Hypothalamic malate dehydrogenase 2 modulates systemic glucose metabolism through oxytocin-mediated thermogenesis
Year: 2026
Type: article
Abstract: Bariatric surgery improves hyperglycemia in obesity and type 2 diabetes (T2D), yet its central mechanisms remain unclear. Through cerebrospinal fluid proteomic profiling of rats, we identify reduced central malate dehydrogenase 2 (MDH2) levels that correlate with surgery-induced restoration of normoglycemia. Central MDH2 blockade with the selective antagonist LW6 attenuates hyperglycemia under high-glucose conditions, independent of its enzymatic activity. Mechanistically, MDH2 inhibition activates oxytocinergic neurons in the hypothalamic paraventricular nucleus (PVN), promoting glucose disposal via sympathetic activation of brown adipose tissue (BAT) thermogenesis. Chemogenetic activation of PVN oxytocin neurons recapitulates this effect, while their silencing, oxytocin receptor blockade, or sympathetic inhibition abolishes LW6's metabolic benefits. PVN-specific Mdh2 deletion abrogates LW6's glucose-lowering effects and impairs systemic glucose homeostasis. LW6 demonstrates robust long-lasting glucose-lowering effects in a T2D mouse model. These findings establish MDH2 as a central glucose modulator and therapeutic target linking hypothalamic signaling to peripheral energy metabolism via an oxytocin-sympathetic nervous system (SNS)-BAT axis.
Source: Cell Reports Medicine
Authors: Ting Yao, Guoming Wu, Yu Zeng, Yinyin Xie, Xiao Cui, Qiongyue Zhang, Chaoying Yan, Zhicheng Cui, Hongyu Gong, Tianze Xiong, Xian Liang, Yan Zhang, Ruiqi Zheng, Hui Wang, Mingchun Gao, Peng Zhang, Ru Wang, Xiao Zhao, Zhihui Feng, Lei Xiao, Tiemin Liu, Zhi Zhang
Institutions: First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Fudan University, Shanghai Medical College of Fudan University, Huashan Hospital, Shanghai Stomatological Hospital, State Key Laboratory of Medical Neurobiology, Frontiers Center for Brain Science of the Ministry of Education, Inner Mongolia University, University of Science and Technology of China, Shanghai University, Capital Medical University, Beijing Friendship Hospital, Shanghai University of Sport, Zhongshan Hospital
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W7128507500