Publication Date

9-1-2024

Journal

Nature Metabolism

DOI

10.1038/s42255-024-01099-4

PMID

39112722

PMCID

PMC11881791

PubMedCentral® Posted Date

5-5-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Male, Mice, Feeding Behavior, Basal Forebrain, Enkephalins, Eating, Protein Precursors, Diet, High-Fat, Mice, Inbred C57BL, Neural Pathways, Obesity, Neurons

Abstract

Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBBPenk neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBBPenk neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBBPenk population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.

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