Tore Christiansen, Søren K Paulsen, Jens M Bruun, Kristian Overgaard, Steffen Ringgaard, Steen B Pedersen, Vincenzo Positano, and Bjørn Richelsen
Weight loss with preferential effect on the visceral adipose tissue (VAT) depot could have important clinical benefits. In this study, we investigated the independent and combined effect of regular exercise and diet induced weight loss on body fat distribution.
Randomized control design of i) exercise-only (EXO; 12 weeks of exercise without diet-restriction), ii) hypocaloric-diet (DIO; 8 weeks of very low energy diet (VLED 600 kcal/day) followed by 4-weeks weight maintenance diet) and iii) hypocaloric-diet and exercise (DEX; 8 weeks VLED 800 kcal/day+a 4-week weight maintenance diet combined with exercise throughout the 12 weeks).
Seventy-nine obese males and females were included.
Body fat distribution was quantified by magnetic resonance imaging (MRI)-technology.
In the EXO group, the weight loss (3.5 kg) and the relative reduction in VAT (18%) was significantly lower compared with the weight losses in the DIO and DEX groups (12.3 kg; P<0.01) and to the reduction in VAT (30–37%; P<0.01). In all the three groups, the relative reduction of VAT was higher as compared with the reduction in fat mass (FM; combining all fat depots determined by MRI; P<0.01 for all comparisons). The changes in VAT were associated with changes in FM and related to the initial VAT/FM ratio (r2=0.72; P<0.01).
Exercise has no additional effects in reduction of the VAT depot, compared with the major effects of hypocaloric diet alone. In addition, the effects of exercise per se on VAT are relatively limited. The effects on the VAT depot are closely associated with changes in total FM.
Mikkel H Vendelbo, Britt Christensen, Solbritt B Grønbæk, Morten Høgild, Michael Madsen, Steen B Pedersen, Jens O L Jørgensen, Niels Jessen, and Niels Møller
Fasting and exercise stimulates, whereas glucose suppresses GH secretion, but it is uncertain how these conditions impact GH signaling in peripheral tissues. To test the original ‘feast and famine hypothesis’ by Rabinowitz and Zierler, according to which the metabolic effects of GH are predominant during fasting, we specifically hypothesized that fasting and exercise act in synergy to increase STAT-5b target gene expression.
Design and methods
Eight healthy men were studied on two occasions in relation to a 1 h exercise bout: i) with a concomitant i.v. glucose infusion (‘feast’) and ii) after a 36 h fast (‘famine’). Muscle and fat biopsy specimens were obtained before, immediately after, and 30 min after exercise.
GH increased during exercise on both examination days and this effect was amplified by fasting, and free fatty acid (FFA) levels increased after fasting. STAT-5b phosphorylation increased similarly following exercise on both occasions. In adipose tissue, suppressors of cytokine signaling 1 (SOCS1) and SOCS2 were increased after exercise on the fasting day and both fasting and exercise increased cytokine inducible SH2-containing protein (CISH). In muscle, SOCS2 and CISH mRNA were persistently increased after fasting. Muscle SOCS1, SOCS3, and CISH mRNA expression increased, whereas SOCS2 decreased after exercise on both examination days.
This study demonstrates that fasting and exercise act in tandem to amplify STAT-5b target gene expression (SOCS and CISH) in adipose and muscle tissue in accordance with the ‘feast and famine hypothesis’; the adipose tissue signaling responses, which hitherto have not been scrutinized, may play a particular role in promoting FFA mobilization.
Peter Breining, Steen B Pedersen, Mads Kjolby, Jacob B Hansen, Niels Jessen, and Bjørn Richelsen
Activation of brown adipose tissue is a promising strategy to treat and prevent obesity and obesity-related disorders. Activation of uncoupling protein 1 (UCP1) leads to uncoupled respiration and dissipation of stored energy as heat. Induction of UCP1-rich adipocytes in white adipose tissue, a process known as ‘browning’, serves as an alternative strategy to increase whole body uncoupling capacity. Here, we aim to assess the association between parathyroid hormone (PTH) receptor expression and UCP1 expression in human adipose tissues and to study PTH effects on human white and brown adipocyte lipolysis and UCP1 expression.
A descriptive study of human neck adipose tissue biopsies substantiated by an interventional study on human neck-derived adipose tissue cell models.
