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Eun Seok Kang, Faidon Magkos, Elizabeth Sienkiewicz and Christos S Mantzoros

Objective

Animal and in vitro studies indicate that leptin alleviates starvation-induced reduction in circulating vaspin and stimulates the production of visfatin. We thus examined whether vaspin and visfatin are affected by short- and long-term energy deprivation and leptin administration in human subjects in vivo.

Design and methods

We measured circulating levels of vaspin and visfatin i) before and after 72 h of starvation (leading to severe hypoleptinemia) with or without leptin administration in replacement doses in 13 normal-weight subjects, ii) before and after 72 h of starvation with leptin administration in pharmacological doses in 13 lean and obese subjects, iii) during chronic energy deficiency in eight women with hypothalamic amenorrhea on leptin replacement for 3 months, and iv) during chronic energy deficiency in 18 women with hypothalamic amenorrhea on leptin replacement or placebo for 3 months.

Results

Acute starvation decreased serum leptin to 21% of baseline values, (P=0.002) but had no significant effect on vaspin and visfatin concentrations (P>0.05). Nor did normalization of leptin levels affect the concentrations of these two adipokines (P>0.9). Leptin replacement in women with hypothalamic amenorrhea did not significantly alter vaspin and visfatin concentrations, whether relative to baseline or placebo administration (P>0.25). Pharmacological doses of leptin did not affect circulating vaspin and visfatin concentrations (P>0.9).

Conclusions

Circulating vaspin and visfatin are not affected by acute or chronic energy deficiency leading to hypoleptinemia and are not regulated by leptin in human subjects, indicating that these adipocyte-secreted hormonal regulators of metabolism are independently regulated in humans.

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Aimilia Eirini Papathanasiou, Eric Nolen-Doerr, Olivia M Farr and Christos S Mantzoros

The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.

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Labros Melistas, Christos S Mantzoros, Meropi Kontogianni, Smaragdi Antonopoulou, Jose M Ordovas and Nikos Yiannakouris

Objective

We explored potential associations of two single nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ; +45T>G, rs2241766 and +276G>T, rs1501299) with circulating total and high-molecular weight (HMW) adiponectin, insulin resistance (IR), and markers of obesity in a healthy Greek female population.

Design and methods

The two SNPs were genotyped in 349 women without diabetes (mean age: 47.0±12.1 years, mean body mass index: 28.9±5.6 kg/m2). Total and HMW adiponectin concentrations, body composition variables, IR parameters, and plasma lipid levels were determined.

Results

In single SNP analysis adjusting for several potential confounders, SNP +276G>T was associated with higher fasting insulin levels (P=0.01) and higher homeostasis model assessment index for IR (HOMA-IR; P=0.009), and SNP +45T>G was associated with lower insulin levels and HOMA-IR (P=0.05 and P=0.07 respectively). No association with total or HMW adiponectin, plasma lipid levels, and body composition variables was observed; however, haplotype analysis revealed that subjects homozygous for the most common +45T/+276G haplotype had lower total adiponectin levels than did noncarriers of this haplotype (P=0.02). The observed differences in HOMA-IR were very significant among women with a higher body fat (BF) percentage (≥ the population median of 41%; all P≤0.005), but not among leaner individuals (P for interactions 0.01–0.07), thus suggesting that ADIPOQ effects on insulin sensitivity may depend upon BF status.

Conclusion

Our data suggest a significant role of ADIPOQ variants at positions +45 and +276 in the development of IR in healthy Greek women possibly through an interaction with BF.

Free access

John P Chamberland, Reena L Berman, Konstantinos N Aronis and Christos S Mantzoros

Objective

Chemerin is an adipocyte-secreted hormone and has recently been associated with obesity and the metabolic syndrome. Although studies in rodents have outlined the aspects of chemerin's function and expression, its physiology and expression patterns are still to be elucidated in humans.

Methods

To evaluate for any day/night variation in chemerin secretion, we analyzed hourly serum samples from six females in the fed state. To examine whether energy deprivation affects chemerin levels, and whether this could be mediated through leptin, we analyzed samples from the same subjects in the fasting state while administering either placebo or leptin. To evaluate for any potential dose–effect relationship between leptin and chemerin, we administered increasing metreleptin doses to five females. A tissue array was used to study the expression of chemerin in different human tissues. Ex vivo treatment of human fat explants from three subjects with leptin was carried out to evaluate for any direct effect of leptin on adipocyte chemerin secretion.

Results

Chemerin does not display a day/night variation, while acute energy deprivation resulted in a significant drop in circulating chemerin levels by ∼42%. The latter was unaltered by metreleptin administration, and leptin administration did not affect the secretion of chemerin by human adipose tissue studied ex vivo. Chemerin was expressed primarily in the pancreas and liver. Chemerin receptor showed increased expression in the lymph nodes and the spleen.

