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 and Jeffrey M. Friedman ()
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Han L. Tan: Howard Hughes Medical Institute, The Rockefeller University
Luping Yin: Neuroscience Institute, New York University Langone Medical Center
Yuqi Tan: Stanford University School of Medicine
Jessica Ivanov: Howard Hughes Medical Institute, The Rockefeller University
Kaja Plucinska: The Rockefeller University
Anoj Ilanges: Howard Hughes Medical Institute, The Rockefeller University
Brian R. Herb: Institute for Genome Sciences, University of Maryland School of Medicine
Putianqi Wang: Howard Hughes Medical Institute, The Rockefeller University
Christin Kosse: Howard Hughes Medical Institute, The Rockefeller University
Paul Cohen: The Rockefeller University
Dayu Lin: Neuroscience Institute, New York University Langone Medical Center
Jeffrey M. Friedman: Howard Hughes Medical Institute, The Rockefeller University

Nature, 2024, vol. 636, issue 8041, 198-205

Abstract: 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 effect3–5. 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.

Date: 2024
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DOI: 10.1038/s41586-024-08108-2

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