F, Li X, Chang B, Li D, Wang Y, Tong Q, Xu Y, Fukuda M & Zhao JJ et al.Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons. Cell Metabolism 2013 18 86–98. (https://doi.org/10.1016/j.cmet.2013.06.014)

    • Search Google Scholar
    • Export Citation
  • 96↑

    Bahrami J, Longuet C, Baggio LL, Li K, Drucker DJ. Glucagon-like peptide-2 receptor modulates islet adaptation to metabolic stress in the ob/ob mouse. Gastroenterology 2010 139 857–868. (https://doi.org/10.1053/j.gastro.2010.05.006)

    • Search Google Scholar
    • Export Citation
  • 97↑

    Tang-Christensen M, Larsen PJ, Thulesen J, Romer J, Vrang N. The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake. Nature Medicine 2000 6 802–807. (https://doi.org/10.1038/77535)

    • Search Google Scholar
    • Export Citation
  • 98↑

    Nelson DW, Sharp JW, Brownfield MS, Raybould HE, Ney DM. Localization and activation of glucagon-like peptide-2 receptors on vagal afferents in the rat. Endocrinology 2007 148 1954–1962. (https://doi.org/10.1210/en.2006-1232)

    • Search Google Scholar
    • Export Citation
  • 99↑

    Guan X, Shi X, Li X, Chang B, Wang Y, Li D, Chan L. GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility. American Journal of Physiology: Endocrinology and Metabolism 2012 303 E853–E864. (https://doi.org/10.1152/ajpendo.00245.2012)

    • Search Google Scholar
    • Export Citation
  • 100↑

    Schmidt PT, Naslund E, Gryback P, Jacobsson H, Hartmann B, Holst JJ, Hellstrom PM. Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety. Regulatory Peptides 2003 116 21–25. (https://doi.org/10.1016/s0167-0115(0300175-7)

    • Search Google Scholar
    • Export Citation
  • 101↑

    Sorensen LB, Flint A, Raben A, Hartmann B, Holst JJ, Astrup A. No effect of physiological concentrations of glucagon-like peptide-2 on appetite and energy intake in normal weight subjects. International Journal of Obesity and Related Metabolic Disorders 2003 27 450–456. (https://doi.org/10.1038/sj.ijo.0802247)

    • Search Google Scholar
    • Export Citation
  • 102↑

    Wojdemann M, Wettergren A, Hartmann B, Hilsted L, Holst JJ. Inhibition of sham feeding-stimulated human gastric acid secretion by glucagon-like peptide-2. Journal of Clinical Endocrinology and Metabolism 1999 84 2513–2517. (https://doi.org/10.1210/jcem.84.7.5840)

    • Search Google Scholar
    • Export Citation
  • 103↑

    Meier JJ, Nauck MA, Pott A, Heinze K, Goetze O, Bulut K, Schmidt WE, Gallwitz B, Holst JJ. Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans. Gastroenterology 2006 130 44–54. (https://doi.org/10.1053/j.gastro.2005.10.004)

    • Search Google Scholar
    • Export Citation
  • 104↑

    Cazzo E, Pareja JC, Chaim EA, Geloneze B, Barreto MR, Magro DO. GLP-1 and GLP-2 levels are correlated with satiety regulation after Roux-en-Y gastric bypass: results of an exploratory prospective study. Obesity Surgery 2017 27 703–708. (https://doi.org/10.1007/s11695-016-2345-3)

    • Search Google Scholar
    • Export Citation
  • 105↑

    le Roux CW, Borg C, Wallis K, Vincent RP, Bueter M, Goodlad R, Ghatei MA, Patel A, Bloom SR, Aylwin SJ. Gut hypertrophy after gastric bypass is associated with increased glucagon-like peptide 2 and intestinal crypt cell proliferation. Annals of Surgery 2010 252 50–56. (https://doi.org/10.1097/SLA.0b013e3181d3d21f)

