Obesity Causes Mitochondrial Fragmentation And Dysfunction In White Adipocytes Due To Rala Activation Wenmin Xia 1 by Wenmin Xia  1, Preethi Veeragandham1, Yu Cao  1, Yayun Xu1, Torrey E. Rhyne1 101038/S42255024009780 instant download after payment.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fssion in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fssion protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fssion, contributing to weight gain and metabolic dysfunction.