Opa3, a novel regulator of mitochondrial function, controls thermogenesis and abdominal fat mass in a mouse model for Costeff syndrome.

Timothy Wells, Jennifer R Davies, Irina A Guschina, Daniel J Ball, Jeffrey S Davies, Vanessa J Davies, Bronwen A J Evans, Marcela Votruba

Human molecular genetics 2012 Nov 15

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The interrelationship between brown adipose tissue (BAT) and white adipose tissue (WAT) is emerging as an important factor in obesity, but the effect of impairing non-shivering thermogenesis in BAT on lipid storage in WAT remains unclear. To address this, we have characterized the metabolic phenotype of a mouse model for Costeff syndrome, in which a point mutation in the mitochondrial membrane protein Opa3 impairs mitochondrial activity. Opa3(L122P) mice displayed an 80% reduction in insulin-like growth factor 1, postnatal growth retardation and hepatic steatosis. A 90% reduction in uncoupling protein 1 (UCP1) expression in interscapular BAT was accompanied by a marked reduction in surface body temperature, with a 2.5-fold elevation in interscapular BAT mass and lipid storage. The sequestration of circulating lipid into BAT resulted in profound reductions in epididymal and retroperitoneal WAT mass, without affecting subcutaneous WAT. The histological appearance and intense mitochondrial staining in intra-abdominal WAT suggest significant 'browning', but with UCP1 expression in WAT of Opa3(L122P) mice only 62% of that in wild-type littermates, any precursor differentiation does not appear to result in thermogenically active beige adipocytes. Thus, we have identified Opa3 as a novel regulator of lipid metabolism, coupling lipid uptake with lipid processing in liver and with thermogenesis in BAT. These findings indicate that skeletal and metabolic impairment in Costeff syndrome may be more significant than previously thought and that uncoupling lipid uptake from lipid metabolism in BAT may represent a novel approach to controlling WAT mass in obesity.

Citation

Timothy Wells, Jennifer R Davies, Irina A Guschina, Daniel J Ball, Jeffrey S Davies, Vanessa J Davies, Bronwen A J Evans, Marcela Votruba. Opa3, a novel regulator of mitochondrial function, controls thermogenesis and abdominal fat mass in a mouse model for Costeff syndrome. Human molecular genetics. 2012 Nov 15;21(22):4836-44