Projection-defined hypothalamic outputs differentially regulate thermogenesis and lipolysis

• 成果类型: Article
• 署名作者: Min, Hyeonyoung; Zheng, Qi; Yang, Yunlei
• 署名单位: Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Montefiore Medical Center; Yeshiva University; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2535878123
• 发表日期: 2026-06-02
• 页码: e2535878123
• 关键词: VMH; thermogenesis; LIPOLYSIS; PVT; rPAG; BROWN ADIPOSE-TISSUE; paraventricular nucleus; periaqueductal gray; SF1 NEURONS; thalamus; stimulation; circuits; leptin

摘要

The ventromedial hypothalamus (VMH) is a key regulator of energy homeostasis, linking central neural activity to peripheral metabolic function. Within the VMH, neurons expressing steroidogenic factor-1 (SF-1; VMHSF1) are essential for regulating energy expenditure, yet the projection-defined pathways through which they differentially control distinct adipose depots remains unclear. Here, we use projection-specific optogenetic and chemogenetic manipulations in SF1-Cre mice to identify two anatomically and functionally distinct VMHSF1 output pathways with complementary metabolic roles. Activation of the VMHSF1 -> rostral periaqueductal gray (rPAG) projection selectively stimulates thermogenesis in brown adipose tissue, elevating its temperature and thermogenic gene expression, whereas activation of the VMHSF1 -> paraventricular thalamus (PVT) pathway promotes lipolysis in white adipose tissue without engaging thermogenic programs. Both effects require intact innervation and target-region activity. These findings reveal that VMHSF1 neurons direct distinct hypothalamic output pathways to differentially regulate thermogenesis and lipid mobilization, delineating a modular neural framework for flexible, state-dependent coordination of energy expenditure and substrate utilization.