Leptin Activated Hypothalamic BNC2 Neurons Acutely Suppress Food Intake

Abstract

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons. However, while AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that suppresses appetite on a rapid time scale. Here, we report the discovery of a novel population of leptin-target neurons expressing basonuclin 2 (Bnc2) that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is finely tuned by leptin, sensory food cues, and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action.

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

“…This raises the possibility that the Glp1r DMH neurons and Trh Arc neurons convey different information to AgRP neurons. For instance, while the Glp1r DMH neurons relay pre-ingestive sensory cues to AgRP neurons 28 , the Trh Arc neurons may instead transmit postabsorptive metabolic cues, such as leptin 84 , consistent with our observation that their synaptic input largely comes from the Arc and DMH (Fig. 7L).…”

“…However, the study does not rule out a role for Trh Arc neurons characterized in the present study, since they also co-express Slc32a1, Lepr, and Glp1r. Indeed, these Trh Arc neurons are the only Arc neurons to express the gene Bnc2 30 and so, as reported in a recent preprint, may be a direct target for leptin in its control of appetite and body weight 84 .…”