1984-P: Optic Atrophy 1 Deletion in Brown Adipose Tissue Induces Browning of White Fat by Inducing FGF-21

Abstract

Optic Atrophy 1 (OPA1) is a mitochondrial inner membrane protein that regulates inner mitochondrial membrane fusion, cristae structure and respiratory capacity. Mitochondria are critical for the thermogenic activation of brown adipocytes. However, the role of OPA1 and mitochondrial dynamics in brown adipose tissue (BAT) physiology and in systemic metabolism is incompletely understood. We generated mice lacking OPA1 specifically in BAT by crossing mice floxed for the Opa1 genewith mice harboring the Cre recombinase under the control of the Ucp1promoter (OPA1 BAT-KO). Although mitochondrial respiratory capacity was reduced in mitochondria isolated from BAT of OPA1 BAT-KO, mitochondria respirations were elevated in the inguinal fat pad of these mice, which correlated with increased UCP1 protein levels and induction of thermogenic genes, consistent with browning of white adipose tissue (WAT). OPA1 BAT-KO mice also had elevated energy expenditure and reduced WAT mass. We, then, hypothesized that a BAT-derived secreted factor, or batokine, mediated these systemic effects. Upon mRNA expression analysis of a panel of batokines in OPA1-BAT KO mice, we found Fibroblast Growth Factor 21 (FGF-21) to be significantly elevated in BAT. We, therefore, generated OPA1/FGF-21 BAT-DKO mice. DKO mice had normalized WAT mass and lacked the induction of thermogenic genes in WAT. In conclusion, OPA1 deletion in BAT results in increased FGF-21 expression, which induces browning of WAT to increase energy expenditure and promote leanness. Disclosure R. Pereira Alambert: None. S. Tadinada: None. E. Abel: None. Funding American Heart Association