GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes

Jayashree Jena; Luis Miguel García-Peña; Eric T Weatherford; Alex Marti; Sarah H Bjorkman; Kevin Kato; Jivan Koneru; Jason H Chen; Randy J Seeley; E Dale Abel; Renata O Pereira

doi:10.7554/eLife.86452

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GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes

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GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes

Jayashree Jena, Luis Miguel García-Peña, Eric T Weatherford, Alex Marti, Sarah H Bjorkman, Kevin Kato, Jivan Koneru, Jason H Chen, Randy J Seeley, E Dale Abel, …

eLife, Vol.12, e86452

10/11/2023

DOI: 10.7554/eLife.86452

PMCID: PMC10567111

PMID: 37819027

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Abstract

We previously reported that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) display induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates under baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice (Pereira et al., 2021). To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15), along with increased protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) levels in BAT. To investigate whether ATF4 induction was mediated by PERK and evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice with reduced OPA1 and PERK levels in BAT had preserved ISR activation. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to DIO and abrogated the improvements in glucose tolerance. Furthermore, GDF15 was required to improve cold-induced thermogenesis in OPA1 BKO mice. Taken together, our data indicate that PERK is dispensable to induce the ISR, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice by increasing energy expenditure.

Biochemistry and Chemical Biology

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Title: Subtitle: GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes
Creators: Jayashree Jena - Fraternal Order of Eagles
Luis Miguel García-Peña - Fraternal Order of Eagles
Eric T Weatherford - Fraternal Order of Eagles
Alex Marti - Fraternal Order of Eagles
Sarah H Bjorkman - Fraternal Order of Eagles
Kevin Kato - Fraternal Order of Eagles
Jivan Koneru - Fraternal Order of Eagles
Jason H Chen - Fraternal Order of Eagles
Randy J Seeley - University of Michigan
E Dale Abel - Fraternal Order of Eagles
Renata O Pereira - Fraternal Order of Eagles
Resource Type: Journal article
Publication Details: eLife, Vol.12, e86452
DOI: 10.7554/eLife.86452
PMID: 37819027
PMCID: PMC10567111
NLM abbreviation: Elife
ISSN: 2050-084X
eISSN: 2050-084X
Publisher: eLife Sciences Publications, Ltd
Grant note: DK125405 / ; 15SDG25710438 / ; 1R25GM116686 / ; T32DK112751 / ;
Language: English
Date published: 10/11/2023
Academic Unit: Orthopedics and Rehabilitation; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984474909802771

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