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...

Objective: The role of lipocalin-2 (Lcn2) was determined in regulating metabolism in cell, animal, and human models. Design and Methods: Adipocytes were treated with recombinant lipocalin-2 (rLcn2) to determine the effect on lipid metabolism. rLcn2 was injected into mice to determine the effect on metabolism in vivo. To assess the relationship between Lcn2 and fat oxidation (FatOx) in humans, normal weight (NW) and obese (OB) women were given three separate high fat (HF) meals followed by indirect calorimetry. The relationship between postprandial Lcn2 with macronutrient metabolism and total energy expenditure (TEE) using Pearson correlations was determined. Results: Lcn2 increased expression of genes involved in b-oxidation including peroxisome proliferatoractivated receptor-d in adipocytes, as well as 3 H labeled oleate b-oxidation. Lcn2 injected into chow-fed mice directly increased TEE by 18% after the first dark cycle (232 6 1.4 cal vs. 341 6 1.4 cal; PBS vs. Lcn2) and remained significantly elevated by 10% after the second dark cycle (296 6 1.4 cal vs. 326 6 1.4 cal; PBS vs. Lcn2). Lcn2 was correlated with TEE in all three HF meal challenges in NW but not OB females. Conclusions: Lipocalin-2 is a novel adipokine that promotes FatOx and TEE and its function may be impaired in obesity.

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Heart failure due to chronic volume overload (VO) in rats and humans is characterized by disorganization of the cardiomyocyte desmin/mitochondrial network. Here, we tested the hypothesis that desmin breakdown is an early and continuous process throughout VO. Male Sprague-Dawley rats had aortocaval fistula (ACF) or sham surgery and were examined 24 h and 4 and 12 wk later. Desmin/mitochondrial ultrastructure was examined by transmission electron microscopy (TEM) and immunohistochemistry (IHC). Protein and kinome analysis were performed in isolated cardiomyocytes, and desmin cleavage was assessed by mass spectrometry in left ventricular (LV) tissue. Echocardiography demonstrated a 40% decrease in the LV mass-to-volume ratio with spherical remodeling at 4 wk with ACF and LV systolic dysfunction at 12 wk. Starting at 24 h and continuing to 4 and 12 wk, with ACF there is TEM evidence of extensive mitochondrial clustering, IHC evidence of disorganization associated with desmin breakdown, and desmin protein cleavage verified by Western blot analysis and mass spectrometry. IHC results revealed that ACF cardiomyocytes at 4 and 12 wk had perinuclear translocation of αB-crystallin from the Z disk with increased α, β-unsaturated aldehyde 4-hydroxynonelal. Use of protein markers with verification by TUNEL staining and kinome analysis revealed an absence of cardiomyocyte apoptosis at 4 and 12 wk of ACF. Significant increases in protein indicators of mitophagy were countered by a sixfold increase in p62/sequestosome-1, which is indicative of an inability to complete autophagy. An early and continuous disruption of the desmin/mitochondrial architecture, accompanied by oxidative stress and inhibition of apoptosis and mitophagy, suggests its causal role in LV dilatation and systolic dysfunction in VO. This study provides new evidence of early onset (24 h) and continuous (4-12 wk) desmin misarrangement and disruption of the normal sarcomeric and mitochondrial architecture throughout the progression of volume overload heart failure, suggesting a causal link between desmin cleavage and mitochondrial disorganization and damage.

Complex diseases such as polycystic ovary syndrome (PCOS) are associated with intricate pathophysiological, hormonal, and metabolic feedbacks that make their early diagnosis challenging, thus increasing the prevalence risks for obesity, cardiovascular, and fatty liver diseases. To explore the crosstalk between endocrine and lipid metabolic pathways, we administered 3‐iodothyronamine (T1AM), a natural analog of thyroid hormone, in a mouse model of PCOS and analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. T1AM administration induces a profound tissue‐specific antilipogenic effect in liver and muscle by lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2, significantly increasing metabolites (glucogenic, amino acids, carnitine, and citrate) levels, while enhancing protection against oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by upregulating STAR , CYP11A1, and CYP17A1. Biochemical measurements provide further evidence of significant reduction in liver cholesterol and triglycerides in post‐T1AM treatment. Our results shed light onto tissue‐specific metabolic vs. hormonal pathway interactions, thus illuminating the intricacies within the pathophysiology of PCOS. This study opens up new avenues to design drugs for targeted therapeutics to improve quality of life in complex metabolic diseases.