Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1

Li Liu, Xiaojing Shi, Soo Choi Cheol, Gerald I. Shulman, Katherine Klaus, K. Sreekumaran Nair, Gary J. Schwartz, Yiying Zhang, Ira J. Goldberg, Yi Hao Yu

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE - Transgenic expression of diacylglycerol acyltransferase-1 (DGAT1) in skeletal muscle leads to protection against fat-induced insulin resistance despite accumulation of intramuscular triglyceride, a phenomenon similar to what is known as the "athlete paradox." The primary objective of this study is to determine how DGAT1 affects muscle fatty acid oxidation in relation to whole-body energy metabolism and insulin sensitivity. RESEARCH DESIGN AND METHODS - We first quantified insulin sensitivity and the relative tissue contributions to the improved whole-body insulin sensitivity in muscle creatine kisase (MCK)-DGAT1 transgenic mice by hyperinsulinemic- euglycemic clamps. Metabolic consequences of DGAT1 overexpression in skeletal muscles were determined by quantifying triglyceride synthesis/storage (anabolic) and fatty acid oxidation (catabolic), in conjunction with gene expression levels of representative marker genes in fatty acid metabolism. Whole-body energy metabolism including food consumption, body weights, oxygen consumption, locomotor activity, and respiration exchange ratios were determined at steady states. RESULTS - MCK-DGAT1 mice were protected against muscle lipoptoxicity, although they remain susceptible to hepatic lipotoxicity. While augmenting triglyceride synthesis, DGAT1 overexpression also led to increased muscle mitochondrial fatty acid oxidation efficiency, as compared with wild-type muscles. On a high-fat diet, MCK-DGAT1 mice displayed higher basal metabolic rates and 5-10% lower body weights compared with wild-type littermates, whereas food consumption was not different. CONCLUSIONS - DGAT1 overexpression in skeletal muscle led to parallel increases in triglyceride synthesis and fatty acid oxidation. Seemingly paradoxical, this phenomenon is characteristic of insulin-sensitive myofibers and suggests that DGAT1 plays an active role in metabolic "remodeling" of skeletal muscle coupled with insulin sensitization.

Original languageEnglish (US)
Pages (from-to)2516-2524
Number of pages9
JournalDiabetes
Volume58
Issue number11
DOIs
StatePublished - Nov 2009

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Diacylglycerol O-Acyltransferase
Skeletal Muscle
Triglycerides
Fatty Acids
Muscles
Insulin Resistance
Creatine
Energy Metabolism
Body Weight
Insulin
Basal Metabolism
Food
Glucose Clamp Technique
High Fat Diet
Locomotion
Oxygen Consumption
Athletes
Transgenic Mice
Respiration
Research Design

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Liu, L., Shi, X., Cheol, S. C., Shulman, G. I., Klaus, K., Nair, K. S., ... Yu, Y. H. (2009). Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1. Diabetes, 58(11), 2516-2524. https://doi.org/10.2337/db08-1096

Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1. / Liu, Li; Shi, Xiaojing; Cheol, Soo Choi; Shulman, Gerald I.; Klaus, Katherine; Nair, K. Sreekumaran; Schwartz, Gary J.; Zhang, Yiying; Goldberg, Ira J.; Yu, Yi Hao.

In: Diabetes, Vol. 58, No. 11, 11.2009, p. 2516-2524.

