Tak1 licenses mitochondrial transfer from astrocytes to POMC neurons to maintain glucose and cholesterol homeostasis

Kaili Yin; Tingting Zhang; Xiyuan Lu; Qing Shen; Kaiyue Gu; Ying Huang; Chaonan Li; Jingyi Hou; Juxue Li; Guo Zhang

doi:10.1016/j.celrep.2024.114983

Tak1 licenses mitochondrial transfer from astrocytes to POMC neurons to maintain glucose and cholesterol homeostasis

Cell Rep. 2024 Nov 19;43(12):114983. doi: 10.1016/j.celrep.2024.114983. Online ahead of print.

Authors

Kaili Yin¹, Tingting Zhang¹, Xiyuan Lu², Qing Shen¹, Kaiyue Gu³, Ying Huang³, Chaonan Li³, Jingyi Hou³, Juxue Li², Guo Zhang⁴

Affiliations

¹ Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
² State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
³ Department of Pathophysiology, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China; Institute of Metabolism and Health, Henan University, Kaifeng, Henan 475004, China; Zhongzhou Laboratory for Integrative Biology, Zhengzhou, Henan 450046, China.
⁴ Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of Pathophysiology, School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China; Institute of Metabolism and Health, Henan University, Kaifeng, Henan 475004, China; Zhongzhou Laboratory for Integrative Biology, Zhengzhou, Henan 450046, China. Electronic address: gzhang@hust.edu.cn.

PMID: 39565693
DOI: 10.1016/j.celrep.2024.114983

Abstract

It remains incompletely understood how the astrocytes in the mediobasal hypothalamus (MBH) regulate systemic glucose and cholesterol metabolism. Here, we show that MBH astrocytic Tak1 (transforming growth factor β [TGF-β]-activated kinase 1) controls the metabolism of glucose and cholesterol. Tak1 is expressed in MBH astrocytes and activated after a short-term nutritional excess. In chow-fed mice, astrocytic deletion of Tak1 across the brain or its suppression in the MBH impairs glucose tolerance, reduces insulin sensitivity, and results in hypercholesterolemia. Astrocytic Tak1 activation in the MBH alleviates these symptoms in mice fed a high-fat diet (HFD). We show that astrocytic Tak1 modulates the activity of proopiomelanocortin (POMC) neurons and enables the transport of mitochondria from astrocytes to POMC neurons. In astrocytic Tak1 knockout mice, supplementation of CD38, a molecule that is crucial in mitochondrial transfer, restores glucose and cholesterol homeostasis. Overall, these findings highlight an important role of MBH astrocytic Tak1 in glucose and cholesterol metabolism.

Keywords: CP: Metabolism; CP: Neuroscience; Tak1; astrocyte; glucose homeostasis; hypothalamus; mitochondrial transfer.