Abstract
199-LB: ATF4 Deletion in Brown Adipose Tissue Impairs Adaptive Thermogenesis but Attenuates Diet-Induced Insulin Resistance
Diabetes (New York, N.Y.), Vol.70(Supplement 1), p.199
06/2021
DOI: 10.2337/db21-199-LB
Abstract
Short-term cold exposure induces the integrated stress response (ISR) and its main effector, the activating transcription factor 4 (ATF4), in brown adipose tissue (BAT). Furthermore, induction of ATF4 in BAT in response to mitochondrial stress is required for systemic metabolic adaptations mediated by BATokine secretion. To test the hypothesis that ATF4 in BAT is required for cold-induced thermogenesis and to promote BATokine secretion, we selectively deleted ATF4 in BAT by crossing Atf4 floxed mice with mice harboring the Cre recombinase under the control of the Ucp1 promoter (ATF4 BAT KO). KO mice experienced a significant reduction in core body temperature after 3 days of cold exposure relative to wild type (WT) mice. Impaired thermogenesis correlated with reduced BAT mass, and decreased UCP1 and tyrosine hydroxylase protein levels. In addition, KO mice had impaired cold-induced browning of white adipose tissue (WAT) and reduced expression of fibroblast growth factor 21 (Fgf21) and growth and differentiation factor 15 (Gdf15), BATokines shown to be induced in response to BAT thermogenic activation. Surprisingly, although KO mice had equivalent weight gain and fat mass relative to WT mice after 12 weeks of high-fat feeding, glucose and insulin intolerance were ameliorated, and fasting insulin levels were significantly reduced, indicating increased insulin sensitivity. Improved glucose clearance correlated with increased levels of glucose transporters 1 and 4 (GLUT1 and GLUT4) in BAT, but not in WAT or skeletal muscle. Taken together, our data indicate that Atf4 expression is required for full thermogenic activation of BAT and to regulate FGF21 and GDF15 release as BATokines, likely coordinating BAT thermogenesis with systemic adaptations. Finally, our data suggest that in diet-induced obesity, ATF4 downregulation may increase glucose utilization in BAT, contributing to improved glucose homeostasis and insulin sensitivity.
Details
- Title: Subtitle
- 199-LB: ATF4 Deletion in Brown Adipose Tissue Impairs Adaptive Thermogenesis but Attenuates Diet-Induced Insulin Resistance
- Creators
- SARAH BJORKMANALEX A MARTIERIC T WEATHERFORDLUIS M GARCÍA-PEÑAMATTHEW J POTTHOFFEVAN D ABELRENATA PEREIRA
- Resource Type
- Abstract
- Publication Details
- Diabetes (New York, N.Y.), Vol.70(Supplement 1), p.199
- DOI
- 10.2337/db21-199-LB
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Language
- English
- Date published
- 06/2021
- Academic Unit
- Biochemistry and Molecular Biology; Neuroscience and Pharmacology; Endocrinology and Metabolism; Internal Medicine; Iowa Neuroscience Institute; Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984094983302771
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