OPA1 deletion in brown adipose tissue Improves thermoregulation and systemic metabolism via FGF21
- University of Iowa, United States
Abstract
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, that is activated independently of BAT thermogenic function.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.
Article and author information
Author details
Luis Miguel García-Peña
Funding
National Institutes of Health (HL127764)
- E Dale Abel
National Institutes of Health (HL112413)
- E Dale Abel
American Heart Association (20SFRN35120123)
- E Dale Abel
American Heart Association (15SDG25710438)
- Renata O Pereira
National Institutes of Health (DK125405)
- Renata O Pereira
National Institutes of Health (T32DK112751)
- Sarah Hartwick Bjorkman
National Institutes of Health (1R25GM116686)
- Luis Miguel García-Peña
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#8051408 and 0032294) of the University of Iowa.
Reviewing Editor
- Joel K Elmquist, University of Texas Southwestern Medical Center, United States
Version history
- Received: January 13, 2021
- Accepted: May 2, 2021
- Accepted Manuscript published: May 4, 2021 (version 1)
- Version of Record published: May 17, 2021 (version 2)
Copyright
© 2021, Pereira et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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OPA1 deletion in brown adipose tissue Improves thermoregulation and systemic metabolism via FGF21
eLife 10:e66519.
https://doi.org/10.7554/eLife.66519
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