Journal article
Loss of FoxOs in muscle reveals sex-based differences in insulin sensitivity but mitigates diet-induced obesity
Molecular metabolism (Germany), Vol.30, pp.203-220
12/2019
DOI: 10.1016/j.molmet.2019.10.001
PMCID: PMC6819874
PMID: 31767172
Abstract
Gender influences obesity-related complications, including diabetes. Females are more protected from insulin resistance after diet-induced obesity, which may be related to fat accumulation and muscle insulin sensitivity. FoxOs regulate muscle atrophy and are targets of insulin action, but their role in muscle insulin sensitivity and mitochondrial metabolism is unknown.
We measured muscle insulin signaling, mitochondrial energetics, and metabolic responses to a high-fat diet (HFD) in male and female muscle-specific FoxO1/3/4 triple knock-out (TKO) mice.
In male TKO muscle, insulin-stimulated AKT activation was decreased. AKT2 protein and mRNA levels were reduced and insulin receptor protein and IRS-2 mRNA decreased. These changes contributed to decreased insulin-stimulated glucose uptake in glycolytic muscle in males. In contrast, female TKOs maintain normal insulin-mediated AKT phosphorylation, normal AKT2 levels, and normal glucose uptake in glycolytic muscle. When challenged with a HFD, fat gain was attenuated in both male and female TKO mice, and associated with decreased glucose levels, improved glucose homeostasis, and reduced muscle triglyceride accumulation. Furthermore, female TKO mice showed increased energy expenditure, relative to controls, due to increased lean mass and maintenance of mitochondrial function in muscle.
FoxO deletion in muscle uncovers sexually dimorphic regulation of AKT2, which impairs insulin signaling in male mice, but not females. However, loss of FoxOs in muscle from both males and females also leads to muscle hypertrophy and increases in metabolic rate. These factors mitigate fat gain and attenuate metabolic abnormalities in response to a HFD.
Details
- Title: Subtitle
- Loss of FoxOs in muscle reveals sex-based differences in insulin sensitivity but mitigates diet-induced obesity
- Creators
- Christie M. Penniman - University of IowaPablo A. Suarez Beltran - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAGourav Bhardwaj - University of IowaTaylor L. Junck - Roy J. and Lucille A. Carver College of MedicineJayashree Jena - University of IowaKennedy Poro - Roy J. and Lucille A. Carver College of MedicineMichael F. Hirshman - Joslin Diabetes CenterLaurie J. Goodyear - Joslin Diabetes CenterBrian T. O'Neill - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
- Resource Type
- Journal article
- Publication Details
- Molecular metabolism (Germany), Vol.30, pp.203-220
- DOI
- 10.1016/j.molmet.2019.10.001
- PMID
- 31767172
- PMCID
- PMC6819874
- NLM abbreviation
- Mol Metab
- ISSN
- 2212-8778
- eISSN
- 2212-8778
- Publisher
- Elsevier GmbH
- Grant note
- DOI: 10.13039/100000002, name: NIH, award: K08DK100543, R03DK112003, R01DK101043; DOI: 10.13039/100007878, name: Joslin Diabetes Center DRC, award: P30 DK36836; DOI: 10.13039/100008893, name: University of Iowa core facility
- Language
- English
- Date published
- 12/2019
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359680102771
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