Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

Sexual dimorphism exists in energy balance, but the underlying mechanisms remain unclear. Here we show that the female mice have more pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus than males, and female POMC neurons display higher neural activities, compared to male counterparts. Strikingly, deletion of the transcription factor, TAp63, in POMC neurons confers “male-like” diet-induced obesity (DIO) in female mice associated with decreased POMC neural activities; but the same deletion does not affect male mice. Our results indicate that TAp63 in female POMC neurons contributes to the enhanced POMC neuron functions and resistance to obesity in females. Thus, TAp63 in POMC neurons is one key molecular driver for the sexual dimorphism in energy homeostasis.

In addition to their well-known role in the female reproductive system, estrogens can act in the brain to regulate a wide range of behaviors and physiological functions in both sexes. Over the past few decades, genetically modified animal models have greatly increased our knowledge about the roles of estrogen receptor (ER) signaling in the brain in behavioral and physiological regulations. However, less attention has been paid to the estrogen-related receptors (ERRs), the members of orphan nuclear receptors whose sequences are homologous to ERs but lack estrogen-binding ability. While endogenous ligands of ERRs remain to be determined, they seemingly share transcriptional targets with ERs and their expression can be directly regulated by ERs through the estrogen-response element embedded within the regulatory region of the genes encoding ERRs. Despite the broad expression of ERRs in the brain, we have just begun to understand the fundamental roles they play at molecular, cellular, and circuit levels. Here, we review recent research advancement in understanding the roles of ERs and ERRs in the brain, with particular emphasis on ERRs, and discuss possible cross-talk between ERs and ERRs in behavioral and physiological regulations.

The paraventricular nucleus of hypothalamus (PVN), an integrative center in the brain, orchestrates a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVN^MC4R+) is involved in feeding regulation, the neuroanatomical organization of PVN^MC4R+ connectivity and its role in other physiological regulations are incompletely understood. Here we aimed to better characterize the input–output organization of PVN^MC4R+ neurons and test their physiological functions beyond feeding. Using a combination of viral tools, we mapped PVN^MC4R+ circuits and tested the effects of chemogenetic activation of PVN^MC4R+ neurons on thermoregulation, cardiovascular control, and other behavioral responses beyond feeding. We found that PVN^MC4R+ neurons innervate many different brain regions that are known to be important not only for feeding but also for neuroendocrine and autonomic control of thermoregulation and cardiovascular function, including but not limited to the preoptic area, median eminence, parabrachial nucleus, pre-locus coeruleus, nucleus of solitary tract, ventrolateral medulla, and thoracic spinal cord. Contrary to these broad efferent projections, PVN^MC4R+ neurons receive monosynaptic inputs mainly from other hypothalamic nuclei (preoptic area, arcuate and dorsomedial hypothalamic nuclei, supraoptic nucleus, and premammillary nucleus), the circumventricular organs (subfornical organ and vascular organ of lamina terminalis), the bed nucleus of stria terminalis, and the parabrachial nucleus. Consistent with their broad efferent projections, chemogenetic activation of PVN^MC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure, and brown adipose tissue temperature. These physiological changes accompanied acute transient hyperactivity followed by hypoactivity and resting-like behavior. Our results elucidate the neuroanatomical organization of PVN^MC4R+ circuits and shed new light on the roles of PVN^MC4R+ pathways in autonomic control of thermoregulation, cardiovascular function, and biphasic behavioral activation.

Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons of the hypothalamus. We recently reported that neuron-specific deletion of GHS-R completely prevents diet-induced obesity (DIO) in mice by activating non-shivering thermogenesis. To further decipher the specific neuronal circuits mediating the metabolic effects of GHS-R, we generated AgRP neuron-specific GHS-R knockout mice (AgRP-Cre;Ghsr^f/f). Our data showed that GHS-R in AgRP neurons is required for ghrelin’s stimulatory effects on growth hormone secretion, acute food intake and adiposity, but not for long-term total food intake. Importantly, deletion of GHS-R in AgRP neurons attenuated diet-induced obesity (DIO) and enhanced cold-resistance in mice fed high fat diet (HFD). The HFD-fed knockout mice showed increased energy expenditure, and exhibited enhanced thermogenic activation in both brown and subcutaneous fat; this implies that GHS-R suppression in AgRP neurons enhances sympathetic outflow. In summary, our results suggest that AgRP neurons are key site for GHS-R mediated thermogenesis, and demonstrate that GHS-R in AgRP neurons plays crucial roles in governing energy utilization and pathogenesis of DIO.

Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERα ^vlVMH ) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERα ^vlVMH neurons. We found that selective activation of ERα ^vlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERα ^vlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERα ^vlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed that 5-HT ^DRN neurons mediate the stimulatory effects of ERα ^vlVMH neurons on BAT thermogenesis and physical activity and that ERα expressed by DRN-projecting ERα ^vlVMH neurons is required for the maintenance of energy balance. Together, these findings support a model that ERα ^vlVMH neurons activate BAT thermogenesis and physical activity through stimulating 5-HT ^DRN neurons.