Conclusions

We outline for the first time chemerin expression and physiology in humans, which are different from those in mice.

Free access

Mary Yannakoulia, Nikos Yiannakouris, Labros Melistas, Evaggelia Fappa, Nikoletta Vidra, Meropi D Kontogianni and Christos S Mantzoros

Objective

Our aim was to investigate associations between dietary factors and high molecular weight (HMW) as well as total adiponectin in a sample of apparently healthy adult Mediterranean women.

Design and methods

Two hundred and twenty women were enrolled in this study. Anthropometric and body composition measurements were performed in all subjects. Fasting blood samples were taken; HMW and total adiponectin concentrations were measured. Food intake was evaluated using 3-day food records. The frequency of consumption of several food groups was approximately quantified in terms of number of servings per day. Furthermore, dietary intakes of betaine, choline, and free choline were estimated.

Results

Women in the highest HMW adiponectin tertile had higher fruit intake compared with those with lower levels, after adjusting for potential confounders (P=0.04). On the contrary, dietary betaine and choline intakes were not different among HMW adiponectin tertiles. In linear models, fruit consumption, controlling for biological and lifestyle variables, was significantly related to HMW adiponectin (partial r=0.15, P=0.04), but the association with total adiponectin did not reach statistical significance (partial r=0.11, P=0.12). A significant negative correlation between total adiponectin and refined cereals was also observed (partial r=−0.16, P=0.03).

Discussion

This is the first study that evaluates associations between dietary factors and HMW adiponectin levels. The associations found are moderate and indicate that, after multivariate adjustment, fruit consumption is related to HMW adiponectin in both linear and nonlinear models.

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Stella S Daskalopoulou, Alexandra B Cooke, Yessica-Haydee Gomez, Andrew F Mutter, Andreas Filippaios, Ertirea T Mesfum and Christos S Mantzoros

Background

Irisin, a recently discovered myokine, has been shown to induce browning of white adipose tissue, enhancing energy expenditure and mediating some of the beneficial effects of exercise. We aimed to estimate the time frame of changes in irisin levels after acute exercise and the effect of different exercise workloads and intensities on circulating irisin levels immediately post-exercise.

Methods

In a pilot study, four healthy subjects (22.5±1.7 years) underwent maximal workload exercise (maximal oxygen consumption, VO2 max) and blood was drawn at prespecified intervals to define the time frame of pre- and post-exercise irisin changes over a 24-h period. In the main study, 35 healthy, non-smoking (23.0±3.3 years) men and women (n=20/15) underwent three exercise protocols ≥48-h apart, in random order: i) maximal workload (VO2 max); ii) relative workload (70% of VO2 max/10 min); and iii) absolute workload (75 W/10 min). Blood was drawn immediately pre-exercise and 3 min post-exercise.

Results

In the pilot study, irisin levels increased by 35% 3 min post-exercise, then dropped and remained relatively constant. In the main study, irisin levels post-exercise were significantly higher than those of pre-exercise after all workloads (all, P<0.001). Post-to-pre-exercise differences in irisin levels were significantly different between workloads (P=0.001), with the greatest increase by 34% following maximal workload (P=0.004 vs relative and absolute).

Conclusions

Circulating irisin levels were acutely elevated in response to exercise, with a greater increase after maximal workload. These findings suggest that irisin release could be a function of muscle energy demand. Future studies need to determine the underlying mechanisms of irisin release and explore irisin's therapeutic potential.

Free access

Jessica L Fargnoli, Qi Sun, Deanna Olenczuk, Lu Qi, Ying Zhu, Frank B Hu and Christos S Mantzoros

The authors and the journal apologise for an error in the funding section of this article published in 2010, vol 162, pp 281–288. The grant number that is listed as DK081923 is actually DK081913. The Funding section with the correct grant numbers is published in full below:

Funding

This work was supported by the National Institute of Health (grants HL65582, HL60712, HL34594, DK58785, DK081913, DK79929, and DK58845), a discretionary grant from BIDMC, and a grant-in-aid by Tanita Corporation. Dr Hu is a recipient of the American Heart Association Established Investigator Award. Dr Sun is supported by a Postdoctoral Fellowship from the Unilever Corporate Research.

Free access

Jessica L Fargnoli, Qi Sun, Deanna Olenczuk, Lu Qi, Ying Zhu, Frank B Hu and Christos S Mantzoros

Objective

Adiponectin and resistin have been linked to inflammation, endothelial dysfunction, and/or insulin secretion or resistance. It remains to be elucidated which of these adipokines is associated primarily with biomarkers of all or only some of these categories, i.e. biomarkers of inflammation, endothelial dysfunction, and/or insulin secretion or insulinemia.

