Regulation of Skeletal Muscle Physiology and Metabolism by Peroxisome Proliferator-Activated Receptor δ

Ehrenborg, Ewa; Krook, Anna

doi:10.1124/pr.109.001560

Cited by 198 publications

(207 citation statements)

References 201 publications

(282 reference statements)

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“…by guest, on May 10, 2018 www.jlr.org Downloaded from ( 40 ); ii ) it is known to be activated by several fatty acids ( 41,42 ); and iii ) overexpression of PPAR ␦ in muscle was shown to increase metabolic function and exercise capacity in mice (37)(38)(39). Therefore, we examined the effect of the three major fatty acid species identifi ed in Fig.…”

Section: Resultsmentioning

confidence: 99%

SCD1 activity in muscle increases triglyceride PUFA content, exercise capacity, and PPARΔ expression in mice

Rogowski

Flowers

Stamatikos

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.orgTo combat the rise in obesity and metabolic diseases, a large number of studies have attempted to defi ne the etiology of impaired glucose metabolism, dyslipidemia, and lipodystrophy ( 1-5 ). The results of these studies have generally shown that development of type 2 diabetes mellitus (T2DM) is dependent on a multitude of factors, including obesity due to overnutrition combined with physical inactivity; consumption of a high-fat/high-carbohydrate diet; and genetic predisposition ( 6-9 ). There have also been a number of studies designed to establish effective treatments and/or defi ne drug targets to prolong the prediabetic state or to reduce the severity of established T2DM in which a wide range of potential targets have been identifi ed. Despite the heterogeneity of causative factors leading to T2DM, there has been nearly unanimous agreement that impaired insulin signaling, increased intramuscular lipid deposition, and a loss of metabolic fl exibility in skeletal muscle is critical for development of the disease ( 10, 11 ).The current study was intended to defi ne the role of a key lipogenic enzyme, stearoyl-CoA desaturase-1 (SCD1), in regulating skeletal muscle lipid metabolism and how its overexpression can actually promote fat oxidation, exercise capacity, and glucose tolerance by increasing triglyceride synthesis. SCD1 is an integral membrane protein of the endoplasmic reticulum that catalyzes the desaturation of long-chain saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA). The enzyme is expressed in nearly all tissues of humans and mice where it converts primarily stearate (18:0) into oleate (18:1) and, to a lesser Abstract Stearoyl-CoA desaturase (SCD)1 converts saturated fatty acids into monounsaturated fatty acids. Using muscle overexpression, we sought to determine the role of SCD1 expression in glucose and lipid metabolism and its effects on exercise capacity in mice. Wild-type C57Bl/6 (WT) and SCD1 muscle transgenic (SCD1-Tg) mice were generated, and expression of the SCD1 transgene was restricted to skeletal muscle. SCD1 overexpression was associated with increased triglyceride (TG) content. The fatty acid composition of the muscle revealed a signifi cant increase in polyunsaturated fatty acid (PUFA) content of TG, including linoleate (18:2n6). Untrained SCD1-Tg mice also displayed significantly increased treadmill exercise capacity (WT = 6.6 ± 3 min, Tg = 71.9 ± 9.5 min; P = 0.0009). SCD1-Tg mice had decreased fasting plasma glucose, glucose transporter (GLUT )1 mRNA, fatty acid oxidation, mitochondrial content, and increased peroxisome proliferator-activated receptor (PPAR) ␦ and Pgc-1 protein expression in skeletal muscle. In vitro studies in C2C12 myocytes revealed that linoleate (18:2n6) and not oleate (18:1n9) caused a 3-fold increase in PPAR ␦ and a 9-fold increase in CPT-1b with a subsequent increase in fat oxidation. The present model suggests that increasing delta-9 desaturase activity of muscle increases metabolic f...

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Section: Resultsmentioning

confidence: 99%

SCD1 activity in muscle increases triglyceride PUFA content, exercise capacity, and PPARΔ expression in mice

Rogowski

Flowers

Stamatikos

et al. 2013

Journal of Lipid Research

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“…PPAR␣ and PPAR␤/␦ are members of a nuclear receptor family important for regulating both metabolism and inflammation (23,33,74,110). PPARs form heterodimers with retinoid X receptors (RXRs) and bind to specific DNA sites known as PPAR response elements (PPREs).…”

Section: Roles Of Specific Lipid Molecules As Ligands For Pparsmentioning

confidence: 99%

Skeletal muscle lipid flux: running water carries no poison

Funai

Semenkovich

2011

American Journal of Physiology-Endocrinology and Metabolism

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Lipids are the most abundant organic constituents in many humans. The rise in obesity prevalence has prompted a need for a more refined understanding of the effects of lipid molecules on cell physiology. In skeletal muscle, deposition of lipids can be associated with insulin resistance that contributes to the development of diabetes. Here, we review the evidence that muscle cells are equipped with the molecular machinery to convert and sequester lipid molecules, thus rendering them harmless. Induction of mitochondrial and lipogenic flux in the setting of elevated lipid deposition can protect muscle from lipid-induced “poisoning” of the cellular machinery. Lipid flux may also be directed toward the synthesis of ligands for nuclear receptors, further enhancing the capacity of muscle for lipid metabolism to promote favorable physiology. Exploiting these mechanisms may have implications for the treatment of obesity-related diseases.

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“…Skeletal muscle is the largest insulin-sensitive organ in humans, accounting for Ͼ80% of insulin-stimulated glucose disposal (15). Physical training leads to extensive adaptations in skeletal muscles (14,46), but the molecular mechanisms underlying these adaptations are still poorly understood, and there is increasing evidence that some individuals may be inherently less responsive to exercise (20,53).…”

mentioning

confidence: 99%

“…Plasticity of skeletal muscle in response to regular exercise extends beyond the metabolic changes, and peroxisome proliferator-activated receptor-␦ (PPAR␦) activation is one of many pathways proposed to be involved in exercise adaptations (15,35). PPAR␦ is an important regulator of skeletal muscle metabolism, in particular lipid oxidation.…”

mentioning

confidence: 99%

Myotubes from lean and severely obese subjects with and without type 2 diabetes respond differently to an in vitro model of exercise

Feng

Nikolić

Bakke

et al. 2015

American Journal of Physiology-Cell Physiology

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Regulation of Skeletal Muscle Physiology and Metabolism by Peroxisome Proliferator-Activated Receptor δ

Cited by 198 publications

References 201 publications

SCD1 activity in muscle increases triglyceride PUFA content, exercise capacity, and PPARΔ expression in mice

SCD1 activity in muscle increases triglyceride PUFA content, exercise capacity, and PPARΔ expression in mice

Skeletal muscle lipid flux: running water carries no poison

Myotubes from lean and severely obese subjects with and without type 2 diabetes respond differently to an in vitro model of exercise

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