Resistance to Diet-Induced Obesity in Mice Lacking OPA1 in Adipose Tissue Occurs Independently of Fat-Derived FGF-21 and BAT Function

Abstract

Optic Atrophy 1 (OPA1) is a mitochondrial protein that regulates mitochondrial dynamics and function. The role of OPA1 in adipose tissue physiology and systemic metabolism is incompletely understood. We generated mice lacking OPA1 in adipose tissue (OPA1 Ad-KO) and demonstrated that OPA1 deletion in adipose tissue completely prevents diet-induced obesity (DIO). This metabolic protection occurs concomitantly with increased levels of FGF-21 in adipose tissue and the circulation and higher energy expenditure. In the present study, we sought to determine the contribution of fat-derived FGF-21 and brown adipocyte function to the phenotype observed in OPA1 Ad-KO mice. To test whether changes in BAT function are responsible for the resistance to DIO, soon after weaning, OPA1 Ad-KO mice were fed either 60% high-fat diet (HFD) or 10% fat diet (control diet) for 8 weeks at thermoneutral conditions (30oC), when BAT function is dampened. To test whether fat-derived FGF-21 is required for the resistance to DIO in OPA1 Ad-KO mice, we generated mice lacking both OPA1 and FGF-21 in adipose tissue, by using the cre recombinase under the control of the adiponectin promoter (DKO). We, then, fed 4-week old DKO mice either 60% HFD or 10% control diet for 4 weeks. OPA1 Ad-KO mice fed a HFD under thermoneutral conditions failed to gain weight. Diet-induced increases in total fat mass was completely prevented. Although BAT mass was equally increased in WT and Ad-KO mice, gonadal and inguinal fat pads were significantly reduced in OPA1 Ad-KO mice fed HFD. Likewise, after 4 weeks of high-fat feeding, DKO mice had significantly reduced body weight and total fat mass compared to WT mice. In conclusion, our data suggest that reducing BAT function is not sufficient to induce fat expansion in OPA1 Ad-KO mice in response to HFD. Additionally, here we show that adipose tissue-derived FGF-21 is dispensable for the resistance to DIO observed in OPA1 Ad-KO mice. Disclosure R. Pereira: None. A.C. Olvera: None. A.A. Marti: None. R. Hewezi: None. W.A. Bui Tran: None. M.J. Potthoff: None. E. Abel: None.