Research output: Contribution to journalArticle

Liu, L, Shi, X, Cheol, SC, Shulman, GI, Klaus, K, Nair, KS, Schwartz, GJ, Zhang, Y, Goldberg, IJ & Yu, YH 2009, 'Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1', Diabetes, vol. 58, no. 11, pp. 2516-2524. https://doi.org/10.2337/db08-1096
Liu, Li ; Shi, Xiaojing ; Cheol, Soo Choi ; Shulman, Gerald I. ; Klaus, Katherine ; Nair, K. Sreekumaran ; Schwartz, Gary J. ; Zhang, Yiying ; Goldberg, Ira J. ; Yu, Yi Hao. / Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1. In: Diabetes. 2009 ; Vol. 58, No. 11. pp. 2516-2524.
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abstract = "OBJECTIVE - Transgenic expression of diacylglycerol acyltransferase-1 (DGAT1) in skeletal muscle leads to protection against fat-induced insulin resistance despite accumulation of intramuscular triglyceride, a phenomenon similar to what is known as the {"}athlete paradox.{"} The primary objective of this study is to determine how DGAT1 affects muscle fatty acid oxidation in relation to whole-body energy metabolism and insulin sensitivity. RESEARCH DESIGN AND METHODS - We first quantified insulin sensitivity and the relative tissue contributions to the improved whole-body insulin sensitivity in muscle creatine kisase (MCK)-DGAT1 transgenic mice by hyperinsulinemic- euglycemic clamps. Metabolic consequences of DGAT1 overexpression in skeletal muscles were determined by quantifying triglyceride synthesis/storage (anabolic) and fatty acid oxidation (catabolic), in conjunction with gene expression levels of representative marker genes in fatty acid metabolism. Whole-body energy metabolism including food consumption, body weights, oxygen consumption, locomotor activity, and respiration exchange ratios were determined at steady states. RESULTS - MCK-DGAT1 mice were protected against muscle lipoptoxicity, although they remain susceptible to hepatic lipotoxicity. While augmenting triglyceride synthesis, DGAT1 overexpression also led to increased muscle mitochondrial fatty acid oxidation efficiency, as compared with wild-type muscles. On a high-fat diet, MCK-DGAT1 mice displayed higher basal metabolic rates and 5-10{\%} lower body weights compared with wild-type littermates, whereas food consumption was not different. CONCLUSIONS - DGAT1 overexpression in skeletal muscle led to parallel increases in triglyceride synthesis and fatty acid oxidation. Seemingly paradoxical, this phenomenon is characteristic of insulin-sensitive myofibers and suggests that DGAT1 plays an active role in metabolic {"}remodeling{"} of skeletal muscle coupled with insulin sensitization.",
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AU - Nair, K. Sreekumaran

AU - Schwartz, Gary J.

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AB - OBJECTIVE - Transgenic expression of diacylglycerol acyltransferase-1 (DGAT1) in skeletal muscle leads to protection against fat-induced insulin resistance despite accumulation of intramuscular triglyceride, a phenomenon similar to what is known as the "athlete paradox." The primary objective of this study is to determine how DGAT1 affects muscle fatty acid oxidation in relation to whole-body energy metabolism and insulin sensitivity. RESEARCH DESIGN AND METHODS - We first quantified insulin sensitivity and the relative tissue contributions to the improved whole-body insulin sensitivity in muscle creatine kisase (MCK)-DGAT1 transgenic mice by hyperinsulinemic- euglycemic clamps. Metabolic consequences of DGAT1 overexpression in skeletal muscles were determined by quantifying triglyceride synthesis/storage (anabolic) and fatty acid oxidation (catabolic), in conjunction with gene expression levels of representative marker genes in fatty acid metabolism. Whole-body energy metabolism including food consumption, body weights, oxygen consumption, locomotor activity, and respiration exchange ratios were determined at steady states. RESULTS - MCK-DGAT1 mice were protected against muscle lipoptoxicity, although they remain susceptible to hepatic lipotoxicity. While augmenting triglyceride synthesis, DGAT1 overexpression also led to increased muscle mitochondrial fatty acid oxidation efficiency, as compared with wild-type muscles. On a high-fat diet, MCK-DGAT1 mice displayed higher basal metabolic rates and 5-10% lower body weights compared with wild-type littermates, whereas food consumption was not different. CONCLUSIONS - DGAT1 overexpression in skeletal muscle led to parallel increases in triglyceride synthesis and fatty acid oxidation. Seemingly paradoxical, this phenomenon is characteristic of insulin-sensitive myofibers and suggests that DGAT1 plays an active role in metabolic "remodeling" of skeletal muscle coupled with insulin sensitization.

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