Gα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling.

Objective: Gα couples multiple receptors, including the melanocortin 4 receptor (MC4R), to intracellular cAMP generation. Germline inactivating Gα mutations lead to obesity in humans and mice. Mice with brain-specific Gα deficiency also develop obesity with reduced energy expenditure and locomotor activity, and impaired adaptive thermogenesis, but the underlying mechanisms remain unclear.

Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations.

Gsα, encoded by Gnas, mediates hormone and neurotransmitter receptor-stimulated cAMP generation. Heterozygous Gsα-inactivating mutations lead to obesity in Albright hereditary osteodystrophy (AHO) patients, but only when the mutations occur on the maternal allele. This parent-of-origin effect is due to Gsα imprinting in the CNS, although the relevant CNS regions are unknown.

Gsα deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight.

Gsα, the G protein that transduces receptor-stimulated cAMP generation, mediates sympathetic nervous system stimulation of brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), which are both potential targets for treating obesity, as well as lipolysis. We generated a mouse line with Gsα deficiency in mature BAT and WAT adipocytes (Ad-GsKO). Ad-GsKO mice had impaired BAT function, absent browning of WAT, and reduced lipolysis, and were therefore cold-intolerant.

Neural innervation of white adipose tissue and the control of lipolysis.

White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) and its activation is necessary for lipolysis. WAT parasympathetic innervation is not supported. Fully-executed SNS-norepinephrine (NE)-mediated WAT lipolysis is dependent on β-adrenoceptor stimulation ultimately hinging on hormone sensitive lipase and perilipin A phosphorylation.

Effect of reducing hypothalamic ghrelin receptor gene expression on energy balance.

Central and peripheral injections of fghrelin potently stimulates food intake via its receptor, GHSR1a expressed in the brain. In this study, we explored the role of GHSR1a in the paraventricular nucleus of the hypothalamus (PVN) by reducing their gene expression using the RNA interference (RNAi). pSUPER plasmids inserted with sh (short hairpin)-GHSR1a were injected into the PVN to reduce its expression.

Direct effects of nutrients, acetylcholine, CCK, and insulin on ghrelin release from the isolated stomachs of rats.

Ghrelin is a powerful orexigenic peptide predominantly secreted by the stomach. Blood concentration of ghrelin increases before meals and fall postprandial. Its regulation appears to be influenced by the type of macronutrient ingested, the vagus nerve stimulation and by other post-meal stimulated hormonal factors.

Role of AgRP on Ghrelin-induced feeding in the hypothalamic paraventricular nucleus.

MT II, agonist for MC3/4-Rs, inhibited Ghrelin's orexigenic effect in the paraventricular nucleus of the hypothalamus (PVN). To further investigate the role of the melanocortin system as mediator of ghrelin's orexigenic actions, we explored the involvement of AgRP in Ghrelin's orexigenic effect by testing the effect on food intake after their co-administration in the PVN, during the light and dark phases of feeding in rats. During both the phases of feeding, co-administration of Ghrelin with either AgRP 50 or AgRP 100 pmol into the PVN did not produce a synergistic effect on the food intake, suggesting that ghrelin induction of feeding occurs by recruiting Agrp as one of the obligatory mediators of its orexigenic effect.

Action of MT-II on ghrelin-induced feeding in the paraventricular nucleus of the hypothalamus.

Ghrelin is a 28 amino-acid peptide that has been shown to induce positive energy balance when administered both peripherally and centrally. This effect appears to occur by increasing food intake and by reducing fat utilization. Ghrelin injected into the PVN increases food intake dose-dependently.

The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis.

Recent research progress indicates a close link between ghrelin, a natural ligand of GH secretagogues receptor (GHS-R), and both the metabolic balance and body composition. To clarify the involvement of ghrelin and GHS-R in the process of adipogenesis, we measured the expression of GHS-R and peroxisome proliferator-activated receptor gamma 2 (PPAR-gamma 2) mRNA in rat adipocytes using semiquantitative RT-PCR methods. The levels of GHS-R mRNA increased by up to 4-fold in adipose tissue from epididymal and parametrial regions as the rat aged from 4-20 wk and were significantly elevated during the differentiation of preadipocytes in vitro.