Highlights d Gipr is expressed in the hypothalamus, as demonstrated using a new Gipr-Cre mouse model d Gipr cells included somatostatin-positive neurons, glia, and vascular cells d Gipr overlapped partially with Glp1r in human and mouse hypothalamus by RNAscope d Activation of Gipr neurons using local AAV-delivered G q-DREADDs reduced food intake

Obesity represents the single most important risk factor for early disability and death in developed societies, and the incidence of obesity remains at staggering levels. CNS systems that modulate energy intake and expenditure in response to changes in body energy stores serve to maintain constant body adiposity; the adipocyte-derived hormone leptin and its receptor (LEPR) represent crucial regulators of these systems. As in the case of insulin resistance, a variety of mechanisms (including feedback inhibition, inflammation, gliosis and endoplasmic reticulum stress) have been proposed to interfere with leptin action and impede the systems that control body energy homeostasis to promote or maintain obesity, although the relative importance and contribution of each of these remain unclear. However, LEPR signalling may be increased (rather than impaired) in common obesity, suggesting that any obesity-associated defects in leptin action must result from lesions somewhere other than the initial LEPR signal. It is also possible that increased LEPR signalling could mediate some of the obesity-associated changes in hypothalamic function.

Highlights d NTS Calcr mediates food intake suppression but not aversive responses to sCT d Activating NTS Calcr neurons non-aversively suppresses feeding d These neurons act via non-CGRP PBN neurons d These neurons control long-term energy balance, not just short-term feeding