Despite its well-documented effectiveness for treating obesity and type 2 diabetes, the clinical approved medicines for weight loss are still limited due to the unclear underlying mechanisms. Current study identified a mitochondrial protein mGPDH, and found that its globally knockout (GKO) resistant to HFD-induced obesity. mGPDH GKO showed 16.7% reduction of body weight compared with WT mice. Further MRI composition analyzer showed that fat mass, but not lean mass was significantly reduced after GKO. The volume and mass of iWAT were reduced significantly in GKO mice, but not eWAT or BAT. Food consumption was similar between GKO and WT mice fed with HFD, while energy expenditure assessed by metabolic cage system was significantly increased in both light and dark phases in HFD-GKO mice. Unexpectedly, neither the adipose- nor liver-specific mGPDH KO could repeat the protective role of GKO on HFD-induced obesity, while the cardiac-specific KO did. Mechanically, by compared tissue and serum proteomics, we identified a secretory protein SERPINA1E and preliminarily proved that it might mediate the obesity against effects of cardiac mGPDH. In sum, our study highlights a novel cross-organ mechanisms underlying weight loss, and mGPDH/SERPINA1E pathway might serve as a potential therapeutic target for obesity and its related diseases.
H. Qu: None.
