2. Academic Validation
  3. Hypothalamic malate dehydrogenase 2 modulates systemic glucose metabolism through oxytocin-mediated thermogenesis

Hypothalamic malate dehydrogenase 2 modulates systemic glucose metabolism through oxytocin-mediated thermogenesis

  • Cell Rep Med. 2026 Feb 17;7(2):102616. doi: 10.1016/j.xcrm.2026.102616.
Ting Yao 1,  Guoming Wu 2,  Yu Zeng 2,  Yinyin Xie 3,  Xiao Cui 4,  Qiongyue Zhang 3,  Chaoying Yan 5,  Zhicheng Cui 2,  Hongyu Gong 6,  Tianze Xiong 2,  Xian Liang 7,  Yan Zhang 8,  Ruiqi Zheng 9,  Hui Wang 2,  Mingchun Gao 10,  Peng Zhang 11,  Ru Wang 12,  Xiao Zhao 9,  Zhihui Feng 13,  Lei Xiao 4,  Tiemin Liu 14,  Zhi Zhang 15
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 2 State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai 200438, China.
  • 3 Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
  • 4 Shanghai Stomatological Hospital & School of Stomatology, The State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai 200032, China.
  • 5 Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 6 Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010000, China.
  • 7 Human Phenome Institute, Fudan University, Shanghai 200032, China.
  • 8 Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China.
  • 9 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 10 School of Medicine, Shanghai University, Shanghai 200444, China.
  • 11 Division of Metabolic and Bariatric Surgery, General Surgery Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
  • 12 School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China.
  • 13 Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
  • 14 State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai 200438, China; Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010000, China; Department of Endocrinology and Metabolism, Zhongshan Hospital, Human Phenome Institute, Fudan University, Shanghai 200032, China.
  • 15 State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai 200438, China. Electronic address: [email protected].
PMID: 41672064 DOI: 10.1016/j.xcrm.2026.102616
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.

Keywords

BAT; MDH2; SNS; T2D; brown adipose tissue; hypothalamus; malate dehydrogenase 2; metabolic surgery; oxytocin; sympathetic nervous system; type 2 diabetes.

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