Cited by 356Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismLipid metabolism and biosynthesis

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Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance

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Liu, Li, Zhang, Yiying, Chen, Nancy, Shi, Xiaojing, Tsang, Bonny, Yu, Yi-Hao·2007·Journal of Clinical Investigation

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Abstract

Increased fat deposition in skeletal muscle is associated with insulin resistance. However, exercise increases both intramyocellular fat stores and insulin sensitivity, a phenomenon referred to as "the athlete's paradox". In this study, we provide evidence that augmenting triglyceride synthesis in skeletal muscle is intrinsically connected with increased insulin sensitivity. Exercise increased diacylglycerol (DAG) acyltransferase (DGAT) activity in skeletal muscle. Channeling fatty acid substrates into TG resulted in decreased DAG and ceramide levels. Transgenic overexpression of DGAT1 in mouse skeletal muscle replicated these findings and protected mice against high-fat diet-induced insulin resistance. Moreover, in isolated muscle, DGAT1 deficiency exacerbated insulin resistance caused by fatty acids, whereas DGAT1 overexpression mitigated the detrimental effect of fatty acids. The heightened insulin sensitivity in the transgenic mice was associated with attenuated fat-induced activation of DAG-responsive PKCs and the stress mediator JNK1. Consistent with these changes, serine phosphorylation of insulin receptor substrate 1 was reduced, and Akt activation and glucose 4 membrane translocation were increased. In conclusion, upregulation of DGAT1 in skeletal muscle is sufficient to recreate the athlete's paradox and illustrates a mechanism of exercise-induced enhancement of muscle insulin sensitivity. Thus, increasing muscle DGAT activity may offer a new approach to prevent and treat insulin resistance and type 2 diabetes mellitus.

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See all 356

Authors: Liu, L., Zhang, Y., Chen, N., Shi, X., Tsang, B., & Yu, Y.-H.
Affiliations: Columbia University (US)
Columbia University Irving Medical Center (US)
Corresponding author: Yu, Yi-Hao
ORCID: Liu, Li
Zhang, Yiying
Chen, Nancy
Shi, Xiaojing
Yu, Yi-Hao
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2007-06-01
Volume: 117
Issue: 6
Pages: 1679-1689
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci30565
PMC: PMC1866250
OpenAlex: W2142416266
Cited by: 356
References: 84
Citations by year: 2026: 3 · 2025: 5 · 2024: 6 · 2023: 14 · 2022: 9 · 2021: 9 · 2020: 19 · 2019: 8 · 2018: 13 · 2017: 16 · 2016: 19 · 2015: 18 · 2014: 27 · 2013: 31 · 2012: 33
FWCI: 12.44
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (HL073029, R01HL073029)
National Institute of Diabetes and Digestive and Kidney Diseases (DK-60530, DK063034, R01DK063034, K08DK060530, DK071866, R03DK071866)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords: DGAT1, diacylglycerol acyltransferase, triglyceride synthesis, skeletal muscle, insulin resistance, physical activity, ceramide, diacylglycerol, protein kinase C, JNK1, IRS-1, Akt signaling, glucose uptake, type 2 diabetes, high-fat diet
MeSH terms: Animals, Base Sequence, Diabetes Mellitus, Type 2, Dietary Fats, Physical Exertion, Humans, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Transgenic, Triglycerides, Up-Regulation, DNA Primers, Mice, Knockout, Muscle, Skeletal, Diacylglycerol O-Acyltransferase, Mice

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Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance

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