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

Abstract

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...

Role of stearoyl-CoA desaturase-1 in skeletal muscle function and metabolism

“…Our laboratory recently completed a project involving an SCD1 transgenic mouse model that overexpresses SCD1 specifically in skeletal muscle (SCD1 Tg) (66). When fed standard chow, results from this study showed that these animals had reduced levels of SFA in their muscle along with increased Review E771 SKELETAL MUSCLE SCD1 AND METABOLISM MUFA compared with control mice, as expected.…”

“…The increased mitochondrial content translated into an increased ability to oxidize 14 C-labeled stearic acid in ex vivo cultured skeletal muscle. SCD1 animals also demonstrated a very large increase in endurance exercise capacity, which may have been partially due to increased mitochondrial content and PPAR␦ expression (66). Evidence demonstrates that insulin resistance directly correlates with increased SFA within IMTG (43), whereas MUFA prevents insulin resistance initiated by SFA in skeletal muscle (11).…”

Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy

“…To clarify possible mechanisms of TG accumulation in the kidney, we examined the expression of enzymes that are key regulators of FA metabolism (SCD1) (19)(20)(21), increased uptake (CD36), and decreased expression of enzymes of fat ␤ -oxidation (ACO and CPT1). The expressions of PPAR ␣ and PPAR ␦ and their downstream enzymes ACO and CPT1 were decreased and correlated with the decline in eGFR ( Fig.…”

Insights into Stearoyl-CoA Desaturase-1 Regulation of Systemic Metabolism

“…Surprisingly, it was shown that increasing SCD1 activity through dietary factors or exercise could be protective against excessive weight gain and type 2 diabetes [47]. It was observed previously that overexpression of SCD1 inhibited inflammation and ER stress response subsequent to palmitate exposure [47].…”