Journal article
ATF4 Deletion in Brown Adipocytes Attenuates Diet-Induced Insulin Resistance in Male Mice Independently of Weight Gain
Endocrinology (Philadelphia), Vol.166(8), bqaf101
06/10/2025
DOI: 10.1210/endocr/bqaf101
PMCID: PMC12641530
PMID: 40458050
Abstract
Expression of the activating transcription factor 4 (ATF4) in thermogenic adipocytes is required to maintain core body temperature and systemic metabolic homeostasis in models of mitochondrial stress. We have recently shown that ATF4 is required for thermoregulation in response to cold stress in mice, establishing a role for ATF4 in regulating BAT function during physiological stress. In the present study, we investigated the role of ATF4 in thermogenic adipocytes in regulating glucose metabolism and energy homeostasis during diet-induced obesity (DIO). To this end, we generated mice with selective Atf4 deletion in brown adipose tissue (ATF4 BKO). After 12 weeks of high-fat-feeding, ATF4 BKO mice had similar weight gain and total fat mass relative to WT mice. Accordingly, no changes in food intake, locomotor activity or energy expenditure were detected between genotypes. Nonetheless, diet-induced glucose intolerance and insulin resistance were attenuated in ATF4 BKO mice, which correlated with reduced markers of inflammation and increased levels of glucose transporters in BAT. Taken together, our results indicate that Atf4 deficiency in BAT during DIO improves glucose homeostasis and insulin sensitivity in mice without affecting energy homeostasis. Mechanistically, our data suggest ATF4 deletion leads to repressed inflammation in BAT of obese mice, while likely increasing glucose uptake and utilization, thereby contributing to overall improvement in glucose homeostasis.
Details
- Title: Subtitle
- ATF4 Deletion in Brown Adipocytes Attenuates Diet-Induced Insulin Resistance in Male Mice Independently of Weight Gain
- Creators
- Alex Marti - University of IowaSarah H Bjorkman - University of IowaLuis Miguel García-Peña - University of Iowa Health CareEric T Weatherford - University of IowaJayashree Jena - University of IowaRenata O Pereira - University of Iowa Health Care
- Resource Type
- Journal article
- Publication Details
- Endocrinology (Philadelphia), Vol.166(8), bqaf101
- DOI
- 10.1210/endocr/bqaf101
- PMID
- 40458050
- PMCID
- PMC12641530
- NLM abbreviation
- Endocrinology
- ISSN
- 1945-7170
- eISSN
- 1945-7170
- Publisher
- Oxford University Press
- Grant note
- American Heart Association: 15SDG25710438 National Institutes of Health: DK125405, T32DK112751-01, 1R25GM116686
This work was supported by the American Heart Association grant 15SDG25710438 and the National Institutes of Health grant DK125405 to R.O.P., the National Institutes of Health grant T32DK112751-01 to S.H.B. and to J.J., and the National Institutes of Health grant 1R25GM116686 to L.M.G.P. Metabolic phenotyping was performed at the Metabolic Phenotyping Core at the Fraternal Order of Eagles Diabetes Research Center. Analysis of mRNA expression by qPCR and RNA sequencing were performed at the Genomics Division at the Iowa Institute of Human Genetics.
- Language
- English
- Electronic publication date
- 06/03/2025
- Date published
- 06/10/2025
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984827332102771
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