Opa1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via fgf21

Renata O. Pereira; Alex Marti; Angela Crystal Olvera; Satya Murthy Tadinada; Sarah Hartwick Bjorkman; Eric Thomas Weatherford; Donald A. Morgan; Michael Westphal; Pooja H. Patel; Ana Karina Kirby; Rana Hewezi; William Bùi Trân; Luis Miguel García-Peña; Rhonda A. Souvenir; Monika Mittal; Christopher M. Adams; Kamal Rahmouni; Matthew J. Potthoff; E. Dale Abel

doi:10.7554/eLife.66519

Opa1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via fgf21

Renata O. Pereira, Alex Marti, Angela Crystal Olvera, Satya Murthy Tadinada, Sarah Hartwick Bjorkman, Eric Thomas Weatherford, Donald A. Morgan, Michael Westphal, Pooja H. Patel, Ana Karina Kirby, Rana Hewezi, William Bùi Trân, Luis Miguel García-Peña, Rhonda A. Souvenir, Monika Mittal, Christopher M. Adams, Kamal Rahmouni, Matthew J. Potthoff, E. Dale Abel

Endocrinology, Diabetes, Metabolism, and Nutrition

Research output: Contribution to journal › Article › peer-review

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, which is activated independently of BAT thermogenic function.

Original language	English (US)
Article number	e66519
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.66519
State	Published - May 2021

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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Pereira, R. O., Marti, A., Olvera, A. C., Tadinada, S. M., Bjorkman, S. H., Weatherford, E. T., Morgan, D. A., Westphal, M., Patel, P. H., Kirby, A. K., Hewezi, R., Trân, W. B., García-Peña, L. M., Souvenir, R. A., Mittal, M., Adams, C. M., Rahmouni, K., Potthoff, M. J., & Abel, E. D. (2021). Opa1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via fgf21. eLife, 10, Article e66519. https://doi.org/10.7554/eLife.66519

Pereira, RO, Marti, A, Olvera, AC, Tadinada, SM, Bjorkman, SH, Weatherford, ET, Morgan, DA, Westphal, M, Patel, PH, Kirby, AK, Hewezi, R, Trân, WB, García-Peña, LM, Souvenir, RA, Mittal, M, Adams, CM, Rahmouni, K, Potthoff, MJ & Abel, ED 2021, 'Opa1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via fgf21', eLife, vol. 10, e66519. https://doi.org/10.7554/eLife.66519

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title = "Opa1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via fgf21",

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, which is activated independently of BAT thermogenic function.",

author = "Pereira, {Renata O.} and Alex Marti and Olvera, {Angela Crystal} and Tadinada, {Satya Murthy} and Bjorkman, {Sarah Hartwick} and Weatherford, {Eric Thomas} and Morgan, {Donald A.} and Michael Westphal and Patel, {Pooja H.} and Kirby, {Ana Karina} and Rana Hewezi and Tr{\^a}n, {William B{\`u}i} and Garc{\'i}a-Pe{\~n}a, {Luis Miguel} and Souvenir, {Rhonda A.} and Monika Mittal and Adams, {Christopher M.} and Kamal Rahmouni and Potthoff, {Matthew J.} and Abel, {E. Dale}",

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year = "2021",

month = may,

doi = "10.7554/eLife.66519",

language = "English (US)",

volume = "10",

journal = "eLife",

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T1 - Opa1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via fgf21

AU - Pereira, Renata O.

AU - Marti, Alex

AU - Olvera, Angela Crystal

AU - Tadinada, Satya Murthy

AU - Bjorkman, Sarah Hartwick

AU - Weatherford, Eric Thomas

AU - Morgan, Donald A.

AU - Westphal, Michael

AU - Patel, Pooja H.

AU - Kirby, Ana Karina

AU - Hewezi, Rana

AU - Trân, William Bùi

AU - García-Peña, Luis Miguel

AU - Souvenir, Rhonda A.

AU - Mittal, Monika

AU - Adams, Christopher M.

AU - Rahmouni, Kamal

AU - Potthoff, Matthew J.

AU - Abel, E. Dale

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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.

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Opa1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via fgf21

Abstract

ASJC Scopus subject areas

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