A High-Fat Diet Elicits Differential Responses in Genes Coordinating Oxidative Metabolism in Skeletal Muscle of Lean and Obese Individuals

Boyle, Kristen E.; Canham, J. P.; Consitt, Leslie A.; Zheng, Donghai; Koves, Timothy R.; Gavin, Timothy P.; Holbert, Donald; Neufer, P. Darrell; Muoio, Deborah M.; Houmard, Joseph A.

doi:10.1210/jc.2010-2253

Cited by 64 publications

(71 citation statements)

References 31 publications

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“…In addition, previous studies demonstrated that HFD increases fat oxidation in lean subjects (8,26, 33, 34) but not in obese or previously obese subjects (2,40). Furthermore, a 5-day HFD increased the expression levels in skeletal muscle of genes related to fatty acid oxidation in lean healthy subjects but not in obese subjects (7). These data suggest that changes in gene expression in response to HFD are important for the adaptation of skeletal muscle to HFD and that these changes may be associated with the interindividual variability of HFD on IMCL and insulin sensitivity.…”

mentioning

confidence: 87%

“…They found that skeletal muscle gene expression levels of important regulators for fat oxidation, namely, PPAR␣ and PGC-1␣, were lower in both the most insulin-sensitive group and the most insulinresistant group compared with the middle two quartiles. In addition, previous studies had demonstrated that HFD enhances fat oxidation (8,26,33,34) and the expression of genes related to fat oxidation in skeletal muscle (7) in lean subjects, but not in obese or previously obese subjects (2,7,40).…”

Section: E37 Imcl and Gene Expression In Muscle After High-fat Dietmentioning

confidence: 99%

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Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet

Kakehi

Tamura

Takeno

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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. Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet. Am J Physiol Endocrinol Metab 310: E32-E40, 2016. First published October 20, 2015 doi:10.1152/ajpendo.00220.2015.-The accumulation of intramyocellular lipid (IMCL) is recognized as an important determinant of insulin resistance, and is increased by a high-fat diet (HFD). However, the effects of HFD on IMCL and insulin sensitivity are highly variable. The aim of this study was to identify the genes in muscle that are related to this inter-individual variation. Fifty healthy men were recruited for this study. Before and after HFD for 3 days, IMCL levels in the tibialis anterior were measured by 1 H magnetic resonance spectroscopy, and peripheral insulin sensitivity was evaluated by glucose infusion rate (GIR) during the euglycemic-hyperinsulinemic clamp. Subjects who showed a large increase in IMCL and a large decrease in GIR by HFD were classified as high responders (HRs), and subjects who showed a small increase in IMCL and a small decrease in GIR were classified as low responders (LRs). In five subjects from each group, the gene expression profile of the vastus lateralis muscle was analyzed by DNA microarray analysis. Before HFD, gene expression profiles related to lipid metabolism were comparable between the two groups. Gene Set Enrichment Analysis demonstrated that five gene sets related to lipid metabolism were upregulated by HFD in the HR group but not in the LR group. Changes in gene expression patterns were confirmed by qRT-PCR using more samples (LR, n ϭ 9; HR, n ϭ 11). These results suggest that IMCL accumulation/impaired insulin sensitivity after HFD is closely associated with changes in the expression of genes related to lipid metabolism in muscle. intramyocellular lipid; insulin sensitivity; high-fat diet

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mentioning

confidence: 87%

Section: E37 Imcl and Gene Expression In Muscle After High-fat Dietmentioning

confidence: 99%

Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet

Kakehi

Tamura

Takeno

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…Amino acid changes are thought to be largely due to anaplerosis, or the use of amino acid oxidative catabolism to replenish tricarboxylic acid cycle (TCA cycle) intermediates in the setting of incomplete β-oxidation (12)(13)(14)(15)(16). In myocytes from OB adults, there is reduced fatty acid oxidation, leading to elevations in long-and medium-chain acylcarnitines and anaplerosis, and decreased oxidative phosphorylation, indicating abnormalities in key energy pathways (13,(17)(18)(19). Similarly, in adipocytes from OB adults, there is decreased fatty acid oxidation, increased lipogenesis, and spared amino acid catabolism (13,20,21).…”

Section: Introductionmentioning

confidence: 99%

Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism

et al. 2017

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“…Mitochondria are the powerhouse of the cell, coupling the majority of energy derived from fuel substrates to ATP turnover and uncoupling less in the form of heat. In humans and rodents with obesity and related type 2 diabetes, fuel overload in the mitochondrial respiratory system and impaired mitochondrial oxidative capacity have been observed in energy-using organs and energy storage organs, such as skeletal muscle (SKM) [5][6][7] and white adipose tissue (WAT) [8,9]. Increasing cellular energy expenditure (EE) by decreasing mitochondrial coupling efficiency has been proposed to be an appealing therapeutic alternative [10,11].…”

Section: Introductionmentioning

confidence: 99%

A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake

Zhang

Turner

et al. 2013

Diabetologia

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Aims/hypothesis Decreasing mitochondrial coupling efficiency has been shown to be an effective therapy for obesity and related metabolic symptoms. Here we identified a novel mitochondrial uncoupler that promoted uncoupled respiration in a cell type-specific manner and investigated its effects on modulation of energy metabolism in vivo and in vitro. Methods We screened a collection of mitochondrial membrane potential depolarising compounds for a novel chemical uncoupler on isolated skeletal muscle mitochondria using a channel oxygen system. The effect on respiration of metabolic cells (L6 myotubes, 3T3-L1 adipocytes and rat primary hepatocytes) was examined and metabolic pathways sensitive to cellular ATP content were also evaluated. The chronic metabolic effects were investigated in high-fat diet-induced obese mice and standard diet-fed (SD) lean mice.Results The novel uncoupler, CZ5, promoted uncoupled respiration in a cell type-specific manner. It stimulated fuel oxidation in L6 myotubes and reduced lipid accumulation in 3T3-L1 adipocytes but did not affect gluconeogenesis or the triacylglycerol content in hepatocytes. The administration of CZ5 to SD mice increased energy expenditure (EE) but did not affect body weight or adiposity. Chronic studies in mice on high-fat diet showed that CZ5 reduced body weight and improved glucose and lipid metabolism via both increased EE and suppressed energy intake. The reduced adiposity was associated with the restoration of expression of key metabolic genes in visceral adipose tissue. Conclusions/interpretation This work demonstrates that a cell type-specific mitochondrial chemical uncoupler may have therapeutic potential for treating high-fat diet-induced metabolic diseases.

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A High-Fat Diet Elicits Differential Responses in Genes Coordinating Oxidative Metabolism in Skeletal Muscle of Lean and Obese Individuals

Abstract: These findings indicate a differential response to a lipid stimulus in the skeletal muscle of lean and insulin resistant obese humans.

Cited by 64 publications

References 31 publications

Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet

Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet

Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism

A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake

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