    • Search Google Scholar
    • Export Citation
  • 106↑

    Romero F, Nicolau J, Flores L, Casamitjana R, Ibarzabal A, Lacy A, Vidal J. Comparable early changes in gastrointestinal hormones after sleeve gastrectomy and Roux-en-Y gastric bypass surgery for morbidly obese type 2 diabetic subjects. Surgical Endoscopy 2012 26 2231–2239. (https://doi.org/10.1007/s00464-012-2166-y)

    • Search Google Scholar
    • Export Citation
  • 107↑

    Butte NF, Brandt ML, Wong WW, Liu Y, Mehta NR, Wilson TA, Adolph AL, Puyau MR, Vohra FA & Shypailo RJ et al.Energetic adaptations persist after bariatric surgery in severely obese adolescents. Obesity 2015 23 591–601. (https://doi.org/10.1002/oby.20994)

    • Search Google Scholar
    • Export Citation
  • 108↑

    Baldissera FG, Holst JJ, Knuhtsen S, Hilsted L, Nielsen OV. Oxyntomodulin (glicentin-(33–69)): pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused lower small intestine of pigs. Regulatory Peptides 1988 21 151–166. (https://doi.org/10.1016/0167-0115(8890099-7)

    • Search Google Scholar
    • Export Citation
  • 109↑

    Gros L, Thorens B, Bataille D, Kervran A. Glucagon-like peptide-1-(7–36) amide, oxyntomodulin, and glucagon interact with a common receptor in a somatostatin-secreting cell line. Endocrinology 1993 133 631–638. (https://doi.org/10.1210/endo.133.2.8102095)

    • Search Google Scholar
    • Export Citation
  • 110↑

    Baggio LL, Huang Q, Brown TJ, Drucker DJ. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 2004 127 546–558. (https://doi.org/10.1053/j.gastro.2004.04.063)

    • Search Google Scholar
    • Export Citation
  • 111↑

    Jorgensen R, Kubale V, Vrecl M, Schwartz TW, Elling CE. Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s). Journal of Pharmacology and Experimental Therapeutics 2007 322 148–154. (https://doi.org/10.1124/jpet.107.120006)

    • Search Google Scholar
    • Export Citation
  • 112↑

    Schepp W, Dehne K, Riedel T, Schmidtler J, Schaffer K, Classen M. Oxyntomodulin: a cAMP-dependent stimulus of rat parietal cell function via the receptor for glucagon-like peptide-1 (7–36)NH2. Digestion 1996 57 398–405. (https://doi.org/10.1159/000201367)

    • Search Google Scholar
    • Export Citation
  • 113↑

    Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin suppresses appetite and reduces food intake in humans. Journal of Clinical Endocrinology and Metabolism 2003 88 4696–4701. (https://doi.org/10.1210/jc.2003-030421)

    • Search Google Scholar
    • Export Citation
  • 114↑

    Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, Wren AM, Frost GS, Meeran K & Ghatei MA et al.Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes 2005 54 2390–2395. (https://doi.org/10.2337/diabetes.54.8.2390)

    • Search Google Scholar
    • Export Citation
  • 115↑

    Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA, Bloom SR. Oxyntomodulin inhibits food intake in the rat. Endocrinology 2001 142 4244–4250. (https://doi.org/10.1210/endo.142.10.8430)

    • Search Google Scholar
    • Export Citation
  • 116↑

    Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS, Bloom SR. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. International Journal of Obesity 2006 30 1729–1736. (https://doi.org/10.1038/sj.ijo.0803344)

    • Search Google Scholar
    • Export Citation
  • 117↑

    Laferrere B, Swerdlow N, Bawa B, Arias S, Bose M, Olivan B, Teixeira J, McGinty J, Rother KI. Rise of oxyntomodulin in response to oral glucose after gastric bypass surgery in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 2010 95 4072–4076. (https://doi.org/10.1210/jc.2009-2767)

    • Search Google Scholar
    • Export Citation
  • 118↑

    Perakakis N, Kokkinos A, Peradze N, Tentolouris N, Ghaly W, Pilitsi E, Upadhyay J, Alexandrou A, Mantzoros CS. Circulating levels of gastrointestinal hormones in response to the most common types of bariatric surgery and predictive value for weight loss over one year: evidence from two independent trials. Metabolism: Clinical and Experimental 2019 101 153997. (https://doi.org/10.1016/j.metabol.2019.153997)