Thermogenic markers and PTH receptor gene expression are assessed in human neck adipose tissue biopsies and are related to individual health records. PTH-initiated lipolysis and thermogenic gene induction are assessed in cultured human white and brown adipocyte cell models. PTH receptor involvement is investigated by PTH receptor silencing.
PTH receptor gene expression correlates with UCP1 gene expression in the deep-neck adipose tissue in humans. In cell models, PTH receptor stimulation increases lipolysis and stimulates gene transcription of multiple thermogenic markers. Silencing of the PTH receptor attenuates the effects of PTH indicating a direct PTH effect via this receptor.
PTH 1 receptor stimulation by PTH may play a role in human adipose tissue metabolism by affecting lipolysis and thermogenic capacity.
Ermina Bach, Andreas B Møller, Jens O L Jørgensen, Mikkel H Vendelbo, Niels Jessen, Steen B Pedersen, Thomas S Nielsen, and Niels Møller
Acute and chronic inflammatory and metabolic responses are generated by lipopolysaccharide (LPS) during acute illness and in the pathogenesis of the metabolic syndrome, type 2 diabetes and cardiovascular disease, but whether these responses depend on intact pituitary release of hormones are not clearly identified. We compared the metabolic effects of LPS in hypopituitary patients (HPs) (in the absence of growth hormone (GH) and ACTH responses) and healthy control subjects (CTR) (with normal pituitary hormone responses).
We compared the effects of LPS on glucose, protein and lipid metabolism in eight HP and eight matched CTR twice during 4-h basal and 2-h hyperinsulinemic–euglycemic clamp conditions with muscle and fat biopsies in each period during infusion with saline or LPS.
LPS increased cortisol and GH levels in CTR but not in HP. Also, it increased whole-body palmitate fluxes (3-fold) and decreased palmitate-specific activity (SA) 40–50% in CTR, but not in HP. G(0)/G(1) Switch Gene 2 (G0S2 – an inhibitor of lipolysis) adipose tissue (AT) mRNA was decreased in CTR. Although LPS increased phenylalanine fluxes significantly more in CTR, there was no difference in glucose metabolism between groups and intramyocellular insulin signaling was unaltered in both groups.
LPS increased indices of lipolysis and amino acid/protein fluxes significantly more in CTR compared with HP and decreased adipocyte G0S2 mRNA only in CTR. Thus, in humans intact pituitary function and appropriate cortisol and GH release are crucial components of the metabolic response to LPS.
Poul F Vestergaard, Mikkel H Vendelbo, Steen B Pedersen, Anders Juul, Steffen Ringgard, Niels Møller, Niels Jessen, and Jens O L Jørgensen
The mechanisms underlying the impact of age and gender on the GH–IGF1 axis remain unclear. We tested the hypothesis that age and gender have impacts on GH signaling in human subjects in vivo.
A total of 20 healthy non-obese adults (‘young group’ <30 years (5F/5M) and ‘old group’ >60 years (5F/5M)) were studied after: i) an i.v. GH bolus (0.5 mg) and ii) saline.
Muscle and fat biopsies were obtained after 30 and 120 min. Total and phosphorylated STAT5B proteins, gene expression of IGF1, SOCS1, SOCS2, SOCS3 and CISH, body composition, VO2max, and muscle strength were measured.
In the GH-unstimulated state, women displayed significantly elevated levels of CISH mRNA in muscle (P=0.002) and fat (P=0.05) and reduced levels of IGF1 mRNA in fat. Phosphorylated STAT5B (pSTAT5b) was maximally increased in all subjects 30 min after GH exposure and more pronounced in women when compared with men (P=0.01). IGF1, SOCS1, SOCS2, SOCS3, and CISH mRNA expression increased significantly in muscle after 120 min in all subjects with no impact of age and gender. GH-induced pSTAT5b correlated inversely with lean body mass (LBM; r=−0.56, P=0.01) and positively with the CISH mRNA response (r=0.533, P=0.05).
i) GH signaling in muscle and fat after a single GH bolus in healthy human subjects is age independent, ii) we hypothesize that constitutive overexpression of CISH may contribute to the relative GH resistance in women, and iii) experimental studies on the impact of sex steroid administration and physical training on GH signaling in human subjects in vivo are required.