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Objective: A great deal of attention has focused on the central role of alpha melanocyte-stimulating hormone (alpha-MSH) and its antagonism at the melanocortin-4 receptor (MC4R) by agouti related protein (AgRP) in the regulation of energy balance. However, very little is known regarding the function of circulating AgRP and alpha-MSH in humans. We aimed to determine whether circulating alpha-MSH and AgRP are responsive to long-term perturbations in energy balance, in a manner consistent with their central putative functions., Design and Measurements: Circulating alpha-MSH, AgRP and leptin were measured in both lean (n = 11) and obese (n = 18) male volunteers, some of whom (lean n = 11, obese n = 12) were then allocated one of two weight-loss dietary strategies to achieve about 5% weight loss. This was achieved by either total starvation (for 4-6 days) for rapid weight loss or a very low calorie diet (VLCD, 2.6 MJ/day) (11-12 days) for less rapid weight loss, in both the lean and obese volunteers., Results: At baseline, prior to any weight loss both plasma alpha-MSH (15.8 +/- 1.2 vs. 5.8 +/- 1.0 pmol/l +/- SEM; P < 0.001) and AgRP (49.4 +/- 2.4 vs. 10.1 +/- 0.9 pg/ml +/- SEM; P < 0.001) were elevated in obese subjects compared with lean. In both cases this correlated closely with fat mass (P < 0.001), percentage body fat (P < 0.001) and leptin (P < 0.05). Plasma AgRP increased significantly during a 6-day fast in lean individuals (11.1 +/- 1.6 vs. 21.6 +/- 3.1 pg/ml +/- SEM; P < 0.05) but not in the VLCD subjects or in the obese, while alpha-MSH was not affected by any changes in energy balance in either the lean or the obese volunteers., Conclusion: We show a difference in alpha-MSH and AgRP in lean and obese subjects that correlates closely with body fat at baseline. We demonstrate an increase in plasma AgRP during a 6-day fast in lean individuals that is coincident with a decrease in plasma leptin. This increase in AgRP was not due to weight loss per se as there was no change in AgRP as a result of the same weight loss in the VLCD intervention in lean individuals. The source of the increase in plasma AgRP and its physiological function in the periphery remains to be elucidated but we suggest that the dynamics of the change in plasma leptin may determine the elevation in fasting plasma AgRP in lean subjects.

A great deal of attention has focused on the central role of alpha melanocyte-stimulating hormone (α-MSH) and its antagonism at the melanocortin-4 receptor (MC4R) by agouti related protein (AgRP) in the regulation of energy balance. However, very little is known regarding the function of circulating AgRP and α-MSH in humans. We aimed to determine whether circulating α-MSH and AgRP are responsive to long-term perturbations in energy balance, in a manner consistent with their central putative functions. Circulating α-MSH, AgRP and leptin were measured in both lean ( n = 11) and obese ( n = 18) male volunteers, some of whom (lean n = 11, obese n = 12) were then allocated one of two weight-loss dietary strategies to achieve about 5% weight loss. This was achieved by either total starvation (for 4–6 days) for rapid weight loss or a very low calorie diet (VLCD, 2·6 MJ/day) (11–12 days) for less rapid weight loss, in both the lean and obese volunteers. At baseline, prior to any weight loss both plasma α-MSH (15·8 ± 1·2 vs. 5·8 ± 1·0 pmol/l ± SEM; P < 0·001) and AgRP (49·4 ± 2·4 vs. 10·1 ± 0·9 pg/ml ± SEM; P < 0·001) were elevated in obese subjects compared with lean. In both cases this correlated closely with fat mass ( P < 0·001), percentage body fat ( P < 0·001) and leptin ( P < 0·05). Plasma AgRP increased significantly during a 6-day fast in lean individuals (11·1 ± 1·6 vs. 21·6 ± 3·1 pg/ml ± SEM; P < 0·05) but not in the VLCD subjects or in the obese, while α-MSH was not affected by any changes in energy balance in either the lean or the obese volunteers. We show a difference in α-MSH and AgRP in lean and obese subjects that correlates closely with body fat at baseline. We demonstrate an increase in plasma AgRP during a 6-day fast in lean individuals that is coincident with a decrease in plasma leptin. This increase in AgRP was not due to weight loss per se as there was no change in AgRP as a result of the same weight loss in the VLCD intervention in lean individuals. The source of the increase in plasma AgRP and its physiological function in the periphery remains to be elucidated but we suggest that the dynamics of the change in plasma leptin may determine the elevation in fasting plasma AgRP in lean subjects. [ABSTRACT FROM AUTHOR]

Factors which regulate expression of the haptoglobin (acute phase reactant) gene in adipocytes have been examined using 3T3-L1 cells. Haptoglobin expression was observed by Northern blotting in each of the major white adipose tissue depots of mice (epididymal, subcutaneous, mesenteric, and perirenal) and in interscapular brown fat. Expression occurred in mature adipocytes, but not in the stromal-vascular fraction. In 3T3-L1 cells, haptoglobin mRNA was detected from day 4 after the induction of differentiation into adipocytes. Lipopolysaccharide and the cytokines, TNFα and interleukin-6, resulted in substantial increases in haptoglobin mRNA in 3T3-L1 adipocytes; the increase (7-fold) was highest with TNFα. Increases in haptoglobin mRNA level were also induced by dexamethasone, noradrenaline, isoprenaline, and a β3-adrenoceptor agonist. In contrast, haptoglobin mRNA was reduced by nicotinic acid and the PPARγ agonist, rosiglitazone. RT-PCR showed that the haptoglobin gene was expressed in human adipose tissue (subcutaneous, omental). It is concluded that haptoglobin gene expression in adipocytes is stimulated by inflammatory cytokines, glucocorticoids, and the sympathetic system, while activation of the PPARγ nuclear receptor is strongly inhibitory. [Copyright &y& Elsevier]

Abstract: In subjects with obesity, diabetes and coronary artery disease, circulating levels of leptin increased while that of adiponectin is decreased. In this study we have investigated effects of physiological and pharmacological weight reduction on leptin and adiponectin mRNA expression. Wistar rats were fed either standard laboratory chow for 16 weeks (chow-fed) or given a fat-enriched, glucose-enriched diet (diet-fed) for 8 weeks. After 8 weeks, diet-fed group was subdivided into three subgroups, namely, an untreated obese, or were returned to chow diet, or treated with fenofibrate for further 8 week. After 16 weeks, compared with chow-fed group, diet-fed rats had significantly higher body weight, epididymal fat pad mass, and plasma levels of insulin, leptin, adiponectin, non-esterified fatty acids and triglycerides (P <0.001, for all). Moreover, untreated obese rats had significantly (P <0.01, for both) raised levels of Ob mRNA but reduced adiponectin mRNA levels in epididymal fat pads compared with chow-fed group. These changes were corrected by chronic removal of the high-energy diet and fenofibrate treatment. These findings indicate that physiological or pharmacological lowering of body weight together with circulating plasma lipids play a significant role in leptin and adiponectin synthesis and metabolism. [Copyright &y& Elsevier]