    • Search Google Scholar
    • Export Citation
  • 119↑

    Nielsen MS, Ritz C, Wewer Albrechtsen NJ, Holst JJ, le Roux CW, Sjodin A. Oxyntomodulin and glicentin may predict the effect of bariatric surgery on food preferences and weight loss. Journal of Clinical Endocrinology and Metabolism 2020 105 dgaa061. (https://doi.org/10.1210/clinem/dgaa061)

    • Search Google Scholar
    • Export Citation
  • 120↑

    Brown JC, Dryburgh JR. A gastric inhibitory polypeptide. II. The complete amino acid sequence. Canadian Journal of Biochemistry 1971 49 867–872. (https://doi.org/10.1139/o71-122)

    • Search Google Scholar
    • Export Citation
  • 121↑

    Turner DS, Etheridge L, Jones J, Marks V, Meldrum B, Bloom SR, Brown JC. The effect of the intestinal polypeptides, IRP and GIP, on insulin release and glucose tolerance in the baboon. Clinical Endocrinology 1974 3 489–493. (https://doi.org/10.1111/j.1365-2265.1974.tb02820.x)

    • Search Google Scholar
    • Export Citation
  • 122↑

    Daousi C, Wilding JP, Aditya S, Durham BH, Cleator J, Pinkney JH, Ranganath LR. Effects of peripheral administration of synthetic human glucose-dependent insulinotropic peptide (GIP) on energy expenditure and subjective appetite sensations in healthy normal weight subjects and obese patients with type 2 diabetes. Clinical Endocrinology 2009 71 195–201. (https://doi.org/10.1111/j.1365-2265.2008.03451.x)

    • Search Google Scholar
    • Export Citation
  • 123↑

    Asmar M, Tangaa W, Madsbad S, Hare K, Astrup A, Flint A, Bulow J, Holst JJ. On the role of glucose-dependent insulintropic polypeptide in postprandial metabolism in humans. American Journal of Physiology: Endocrinology and Metabolism 2010 298 E614–E621. (https://doi.org/10.1152/ajpendo.00639.2009)

    • Search Google Scholar
    • Export Citation
  • 124↑

    Bergmann NC, Lund A, Gasbjerg LS, Meessen ECE, Andersen MM, Bergmann S, Hartmann B, Holst JJ, Jessen L & Christensen MB et al.Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study. Diabetologia 2019 62 665–675. (https://doi.org/10.1007/s00125-018-4810-0)

    • Search Google Scholar
    • Export Citation
  • 125↑

    Tseng CC, Jarboe LA, Wolfe MM. Regulation of glucose-dependent insulinotropic peptide gene expression by a glucose meal. American Journal of Physiology 1994 266 G887–G 891. (https://doi.org/10.1152/ajpgi.1994.266.5.G887)

    • Search Google Scholar
    • Export Citation
  • 126↑

    Bailey CJ, Flatt PR, Kwasowski P, Powell CJ, Marks V. Immunoreactive gastric inhibitory polypeptide and K cell hyperplasia in obese hyperglycaemic (ob/ob) mice fed high fat and high carbohydrate cafeteria diets. Acta Endocrinologica 1986 112 224–229. (https://doi.org/10.1530/acta.0.1120224)

    • Search Google Scholar
    • Export Citation
  • 127↑

    Salera M, Giacomoni P, Pironi L, Cornia G, Capelli M, Marini A, Benfenati F, Miglioli M, Barbara L. Gastric inhibitory polypeptide release after oral glucose: relationship to glucose intolerance, diabetes mellitus, and obesity. Journal of Clinical Endocrinology and Metabolism 1982 55 329–336. (https://doi.org/10.1210/jcem-55-2-329)

    • Search Google Scholar
    • Export Citation
  • 128↑

    Finan B, Muller TD, Clemmensen C, Perez-Tilve D, DiMarchi RD, Tschop MH. Reappraisal of GIP pharmacology for metabolic diseases. Trends in Molecular Medicine 2016 22 359–376. (https://doi.org/10.1016/j.molmed.2016.03.005)

