Lipid droplet lipolysis in POMC neurons regulates energy homeostasis in a sex-specific manner
- 1Universite de Montreal - CRCHUM
Abstract
The hypothalamus is a central regulator of glucose and energy homeostasis, with arcuate nucleus (ARC) neurons orchestrating these processes. Agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) neurons integrate metabolic cues to control feeding behavior and systemic metabolism. Among these cues, fatty acids (FA) have emerged as key modulators of ARC neuronal activity. While neuronal sensing of circulating FA has begun to be defined, the contribution of FA derived from endogenous lipid stores to ARC neuron function and energy homeostasis remains largely unexplored. We recently identified lipid droplets (LD) as regulated FA reservoirs that control FA availability and metabolism in orexigenic AgRP neurons, thereby modulating their activity and regulating feeding. This prompted us to investigate whether LD-derived FA similarly regulate POMC neuron function. To this end, we targeted adipose triglyceride lipase (ATGL), which catalyzes the first committed step of LD lipolysis, in POMC neurons. We show that LD are present in POMC neurons under basal conditions both in vitro and in vivo, and that pharmacological or genetic inhibition of ATGL increases LD abundance. ATGL deficiency enhances spontaneous firing of POMC neurons and leads to reduced body weight, fat and lean mass in males, but not females. Consistent with enhanced glucose metabolism, ATGL loss lowers glycemia and insulinemia and increases carbohydrate utilization in chow-fed males. In contrast, ATGL deficiency does not alter metabolic adaptations to cold exposure, fasting or diet-induced obesity in either sex. Collectively, these findings establish ATGL-dependent LD lipolysis in POMC neurons as a previously unrecognized, sex-dependent regulator of energy homeostasis.
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BibTeX
@misc{majeur2026lipid,
title = {{Lipid droplet lipolysis in POMC neurons regulates energy homeostasis in a sex-specific manner}},
author = {D. Majeur and R. Manceau and F. Boisjoly and L. R. Depaauw-Holt and M.-F. Fourn and J. L. Robb and D. Rodaros and K. Bouyakdan and S. Fulton and C. Murphy-Royal and T. Alquier},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.752127},
url = {https://www.biorxiv.org/content/10.64898/2026.09.16.752127v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Lipid droplet lipolysis in POMC neurons regulates energy homeostasis in a sex-specific manner
AU - D. Majeur
AU - R. Manceau
AU - F. Boisjoly
AU - L. R. Depaauw-Holt
AU - M.-F. Fourn
AU - J. L. Robb
AU - D. Rodaros
AU - K. Bouyakdan
AU - S. Fulton
AU - C. Murphy-Royal
AU - T. Alquier
PY - 2026
DA - 2026/09/16
PB - bioRxiv
DO - 10.64898/2026.09.16.752127
UR - https://www.biorxiv.org/content/10.64898/2026.09.16.752127v1
AB - The hypothalamus is a central regulator of glucose and energy homeostasis, with arcuate nucleus (ARC) neurons orchestrating these processes. Agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) neurons integrate metabolic cues to control feeding behavior and systemic metabolism. Among these cues, fatty acids (FA) have emerged as key modulators of ARC neuronal activity. While neuronal sensing of circulating FA has begun to be defined, the contribution of FA derived from endogenous lipid stores to ARC neuron function and energy homeostasis remains largely unexplored. We recently identified lipid droplets (LD) as regulated FA reservoirs that control FA availability and metabolism in orexigenic AgRP neurons, thereby modulating their activity and regulating feeding. This prompted us to investigate whether LD-derived FA similarly regulate POMC neuron function. To this end, we targeted adipose triglyceride lipase (ATGL), which catalyzes the first committed step of LD lipolysis, in POMC neurons. We show that LD are present in POMC neurons under basal conditions both in vitro and in vivo, and that pharmacological or genetic inhibition of ATGL increases LD abundance. ATGL deficiency enhances spontaneous firing of POMC neurons and leads to reduced body weight, fat and lean mass in males, but not females. Consistent with enhanced glucose metabolism, ATGL loss lowers glycemia and insulinemia and increases carbohydrate utilization in chow-fed males. In contrast, ATGL deficiency does not alter metabolic adaptations to cold exposure, fasting or diet-induced obesity in either sex. Collectively, these findings establish ATGL-dependent LD lipolysis in POMC neurons as a previously unrecognized, sex-dependent regulator of energy homeostasis.
ER -