G_sα, encoded by Gnas, mediates hormone and neurotransmitter receptor–stimulated cAMP generation. Heterozygous G_sα-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 G_sα imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting G_sα expression on the maternal allele, but not the paternal allele, in the dorsomedial nucleus of the hypothalamus (DMH) developed obesity and reduced energy expenditure without hyperphagia. Although maternal Gnas deletion impaired activation of brown adipose tissue (BAT) in mice, their responses to cold environment remained intact. Similar findings were observed in mice with DMH-specific deficiency of melanocortin MC4R receptors, which are known to activate G_sα. Our results show that G_sα imprinting in the DMH underlies the parent-of-origin metabolic phenotype that results from G_sα mutations and that DMH MC4R/G_sα signaling is important for regulation of energy expenditure and BAT activation, but not the metabolic response to cold.

Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate G_sα/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/G_sα signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/G_q/11α signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific G_q/11α inhibitor was delivered to the PVN; this provided evidence that a G_sα-independent signaling pathway, namely G_q/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates G_q/11α may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects.

The blood hormone erythropoietin (EPO), upon binding to its receptor (EpoR), modulates high-fat diet–induced (HFD-induced) obesity in mice, improves glucose tolerance, and prevents white adipose tissue inflammation. Transgenic mice with constitutive overexpression of human EPO solely in the brain ( Tg21 ) were used to assess the neuroendocrine EPO effect without increasing the hematocrit. Male Tg21 mice resisted HFD-induced weight gain; showed lower serum adrenocorticotropic hormone, corticosterone, and C-reactive protein levels; and prevented myeloid cell recruitment to the hypothalamus compared with WT male mice. HFD-induced hypothalamic inflammation (HI) and microglial activation were higher in male mice, and Tg21 male mice exhibited a lower increase in HI than WT male mice. Physiological EPO function in the brain also showed sexual dimorphism in regulating HFD response. Female estrogen production blocked reduced weight gain and HI. Targeted deletion of EpoR gene expression in neuronal cells worsened HFD-induced glucose intolerance in both male and female mice but increased weight gain and HI in the hypothalamus in male mice only. Both male and female Tg21 mice kept on normal chow and HFD showed significantly improved glycemic control. Our data indicate that cerebral EPO regulates weight gain and HI in a sex-dependent response, distinct from EPO regulation of glycemic control, and independent of erythropoietic EPO response.

Precise neural regulation is required for maintenance of energy homeostasis. Essential to this are the hypothalamic and brainstem nuclei which are located adjacent and supra-adjacent to the circumventricular organs. They comprise multiple distinct neuronal populations which receive inputs not only from other brain regions, but also from circulating signals such as hormones, nutrients, metabolites and postprandial signals. Hence, they are ideally placed to exert a multi-tier control over metabolism. The neuronal sub-populations present in these key metabolically relevant nuclei regulate various facets of energy balance which includes appetite/satiety control, substrate utilization by peripheral organs and glucose homeostasis. In situations of heightened energy demand or excess, they maintain energy homeostasis by restoring the balance between energy intake and expenditure. While research on the metabolic role of the central nervous system has progressed rapidly, the neural circuitry and molecular mechanisms involved in regulating distinct metabolic functions have only gained traction in the last few decades. The focus of this review is to provide an updated summary of the mechanisms by which the various neuronal subpopulations, mainly located in the hypothalamus and the brainstem, regulate key metabolic functions.

Keywords: Obesity; hypothalamus; appetite; glucose homeostasis; weight-loss drugs; AGRP; POMC; NTS; incretins.