    • Search Google Scholar
    • Export Citation
  • 129↑

    Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, Fujimoto S, Oku A, Tsuda K & Toyokuni S et al.Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nature Medicine 2002 8 738–742. (https://doi.org/10.1038/nm727)

    • Search Google Scholar
    • Export Citation
  • 130↑

    Gogebakan Ö, Andres J, Biedasek K, Mai K, Kuhnen P, Krude H, Isken F, Rudovich N, Osterhoff MA & Kintscher U et al.Glucose-dependent insulinotropic polypeptide reduces fat-specific expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 and inhibits release of free fatty acids. Diabetes 2012 61 292–300. (https://doi.org/10.2337/db10-0902)

    • Search Google Scholar
    • Export Citation
  • 131↑

    Wasada T, McCorkle K, Harris V, Kawai K, Howard B, Unger RH. Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs. Journal of Clinical Investigation 1981 68 1106–1107. (https://doi.org/10.1172/jci110335)

    • Search Google Scholar
    • Export Citation
  • 132↑

    Beck B, Max JP. Direct metabolic effects of gastric inhibitory polypeptide (GIP): dissociation at physiological levels of effects on insulin-stimulated fatty acid and glucose incorporation in rat adipose tissue. Diabetologia 1986 29 68. (https://doi.org/10.1007/BF02427284)

    • Search Google Scholar
    • Export Citation
  • 133↑

    Nasteska D, Harada N, Suzuki K, Yamane S, Hamasaki A, Joo E, Iwasaki K, Shibue K, Harada T, Inagaki N. Chronic reduction of GIP secretion alleviates obesity and insulin resistance under high-fat diet conditions. Diabetes 2014 63 2332–2343. (https://doi.org/10.2337/db13-1563)

    • Search Google Scholar
    • Export Citation
  • 134↑

    Althage MC, Ford EL, Wang S, Tso P, Polonsky KS, Wice BM. Targeted ablation of glucose-dependent insulinotropic polypeptide-producing cells in transgenic mice reduces obesity and insulin resistance induced by a high fat diet. Journal of Biological Chemistry 2008 283 18365–18376. (https://doi.org/10.1074/jbc.M710466200)

    • Search Google Scholar
    • Export Citation
  • 135↑

    Kim SJ, Nian C, Karunakaran S, Clee SM, Isales CM, McIntosh CH. GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. PLoS ONE 2012 7 e40156. (https://doi.org/10.1371/journal.pone.0040156)

    • Search Google Scholar
    • Export Citation
  • 136↑

    Ambati S, Duan J, Hartzell DL, Choi YH, Della-Fera MA, Baile CA. GIP-dependent expression of hypothalamic genes. Physiological Research 2011 60 941–950. (https://doi.org/10.33549/physiolres.932151)

    • Search Google Scholar
    • Export Citation
  • 137↑

    Eberlein GA, Eysselein VE, Schaeffer M, Layer P, Grandt D, Goebell H, Niebel W, Davis M, Lee TD, Shively JE. A new molecular form of PYY: structural characterization of human PYY(3–36) and PYY(1–36). Peptides 1989 10 797–803. (https://doi.org/10.1016/0196-9781(8990116-2)

    • Search Google Scholar
    • Export Citation
  • 138↑

    Adrian TE, Long RG, Fuessl HS, Bloom SR. Plasma peptide YY (PYY) in dumping syndrome. Digestive Diseases and Sciences 1985 30 1145–1148. (https://doi.org/10.1007/BF01314048)

    • Search Google Scholar
    • Export Citation
  • 139↑

    Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ & Ghatei MA et al.Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 2002 418 650–654. (https://doi.org/10.1038/nature00887)

    • Search Google Scholar
    • Export Citation
  • 140↑

    Challis BG, Pinnock SB, Coll AP, Carter RN, Dickson SL, O’Rahilly S. Acute effects of PYY3-36 on food intake and hypothalamic neuropeptide expression in the mouse. Biochemical and Biophysical Research Communications 2003 311 915–919. (https://doi.org/10.1016/j.bbrc.2003.10.089)