Design and methods

We studied 1065 healthy women, Nurses' Health Study participants, who provided blood samples in 1989–1990. A cross-sectional analysis was conducted to assess the relationships between total and high-molecular weight (HMW) adiponectin and resistin with inflammatory markers and biomarkers of endothelial dysfunction, insulin secretion, and insulinemia.

Results

Resistin was positively associated with the inflammatory markers soluble tumour necrosis factor-α receptor II and interleukin-6 but not with any biomarkers of endothelial function, glycemia, insulinemia, or markers of insulin secretion after multivariate adjustment for age and body mass index (BMI). In both crude and multivariate analyses, total adiponectin was inversely associated with insulin, proinsulin, C-peptide, HbA1c, sE-selectin, and C-reactive protein (CRP) levels. HMW adiponectin was inversely associated with circulating insulin, proinsulin, C-peptide, HbA1c, sE-selectin, and CRP concentrations, even after adjustment for age, BMI, lifestyle factors, exercise, the use of medications as well as the other biomarkers of interest. Total and HMW adiponectin demonstrated negative associations with soluble intercellular adhesion molecule-1, which became nonsignificant after adjustment for confounders, whereas positive associations between soluble vascular cell adhesion molecule-1 and total adiponectin became significant only after multivariate adjustment.

Conclusions

Total and HMW adiponectin are inversely associated with markers of insulin secretion/insulinemia, endothelial function, and inflammation. Resistin is positively associated only with markers of inflammation.

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Karen Ruschke, Lauren Fishbein, Arne Dietrich, Nora Klöting, Anke Tönjes, Andreas Oberbach, Mathias Fasshauer, Jost Jenkner, Michael R Schön, Michael Stumvoll, Matthias Blüher and Christos S Mantzoros

Objective

Obesity and type 2 diabetes (T2D) are reaching epidemic proportions in Western societies, and they contribute to substantial morbidity and mortality. The peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivator-1α (PGC-1α) system plays an important role in the regulation of efficient energy utilization and oxidative phosphorylation, both of which are decreased in obesity and insulin resistance.

Design and methods

We measured the metabolic parameters and the expression of PPARγ and PGC-1α mRNA using quantitative real-time PCR in omental and subcutaneous (SC) adipose tissues in an observational study of 153 individuals as well as in SC fat and skeletal muscle in an interventional study of 60 subjects (20 each with normal glucose tolerance, impaired glucose tolerance, and T2D) before and after intensive physical training for 4 weeks.

Results

PPARγ and PGC-1α mRNA expression in both fat depots as well as in skeletal muscle is associated with markers of insulin resistance and cardiovascular risk. PGC-1α mRNA expression is significantly higher in SC fat than in omental fat, whereas PPARγ mRNA expression is not significantly different between these fat depots. Skeletal muscle and SC fat PPARγ and PGC-1α mRNA expression increased significantly in response to physical training.

Conclusions

Gene expression of PPARγ and PGC-1α in human adipose tissue is related to markers of insulin resistance and cardiovascular risk. Increased muscle and adipose tissue PPARγ and PGC-1α expression in response to physical training may mediate the beneficial effects of exercise on insulin sensitivity.

Free access

Xiaowen Liu, Ole-Petter R Hamnvik, Michael Petrou, Huizhi Gong, John P Chamberland, Costas A Christophi, Stefanos N Kales, David C Christiani and Christos S Mantzoros

Objective

Lipocalin 2 (LCN2 or NGAL), a protein derived from neutrophils, macrophages, adipocytes, and other cells, has been proposed to be a link between obesity and insulin resistance (IR), but animal and cross-sectional human studies have revealed conflicting results. We studied the association of serum lipocalin 2 with anthropometric, metabolic, and cardiovascular risk markers in young healthy men cross-sectionally and, for the first time, prospectively after 2 years of follow-up, with and without adjustment for potential confounders including serum creatinine.

Design

Two hundred and seventy-two participants were randomly selected from the Cyprus Metabolism Study (1056 men, 18 years), of whom 93 subjects participated in the follow-up study 2 years after baseline assessment. Associations were also explored between total and free leptin levels (to serve as positive controls) and anthropometric metabolic variables.

Results

In the cross-sectional study, lipocalin 2 levels were marginally correlated in the unadjusted model with central fat distribution but not with body weight or total body fat mass. After adjusting for age, smoking, activity, body mass index, fat percentage, waist-to-hip ratio, and serum creatinine, no correlation was found with any cardiovascular risk factor. There was no correlation with the homeostasis model assessment of IR (HOMA-IR) at baseline. In the prospective analyses, baseline levels of lipocalin 2 were not predictive of any variables in unadjusted or adjusted models. As expected, total and free leptin were associated with anthropometric and metabolic variables both cross-sectionally and prospectively.

Conclusions

We demonstrate that lipocalin 2 is not an independent predictor of metabolic and cardiovascular risk factors in young men cross-sectionally or prospectively.