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Steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus play key roles in the regulation of food intake, body weight and glucose metabolism. The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) is expressed in the hypothalamus, where it determines some of the actions of bile acids on food intake and body weight through still poorly defined neuronal mechanisms. Here, we examined the role of TGR5 in SF1 neurons in the regulation of energy balance and glucose metabolism. We used a genetic approach combined with metabolic phenotyping and molecular analyses to establish the effect of TGR5 deletion in SF1 neurons on meal pattern, body weight, body composition, energy expenditure and use of energy substrates as well as on possible changes in glucose handling and insulin sensitivity. Our findings reveal that TGR5 in SF1 neurons does not play a major role in the regulation of food intake or body weight under standard chow, but it is involved in the adaptive feeding response to the acute exposure to cold or to a hypercaloric, high-fat diet, without changes in energy expenditure. Notably, TGR5 in SF1 neurons hinder glucose metabolism, since deletion of the receptor improves whole-body glucose uptake through heightened insulin signaling in the hypothalamus and in the brown adipose tissue. TGR5 in SF1 neurons favours satiety by differently modifying the meal pattern in response to specific metabolic cues. These studies also reveal a novel key function for TGR5 in SF1 neurons in the regulation of whole-body insulin sensitivity, providing new insight into the role played by neuronal TGR5 in the regulation of metabolism. • TGR5 in SF1 neurons favours satiety by modifying meal pattern responses to cold and high-fat diet. • These findings strengthen the general satietogenic role played by neuronal TGR5. • Loss of TGR5 in SF1 neurons heightens insulin signaling in the hypothalamus and brown adipose tissue. • Opposite to its action in the periphery, TGR5 in SF1 neurons hinders glucose metabolism. [ABSTRACT FROM AUTHOR]

Ghrelin and obestatin are two gastrointestinal peptides obtained by post-translational processing of a common precursor, preproghrelin. Ghrelin is an orexigenic and adipogenic peptide and a potent growth hormone secretagogue (GHS) modified by the enzyme ghrelin- O-acyl-transferase to bind and activate its receptor, the GHS-R. The ghrelin/GHS-R pathway is complex and the effects of ghrelin on GH secretion, adiposity and food intake appear to be relayed by distinct mechanisms involving different transduction signals and constitutive activity for the GH-R, different cofactors as modulators of endogenous ghrelin signalling and/or alternative ghrelin receptors. The discovery of obestatin in 2005 brought an additional level of complexity to this fascinating system. Obestatin was initially identified as an anorexigenic peptide and as the cognate ligand for GPR39, but its effect on food intake and its ability to activate GPR39 are still controversial. Although several teams failed to reproduce the anorexigenic actions of obestatin, this peptide has been shown to antagonise GH secretion and food intake induced by ghrelin and could be an interesting pharmacological tool to counteract the actions of ghrelin. Ghrelin and obestatin immunoreactivities are recovered in the blood with an ultradian pulsatility and their concentrations in plasma vary with the nutritional status of the body. It is still a matter of debate whether both hormones are regulated by independent mechanisms and whether obestatin is a physiologically relevant peptide. Nevertheless, a significant number of studies show that the ghrelin/obestatin ratio is modified in anorexia nervosa and obesity. This suggests that the ghrelin/obestatin balance could be essential to adapt the body’s response to nutritional challenges. Although measuring ghrelin and obestatin in plasma is challenging because many forms of the peptides circulate, more sensitive and selective assays to detect the different preproghrelin-derived peptides are being developed and may be the key to obtaining a better understanding of their roles in different physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Both growth hormone (GH)/insulin growth factor (IGF)-1 axis and energy balance have been implicated in longevity independently. The aim of the present study was to characterize the effect of a 72-h fasting period at 3 months of age in four different rat strains: (i) Wistar and (ii) Fischer 344 rats, which develop obesity with age, and (iii) Brown Norway and (iv) Lou C rats, which do not. Wistar rats ate more, were significantly bigger, and presented with higher plasma leptin and lower ghrelin levels and hypothalamic growth hormone-releasing hormone (GHRH) content than rats from the three other strains. Plasma insulin and IGF-1 levels were lower in Brown Norway and Lou C rats, and somatostatin content was lower in Brown Norway rats only. Glycaemia was lower in Lou C rats that displayed a lower relative food intake compared to Fischer and Wistar rats. Brown Norway rats showed a greater caloric efficiency than the three other strains. Concerning major hypothalamic neuropeptides implicated in feeding, similar amounts were detected in the four strains for neuropeptide Y, agouti-related peptide, galanin, melanin-concentrating hormone,α-melanocortin-stimulating hormone (α-MSH) and corticotropin-releasing hormone. Orexin A appeared to be slightly elevated in Fischer rats and cocaine amphetamine-regulated transcript (CART)55−102 diminished in Brown Norway. At the mRNA level, orexin A, GHSR1,α-MSH and CART expression were higher in Wistar and Lou C rats. Principal component analysis confirmed the presence of two main factors in thead libitumrat population; the first being associated with growth-related parameters and the second being associated with food intake regulation. Hypothalamic GHRH and somatostatin content were positively correlated with feeding-related neuropeptides such asα-MSH for GHRH, and orexin A and CART for both peptides. Plasma ghrelin levels were negatively correlated with leptin and IGF-1 levels. Finally, a 72-h fasting period affected minimally body weight, plasma IGF-1 and leptin levels in Lou C rats compared to the three other strains, and plasma insulin levels were less affected in Brown Norway rats. In conclusion, Wistar shorter life span is consistent with its already fatter phenotype at 3 months of age. In terms of IGF-1, glycaemia and leptin responses to fasting, the Lou strain, which presents with a low food intake/body weight and caloric efficiency, is the least affected. The link between food intake regulation, GH axis and ageing is further demonstrated by principal component analysis, where GHRH and somatostatin were found to be strongly associated with energy homeostasis parameters. [ABSTRACT FROM AUTHOR]