    • Search Google Scholar
    • Export Citation
  • 141↑

    Halatchev IG, Ellacott KL, Fan W, Cone RD. Peptide YY3–36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology 2004 145 2585–2590. (https://doi.org/10.1210/en.2003-1754)

    • Search Google Scholar
    • Export Citation
  • 142↑

    Pittner RA, Moore CX, Bhavsar SP, Gedulin BR, Smith PA, Jodka CM, Parkes DG, Paterniti JR, Srivastava VP, Young AA. Effects of PYY[3–36] in rodent models of diabetes and obesity. International Journal of Obesity and Related Metabolic Disorders 2004 28 963–971. (https://doi.org/10.1038/sj.ijo.0802696)

    • Search Google Scholar
    • Export Citation
  • 143↑

    De Silva A, Salem V, Long CJ, Makwana A, Newbould RD, Rabiner EA, Ghatei MA, Bloom SR, Matthews PM & Beaver JD et al.The gut hormones PYY 3–36 and GLP-1 7–36 amide reduce food intake and modulate brain activity in appetite centers in humans. Cell Metabolism 2011 14 700–706. (https://doi.org/10.1016/j.cmet.2011.09.010)

    • Search Google Scholar
    • Export Citation
  • 144↑

    Schmidt JB, Gregersen NT, Pedersen SD, Arentoft JL, Ritz C, Schwartz TW, Holst JJ, Astrup A, Sjodin A. Effects of PYY3-36 and GLP-1 on energy intake, energy expenditure, and appetite in overweight men. American Journal of Physiology: Endocrinology and Metabolism 2014 306 E1248–E1256. (https://doi.org/10.1152/ajpendo.00569.2013)

    • Search Google Scholar
    • Export Citation
  • 145↑

    Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A. Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. American Journal of Physiology: Endocrinology and Metabolism 2007 292 E1062–E1068. (https://doi.org/10.1152/ajpendo.00450.2006)

    • Search Google Scholar
    • Export Citation
  • 146↑

    Tan T, Behary P, Tharakan G, Minnion J, Al-Najim W, Albrechtsen NJW, Holst JJ, Bloom SR. The effect of a subcutaneous infusion of GLP-1, OXM, and PYY on energy intake and expenditure in obese volunteers. Journal of Clinical Endocrinology and Metabolism 2017 102 2364–2372. (https://doi.org/10.1210/jc.2017-00469)

    • Search Google Scholar
    • Export Citation
  • 147↑

    Doucet E, Laviolette M, Imbeault P, Strychar I, Rabasa-Lhoret R, Prud’homme D. Total peptide YY is a correlate of postprandial energy expenditure but not of appetite or energy intake in healthy women. Metabolism: Clinical and Experimental 2008 57 1458–1464. (https://doi.org/10.1016/j.metabol.2008.05.017)

    • Search Google Scholar
    • Export Citation
  • 148↑

    Hill BR, De Souza MJ, Williams NI. Characterization of the diurnal rhythm of peptide YY and its association with energy balance parameters in normal-weight premenopausal women. American Journal of Physiology: Endocrinology and Metabolism 2011 301 E409–E415. (https://doi.org/10.1152/ajpendo.00171.2011)

    • Search Google Scholar
    • Export Citation
  • 149↑

    Karamanakos SN, Vagenas K, Kalfarentzos F, Alexandrides TK. Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Annals of Surgery 2008 247 401–407. (https://doi.org/10.1097/SLA.0b013e318156f012)

    • Search Google Scholar
    • Export Citation
  • 150↑

    Peterli R, Wolnerhanssen B, Peters T, Devaux N, Kern B, Christoffel-Courtin C, Drewe J, von Flue M, Beglinger C. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial. Annals of Surgery 2009 250 234–241. (https://doi.org/10.1097/SLA.0b013e3181ae32e3)

