FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes

Joshua Peterson; Jayashree Jena; Ayushi Sood; Shelly Roitershtein; David Smith; Renata O Pereira

doi:10.1002/oby.70004

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FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes

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FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes

Joshua Peterson, Jayashree Jena, Ayushi Sood, Shelly Roitershtein, David Smith and Renata O Pereira

Obesity (Silver Spring, Md.), Vol.33(10), pp.1909-1920

10/2025

DOI: 10.1002/oby.70004

PMCID: PMC12477105

PMID: 40897647

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Abstract

Our previous studies showed that mice lacking the mitochondrial fusion protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have high metabolic rates and are resistant to diet-induced obesity (DIO) via effects partially mediated by independent actions of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) secretion from BAT. We examined whether FGF21 and GDF15 act synergistically, contributing to the systemic metabolic adaptations reported in OPA1 BKO mice. We generated mice simultaneously lacking the Opa1, Fgf21, and Gdf15 genes in thermogenic adipocytes (TKO) and assessed energy homeostasis and glucose metabolism after regular chow or high-fat diet feeding. Young TKO mice fed regular chow had impaired glucose tolerance, while insulin sensitivity was unchanged. Notably, combined Fgf21 and Gdf15 deletion in OPA1 BKO significantly blunted the resistance to DIO and insulin resistance observed in OPA1 BKO mice. FGF21 and GDF15 act synergistically to maintain glucose homeostasis and promote resistance to DIO in mice lacking OPA1 in BAT, highlighting the potential of combined therapies using FGF21 and GDF15 for the treatment of metabolic disorders.

Obesity

Brown Adipose Tissue

GDF15

Mitochondrial Stress

FGF21

UIOWA OA Agreement

Details

Title: Subtitle: FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes
Creators: Joshua Peterson - University of Iowa
Jayashree Jena - University of Iowa, Internal Medicine
Ayushi Sood - University of Iowa, Internal Medicine
Shelly Roitershtein - University of Iowa, Internal Medicine
David Smith - University of Iowa, Internal Medicine
Renata O Pereira - University of Iowa, Endocrinology and Metabolism
Resource Type: Journal article
Publication Details: Obesity (Silver Spring, Md.), Vol.33(10), pp.1909-1920
DOI: 10.1002/oby.70004
PMID: 40897647
PMCID: PMC12477105
NLM abbreviation: Obesity (Silver Spring)
ISSN: 1930-7381
eISSN: 1930-739X
Publisher: Wiley
Grant note: 15SDG25710438 / American Heart Association 25PRE1361334 / American Heart Association 25POST1377539 / American Heart Association NIH DK125405 / NIDDK NIH HHS T32DK112751-01 / NIDDK NIH HHS
Language: English
Electronic publication date: 09/02/2025
Date published: 10/2025
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984963937602771

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