2. Academic Validation
  3. 27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior

27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior

  • Sci Adv. 2024 Jul 12;10(28):eadi4746. doi: 10.1126/sciadv.adi4746.
Hui Ye 1 2,  Xiaohua Yang 2 3,  Bing Feng 4,  Pei Luo 2 3,  Valeria C Torres Irizarry 2 5,  Leslie Carrillo-Sáenz 2 5,  Meng Yu 6,  Yongjie Yang 6,  Benjamin P Eappen 6,  Marcos David Munoz 2,  Nirali Patel 2,  Sarah Schaul 2,  Lucas Ibrahimi 2,  Penghua Lai 2,  Xinyue Qi 1,  Yuliang Zhou 1,  Maya Kota 2,  Devin Dixit 2,  Madeline Mun 2,  Chong Wee Liew 2 5,  Yuwei Jiang 2 5,  Chunmei Wang 6,  Yanlin He 4,  Pingwen Xu 2 5
Affiliations

Affiliations

  • 1 School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 639798, Singapore.
  • 2 Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA.
  • 3 Guangdong Laboratory of Lingnan Modern Agriculture and Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China.
  • 4 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA.
  • 5 Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL 60612, USA.
  • 6 Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
PMID: 38996023 DOI: 10.1126/sciadv.adi4746
Abstract

Oxysterols are metabolites of Cholesterol that regulate Cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective Estrogen receptor Modulator, we hypothesize that 27HC binds to the Estrogen Receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating Cholesterol.

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