Mitochondrial dysfunction has been implicated in the development of obesity, insulin resistance and fatty liver disease. Here we report that mitochondria undergo fragmentation and reduced oxidative capacity specifically in inguinal white adipose tissue after high fat diet, and that this process is regulated by the small GTPase RalA. RalA mRNA, protein and GTP binding activity are increased in inguinal white adipose tissue after HFD feeding. Targeted deletion of Rala in white adipocytes prevents the obesity-dependent fragmentation of mitochondria, and produces mice who are resistant to HFD-induced weight gain via increased energy expenditure, as well as improvements in glucose homeostasis and liver metabolism. In vitro studies revealed that RalA suppresses mitochondrial oxidative function in adipocytes by increasing fission through reversing the inhibitory phosphorylation of the mitochondrial fission protein Drp1. This reduced phosphorylation results from the recruitment of the regulatory subunit of protein phosphatase PP2A, which acts as a bona fide effector of RalA, leading to the specific dephosphorylation of the inhibitory Ser637 residue on Drp1, rendering the protein active. Thus, RalA plays a key role in repressing energy expenditure in obese adipose tissue through maintaining mitochondrial fission, contributing to weight gain and related metabolic dysfunction, including glucose intolerance and fatty liver, and may explain in part how energy expenditure is repressed in prolonged obesity.


W. Xia: None. A. Saltiel: Board Member; Elgia Therapeutics. P. Veeragandham: None. Y. Cao: None. Y. Xu: None. T. E. Rhyne: None. Y. Jones: None. R. T. Yu: None. M. Rydén: Advisory Panel; Boehringer-Ingelheim, Eli Lilly and Company, Consultant; Sigrid Therapeutics, Other Relationship; Novo Nordisk Foundation, Speaker's Bureau; Sanofi, Novo Nordisk. M. Wabitsch: None.

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