TY - JOUR T1 - OPA1 Deletion in Brown Adipose Tissue Improves Thermoregulation and Systemic Metabolism via FGF21 JF - bioRxiv DO - 10.1101/2021.01.04.425181 SP - 2021.01.04.425181 AU - Renata O. Pereira AU - Alex Marti AU - Angela C. Olvera AU - Satya M. Tadinada AU - Sarah H. Bjorkman AU - Eric T. Weatherford AU - Michael Westphal AU - Pooja H. Patel AU - Ana K. Kirby AU - Rana Hewezi AU - William Bùi Trần AU - Luis M Garcia Pena AU - Rhonda A. Souvenir AU - Monika Mittal AU - Christopher M. Adams AU - Matthew J. Potthoff AU - E. Dale Abel Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/12/2021.01.04.425181.abstract N2 - Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including proteolytic processing of the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. By deleting OPA1 selectively in BAT (OPA1 BAT KO), we demonstrate that OPA1 is required for cold-induced thermogenesis. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)- dependent manner. BAT-derived FGF21 mediates an adaptive response in OPA1 BAT KO mice, by inducing browning of white adipose tissue (WAT), increasing resting metabolic rates, and improving thermoregulation. However, FGF21 does not mediate the resistance to diet-induced obesity observed in these animals. These findings reveal a requirement for OPA1 in BAT thermogenesis, and uncovers a homeostatic mechanism of BAT-mediated metabolic protection governed by an ATF4-FGF21 axis, that is activated independently of BAT thermogenic function.Competing Interest StatementThe authors have declared no competing interest. ER -