OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21.
Adipocytes, Brown
/ physiology
Adipose Tissue, Brown
/ metabolism
Adipose Tissue, White
/ physiology
Animals
Body Temperature Regulation
/ genetics
Female
Fibroblast Growth Factors
/ genetics
GTP Phosphohydrolases
/ genetics
Gene Deletion
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Obesity
/ genetics
activating transcription factor 4
biochemistry
brown adipose tissue
browning
chemical biology
fibroblast growth factor 21
mouse
optic atrophy 1
thermogenesis
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
04 05 2021
04 05 2021
Historique:
received:
13
01
2021
accepted:
02
05
2021
pubmed:
5
5
2021
medline:
8
1
2022
entrez:
4
5
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33944779
doi: 10.7554/eLife.66519
pii: 66519
pmc: PMC8128440
doi:
pii:
Substances chimiques
fibroblast growth factor 21
0
Fibroblast Growth Factors
62031-54-3
GTP Phosphohydrolases
EC 3.6.1.-
Opa1 protein, mouse
EC 3.6.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : BLRD VA
ID : I01 BX000976
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007344
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127764
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG060637
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK112751
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM116686
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK054759
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL112413
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK091317
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125405
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR071762
Pays : United States
Informations de copyright
© 2021, Pereira et al.
Déclaration de conflit d'intérêts
RP, AM, AO, ST, SB, EW, DM, MW, PP, AK, RH, WB, LG, RS, MM, CA, KR, MP, EA No competing interests declared
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