Leptin-activated hypothalamic BNC2 neurons acutely suppress food intake

Han L Tan; Luping Yin; Yuqi Tan; Jessica Ivanov; Kaja Plucinska; Anoj Ilanges; Brian R Herb; Putianqi Wang; Christin Kosse; Paul Cohen; Dayu Lin; Jeffrey M Friedman

doi:10.1038/s41586-024-08108-2

Leptin-activated hypothalamic BNC2 neurons acutely suppress food intake

Nature. 2024 Oct 30. doi: 10.1038/s41586-024-08108-2. Online ahead of print.

Authors

Affiliations

¹ Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
² Department of Psychiatry, Neuroscience Institute, New York University Langone Medical Center, New York, NY, USA.
³ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA.
⁵ Department of Pharmacology, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
⁶ Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA. [email protected].

PMID: 39478220
DOI: 10.1038/s41586-024-08108-2

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 metabolism¹. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons². However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect^3-5. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that rapidly suppresses appetite. Here we report the discovery of a new population of leptin-target neurons expressing basonuclin 2 (Bnc2) in the arcuate nucleus 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 modulated 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.