The DOI matches its Crossref record; 86 of the 86 references it cites were found in a registry or an index.
Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance
Open accessAbstract
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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“To this end, muscle-specific overexpression of Dgat1 as well as an acute bout of exercise (which increases mitochondrial GPAT and DGAT1 abundance) prevents HFD-and lipid-induced impairments in insulin action in conjunction with increased IMTG synthesis and decreased DAG and ceramide accumulation as well as reduced activation of nPKC/cPKC, JNK, and/or”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [53]
Experimental — accuracy not yet measuredIn the citing paper
“In these mice, increased DGAT activity in muscle resulted in higher IMTG levels, decreased DAG and ceramide levels, and resistance to diet-induced glucose intolerance.”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [54]
In the citing paper
“In these mice, increased DGAT activity in muscle resulted in higher IMTG levels, decreased DAG and ceramide levels, and resistance to diet-induced glucose intolerance.”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [54]
In the citing paper
“In these mice, increased DGAT activity in muscle resulted in higher IMTG levels, decreased DAG and ceramide levels, and resistance to diet-induced glucose intolerance.”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [54]
In the citing paper
“The concentration of IMTG, fatty acyl-CoAs, DAG, and/or ceramide are elevated in skeletal muscle from obese humans, genetically obese rats, and HFD-fed, obese mice in association with insulin resistance (53)(54)(55)(56)(57).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [53]
In the citing paper
“Mice overexpressing DGAT1 in skeletal muscles (MCK-DGAT1)61 accumulate tri glycerides in their muscles, but are protected from fat-induced muscle insulin resistance.”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [61]
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Citations
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Cited by
Sorted by citations
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611
Mechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294
Lipid Droplets and Cellular Lipid Metabolism
Walther, T. C., & Farese, R. V. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061009-102430 · Cited by 1,701
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Metadata
- 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
- Venue
- Journal of Clinical Investigation
- Published
- 2007-06-01
- Volume
- 117
- Issue
- 6
- Pages
- 1679-1689
- ISSN
- 0021-9738 (ISSN-L)
- 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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