    • Search Google Scholar
    • Export Citation
  • 151↑

    Papamargaritis D, le Roux CW, Sioka E, Koukoulis G, Tzovaras G, Zacharoulis D. Changes in gut hormone profile and glucose homeostasis after laparoscopic sleeve gastrectomy. Surgery for Obesity and Related Diseases 2013 9 192–201. (https://doi.org/10.1016/j.soard.2012.08.007)

    • Search Google Scholar
    • Export Citation
  • 152↑

    Guida C, Stephen SD, Watson M, Dempster N, Larraufie P, Marjot T, Cargill T, Rickers L, Pavlides M & Tomlinson J et al.PYY plays a key role in the resolution of diabetes following bariatric surgery in humans. EBiomedicine 2019 40 67–76. (https://doi.org/10.1016/j.ebiom.2018.12.040)

    • Search Google Scholar
    • Export Citation
  • 153↑

    Eberlein GA, Eysselein VE, Goebell H. Cholecystokinin-58 is the major molecular form in man, dog and cat but not in pig, beef and rat intestine. Peptides 1988 9 993–998. (https://doi.org/10.1016/0196-9781(8890079-4)

    • Search Google Scholar
    • Export Citation
  • 154↑

    Little TJ, Horowitz M, Feinle-Bisset C. Role of cholecystokinin in appetite control and body weight regulation. Obesity Reviews 2005 6 297–306. (https://doi.org/10.1111/j.1467-789X.2005.00212.x)

    • Search Google Scholar
    • Export Citation
  • 155↑

    Gibbs J, Young RC, Smith GP. Cholecystokinin decreases food intake in rats. Journal of Comparative and Physiological Psychology 1973 84 488–495. (https://doi.org/10.1037/h0034870)

    • Search Google Scholar
    • Export Citation
  • 156↑

    Antin J, Gibbs J, Holt J, Young RC, Smith GP. Cholecystokinin elicits the complete behavioral sequence of satiety in rats. Journal of Comparative and Physiological Psychology 1975 89 784–790. (https://doi.org/10.1037/h0077040)

    • Search Google Scholar
    • Export Citation
  • 157↑

    Muurahainen N, Kissileff HR, Derogatis AJ, Pi-Sunyer FX. Effects of cholecystokinin-octapeptide (CCK-8) on food intake and gastric emptying in man. Physiology and Behavior 1988 44 645–649. (https://doi.org/10.1016/0031-9384(8890330-7)

    • Search Google Scholar
    • Export Citation
  • 158↑

    Kissileff HR, Pi-Sunyer FX, Thornton J, Smith GP. C-terminal octapeptide of cholecystokinin decreases food intake in man. American Journal of Clinical Nutrition 1981 34 154–160. (https://doi.org/10.1093/ajcn/34.2.154)

    • Search Google Scholar
    • Export Citation
  • 159↑

    MacIntosh CG, Morley JE, Wishart J, Morris H, Jansen JB, Horowitz M, Chapman IM. Effect of exogenous cholecystokinin (CCK)-8 on food intake and plasma CCK, leptin, and insulin concentrations in older and young adults: evidence for increased CCK activity as a cause of the anorexia of aging. Journal of Clinical Endocrinology and Metabolism 2001 86 5830–5837. (https://doi.org/10.1210/jcem.86.12.8107)

    • Search Google Scholar
    • Export Citation
  • 160↑

    Lieverse RJ, Jansen JB, Masclee AM, Lamers CB. Satiety effects of cholecystokinin in humans. Gastroenterology 1994 106 1451–1454. (https://doi.org/10.1016/0016-5085(9490397-2)

    • Search Google Scholar
    • Export Citation
  • 161↑

    Kellum JM, Kuemmerle JF, O’Dorisio TM, Rayford P, Martin D, Engle K, Wolf L, Sugerman HJ. Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty. Annals of Surgery 1990 211 763–770; discussion 770–761. (https://doi.org/10.1097/00000658-199006000-00016)

    • Search Google Scholar
    • Export Citation
  • 162↑

    Foschi D, Corsi F, Pisoni L, Vago T, Bevilacqua M, Asti E, Righi I, Trabucchi E. Plasma cholecystokinin levels after vertical banded gastroplasty: effects of an acidified meal. Obesity Surgery 2004 14 644–647. (https://doi.org/10.1381/096089204323093426)

