Introduction and Objective: GLYAT is a mitochondrial enzyme involved in medium-chain acyl-CoA metabolism, but its function in adipose tissue is unknown. We investigated the role of adipose GLYAT in obesity-associated metabolic dysfunction and its regulation of adipocyte mitochondrial function.Methods: Transcriptomic analysis was performed on paired subcutaneous and visceral adipose tissue samples from 236 participants (56 men, 180 women; age range 18-68 years). Using a BMI threshold of ≥25 kg/m² to classify overweight/obesity, the study population included 65 normal-weight and 171 overweight/obese individuals. Functional studies were performed in primary human and mouse adipocytes and in mice with AAV-mediated overexpression of GLYAT in inguinal white adipose tissue under cold exposure. Transcriptomic and targeted metabolomic analyses were used to explore underlying mechanisms.Results: Mitochondrial function-related genes were globally downregulated in adipose tissue from individuals with obesity. GLYAT expression correlated positively with BMI, WHR, body fat percentage, HOMA-IR, fatty liver index, adipose tissue insulin resistance index (Adipo-IR), and serum leptin level., and was inversely associated with adiponectin. GLYAT was enriched in mature adipocytes and increased during differentiation. Overexpression of GLYAT suppressed adipocyte energy metabolism, reduced mitochondrial respiratory complex proteins, and impaired cold-induced thermogenesis in vivo. Mechanistically, GLYAT overexpression inhibited fatty acid elongation, fatty acid metabolism, and oxidative phosphorylation and decreased the glycolytic intermediate 2-phospho-D-glycerate.Conclusion: GLYAT acts as a negative regulator of adipocyte mitochondrial function and glycolytic flux, contributing to impaired lipid metabolism and thermogenesis in obesity.
X. Li: None. T. Hu: None. X. Ma: None. Y. Bao: None.
National Natural Science Foundation of China (Grant NO.82400999)China Postdoctoral Science Foundation (2024M762052)
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