OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21

eLife

Donald A Morgan¹  Pooja H Patel²  Rana Hewezi²  Angela Crystal Olvera²  Eric Thomas Weatherford²  Michael Westphal²  Renata O Pereira²  Ana Karina Kirby²  Satya Murthy Tadinada²  William Bùi Trân²  Monika Mittal²  Rhonda A Souvenir²  Alex Marti²  Christopher M Adams²  E Dale Abel²  Luis Miguel García-Peña²  Kamal Rahmouni³  Matthew J Potthoff³  Sarah Hartwick Bjorkman⁴ 

[1] Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States;Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States;Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States;Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States;Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States;Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility, Roy J. and Lucille A. Carver College of Medicine, Iowa City, United States;

关键词: brown adipose tissue;    thermogenesis;    optic atrophy 1;    fibroblast growth factor 21;    activating transcription factor 4;    browning;    Mouse;   

DOI  :  10.7554/eLife.66519

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. 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 by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, which is activated independently of BAT thermogenic function.

【 授权许可】

CC BY