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity. [Display omitted] • Diet-induced obesity induces changes in the hypothalamic BA-TGR5 system • Central TGR5 agonism reduces obesity by activating the sympathetic nervous system • Hypothalamic TGR5 protects from the onset and worsening of diet-induced obesity • Hypothalamic TGR5 participates in the anti-obesity effects of BA supplementation Castellanos-Jankiewicz et al. demonstrate that activation of central TGR5 signaling counteracts diet-induced obesity, whereas genetic downregulation of hypothalamic TGR5 promotes it. These effects involve modulation of food intake and energy expenditure through the sympathetic nervous system, revealing a long-range bile acid-dependent hypothalamic mechanism contributing to weight regulation in obesity. [ABSTRACT FROM AUTHOR]

Abstract A cDNA membrane array displaying 1183 probes was used to detect hypothalamic and pituitary changes in gene expression accompanying ageing and age-associated pituitary macroadenomas. Four groups of male Sprague-Dawley rats (3-, 15-, 24-month-old and 24-month-old with prolactinoma) were compared in two independent hybridizations. cDNA array data were confirmed and completed by comparative reverse transcriptase-polymerase chain reaction on selected genes. The expression of 454 and 116 mRNAs was detected in hypothalamus and pituitary, respectively. Growth hormone (GH) mRNA alone represented 85% of total gene expression in the gland of young rats, and other pituitary hormone transcripts 2.8%, while melanin-concentrating hormone (MCH) mRNA, the most expressed neuropeptide transcript involved in neuroendocrine regulation, accounted for only 0.8% of total hypothalamic transcripts. The proportion of genes modified in the hypothalamus and pituitary was rather modest: 1.5% and 5.2%, respectively, for ageing per se , and 1.1% and 5.2% for age-associated macroprolactinomas. Among pituitary specific RNAs, GH mRNA expression was notably decreased with age. At the hypothalamic level, expression of genes directly involved in GH regulation, such as somatostatin and growth hormone-releasing hormone, was not altered, while neuropeptide transcripts involved in feeding behaviour [orexin/hypocretin, MCH, pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART)] were significantly altered. In addition, a few ubiquitous transcripts (hnRNP-K, PFKm, CCND 2, calponin and set) were differently affected in both tissues. Modifications in hypothalamic orexigenic (orexin, MCH) and anorexigenic (POMC, CART) gene expression are in keeping with an age-associated decrease in energy consumption but a higher one in the presence of macroprolactinomas. [ABSTRACT FROM AUTHOR]