The FDA-approved glucagon-like-peptide-1 receptor (GLP-1R) agonists exendin-4 and liraglutide reduce food intake and body weight. Nausea is the most common adverse side effect reported with these GLP-1R agonists. Whether food intake suppression by exendin-4 and liraglutide occurs independently of nausea is unknown. Further, the neurophysiological mechanisms mediating the nausea associated with peripheral GLP-1R agonist use are poorly understood. Using two established rodent models of nausea [conditioned taste avoidance (CTA) and pica (ingestion of non-nutritive substances)], results show that all peripheral doses of exendin-4 that suppress food intake also produce CTA, whereas one dose of liraglutide suppresses intake without producing CTA. Chronic (12 days) daily peripheral administration of exendin-4 produces a progressive increase in pica coupled with stable, sustained food intake and body weight suppression, whereas the pica response and food intake reduction by daily liraglutide are more transient. Results demonstrate that the nausea response accompanying peripheral exendin-4 occurs via a vagal-independent pathway involving GLP-1R activation in the brain as the exendin-4-induced pica response is attenuated with CNS co-administration of the GLP-1R antagonist exendin-(9-39), but not by vagotomy. Direct administration of exendin-4 to the medial subnucleus of the nucleus tractus solitarius (mNTS), but not to the central nucleus of the amygdala, reduced food intake and produced a pica response, establishing the mNTS as a potential GLP-1R-expressing site mediating nausea responses associated with GLP-1R agonists.

Summary Glucagon-like-peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are unknown. Here, hindbrain (4th icv) GLP-1R activation by Exendin-4 increased PKA and MAPK activity and decreased phosphorylation of AMPK in NTS. PKA and MAPK signaling contribute to food intake and BW suppression by Exendin-4, as inhibitors RpcAMP and U0126 (4th icv), respectively, attenuated Exendin-4's effects. Hindbrain GLP-1R activation inhibited feeding by reducing meal number, not meal size. This effect was attenuated with stimulation of AMPK activity by AICAR (4th icv). The PKA, MAPK and AMPK signaling responses by Ex-4 were present in immortalized GLP-1R-expressing neurons (GT1-7). In conclusion, hindbrain GLP-1R activation suppresses food intake and BW through coordinated PKA-mediated suppression of AMPK and activation of MAPK. Pharmacotherapies targeting these signaling pathways, which mediate intake-suppressive effects of CNS GLP-1R activation, may prove efficacious in treating obesity.

Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and has become a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function. Here, we examined feeding

Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuronspecific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron-specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b -/-mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron-specific deletion of the gene encoding SHP2 (referred to herein as POMC-Shp2 -/-mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b -/-mice showed substantially improved glucose homeostasis on a high-fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMCShp2 -/-mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and α-melanocyte-stimulating hormone (αMSH) peptide levels were markedly reduced in POMC-Shp2 -/-mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system. IntroductionObesity has become a major health concern worldwide (1). Currently there are few effective therapies for targeting obesity and its associated comorbidities in humans. The CNS has long been implicated in the control of energy balance, with the hypothalamus playing a key role as an integrator of metabolic information (reviewed in ref. 2). Thus, an important area of obesity research centers on understanding the neural signaling pathways that control energy balance.Within the hypothalamus, first-order neurons in the arcuate nucleus (ARC) respond to circulating adiposity signals, such as insulin and leptin, and project to second-order neurons in the paraventricular nucleus (PVN), the dorsomedial hypothalamus (DMH), and the lateral hypothalamus (LHA) to mediate effects on food intake and energy expenditure (3-7). Two distinct populations of first-order neurons synthesize either agouti-related protein (AgRP) or proopiomelanocortin (POMC) and mediate opposing effects on energy balance (4,8). The POMC precursor is cleaved into biologically active peptides, including α-melanocyte-stimulating hormone (αMSH), which binds to melanocortin-3 and -4 receptors on target second-order neurons (9). The adipocyte-secreted hormone leptin acts in the brain as a catabolic hormone to decrease appetite and increase energy expenditure via simultaneous suppression of AgRP neurons and stimulation of POMC neurons (4, 10, 11).The discovery of leptin init...

SUMMARY Hunger and pain are two competing signals that individuals must resolve to ensure survival. However, the neural processes that prioritize conflicting survival needs are poorly understood. We discovered that hunger attenuates behavioral responses and affective properties of inflammatory pain without altering acute nociceptive responses. This effect is centrally controlled, as activity in hunger-sensitive Agouti-Related Protein (AgRP)-expressing neurons abrogates inflammatory pain. Systematic analysis of AgRP projection subpopulations revealed that the neural processing of hunger and inflammatory pain converge in the hindbrain parabrachial nucleus (PBN). Strikingly, activity in AgRP→PBN neurons blocked the behavioral response to inflammatory pain as effectively as hunger or analgesics. The anti-nociceptive effect of hunger is mediated by Neuropeptide Y (NPY) signaling in the PBN. By investigating the intersection between hunger and pain, we have identified a neural circuit that mediates competing survival needs and uncovered NPY Y1 receptor signaling in the PBN as a target for pain suppression.