    • Search Google Scholar
    • Export Citation
  • 163↑

    Lo CM, King A, Samuelson LC, Kindel TL, Rider T, Jandacek RJ, Raybould HE, Woods SC, Tso P. Cholecystokinin knockout mice are resistant to high-fat diet-induced obesity. Gastroenterology 2010 138 1997–2005. (https://doi.org/10.1053/j.gastro.2010.01.044)

    • Search Google Scholar
    • Export Citation
  • 164↑

    Miyasaka K, Ichikawa M, Ohta M, Kanai S, Yoshida Y, Masuda M, Nagata A, Matsui T, Noda T & Takiguchi S et al.Energy metabolism and turnover are increased in mice lacking the cholecystokinin-B receptor. Journal of Nutrition 2002 132 739–741. (https://doi.org/10.1093/jn/132.4.739)

    • Search Google Scholar
    • Export Citation
  • 165↑

    Valentino MA, Lin JE, Snook AE, Li P, Kim GW, Marszalowicz G, Magee MS, Hyslop T, Schulz S, Waldman SA. A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. Journal of Clinical Investigation 2011 121 3578–3588. (https://doi.org/10.1172/JCI57925)

    • Search Google Scholar
    • Export Citation
  • 166↑

    Fruhbeck G Gastrointestinal hormones: uroguanylin-a new gut-derived weapon against obesity? Nature Reviews: Endocrinology 2011 8 5–6. (https://doi.org/10.1038/nrendo.2011.206)

    • Search Google Scholar
    • Export Citation
  • 167↑

    Currie MG, Fok KF, Kato J, Moore RJ, Hamra FK, Duffin KL, Smith CE. Guanylin: an endogenous activator of intestinal guanylate cyclase. Proceedings of the National Academy of Sciences of the United States of America 1992 89 947–951. (https://doi.org/10.1073/pnas.89.3.947)

    • Search Google Scholar
    • Export Citation
  • 168↑

    Schulz S, Green CK, Yuen PS, Garbers DL. Guanylyl cyclase is a heat-stable enterotoxin receptor. Cell 1990 63 941–948. (https://doi.org/10.1016/0092-8674(9090497-3)

    • Search Google Scholar
    • Export Citation
  • 169↑

    Kulaksiz H, Schlenker T, Rost D, Stiehl A, Volkmann M, Lehnert T, Cetin Y, Stremmel W. Guanylin regulates chloride secretion in the human gallbladder via the bile fluid. Gastroenterology 2004 126 732–740. (https://doi.org/10.1053/j.gastro.2003.11.053)

    • Search Google Scholar
    • Export Citation
  • 170↑

    Krause WJ, London RM, Freeman RH, Forte LR. The guanylin and uroguanylin peptide hormones and their receptors. Acta Anatomica 1997 160 213–231. (https://doi.org/10.1159/000148015)

    • Search Google Scholar
    • Export Citation
  • 171↑

    Forte LR, Currie MG. Guanylin: a peptide regulator of epithelial transport. FASEB Journal 1995 9 643–650. (https://doi.org/10.1096/fasebj.9.8.7768356)

    • Search Google Scholar
    • Export Citation
  • 172↑

    Folgueira C, Sanchez-Rebordelo E, Barja-Fernandez S, Leis R, Tovar S, Casanueva FF, Dieguez C, Nogueiras R, Seoane LM. Uroguanylin levels in intestine and plasma are regulated by nutritional status in a leptin-dependent manner. European Journal of Nutrition 2016 55 529–536. (https://doi.org/10.1007/s00394-015-0869-2)

    • Search Google Scholar
    • Export Citation
  • 173↑

    Trayhurn P, Thomas ME, Duncan JS, Rayner DV. Effects of fasting and refeeding on ob gene expression in white adipose tissue of lean and obese (oblob) mice. FEBS Letters 1995 368 488–490. (https://doi.org/10.1016/0014-5793(9500719-p)