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Ellis J.M.,University of North Carolina at Chapel Hill | Li L.O.,University of North Carolina at Chapel Hill | Wu P.-C.,University of North Carolina at Chapel Hill | Koves T.R.,Duke University | And 5 more authors.
Cell Metabolism

Long-chain acyl-CoA synthetase-1 (ACSL1) contributes 80% of total ACSL activity in adipose tissue and was believed to be essential for the synthesis of triacylglycerol. We predicted that an adipose-specific knockout of ACSL1 (Acsl1A-/-) would be lipodystrophic, but compared to controls, Acsl1A-/- mice had 30% greater fat mass when fed a low-fat diet and gained weight normally when fed a high-fat diet. Acsl1A-/- adipocytes incorporated [14C]oleate into glycerolipids normally, but fatty acid (FA) oxidation rates were 50%-90% lower than in control adipocytes and mitochondria. Acsl1A-/- mice were markedly cold intolerant, and β3-adrenergic agonists did not increase oxygen consumption, despite normal adrenergic signaling in brown adipose tissue. The reduced adipose FA oxidation and marked cold intolerance of Acsl1A-/- mice indicate that normal activation of FA for oxidation in adipose tissue in vivo requires ACSL1. Thus, ACSL1 has a specific function in directing the metabolic partitioning of FAs toward β-oxidation in adipocytes. © 2010 Elsevier Inc. Source

Lu M.,University of California at San Diego | Patsouris D.,University of California at San Diego | Li P.,University of California at San Diego | Flores-Riveros J.,Hollis Eden Pharmaceuticals | And 4 more authors.
American Journal of Physiology - Endocrinology and Metabolism

Lu M, Patsouris D, Li P, Flores-Riveros J, Frincke JM, Watkins S, Schenk S, Olefsky JM. A new antidiabetic compound attenuates inflammation and insulin resistance in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab 298: E1036-E1048, 2010. First published February 16, 2010; doi:10.1152/ajpendo.00668. 2009. - Tissue macrophage inflammatory pathways contribute to obesity-associated insulin resistance. Here, we have examined the efficacy and mechanisms of action of a novel anti-inflammatory compound (HE3286) in vitro and in vivo. In primary murine macrophages, HE3286 attenuates LPS- and TNFα-stimulated inflammation. In Zucker diabetic fatty rats, inflammatory cytokine/chemokine expression was downregulated in liver and adipose tissue by HE3286 treatment, as was macrophage infiltration into adipose tissue. In line with reduced inflammation, HE3286 treatment normalized fasting and fed glucose levels, improved glucose tolerance, and enhanced skeletal muscle and liver insulin sensitivity, as assessed by hyperinsulinemic euglycemic clamp studies. In phase 2 clinical trials, HE3286 treatment led to an enhancement in insulin sensitivity in humans. Gluconeogenic capacity was also reduced by HE3286 treatment, as evidenced by a reduced glycemic response during pyruvate tolerance tests and decreased basal hepatic glucose production (HGP) rates. Since serum levels of gluconeogenic substrates were decreased by HE3286, it indicates that the reduction of both intrinsic gluconeogenic capacity and substrate availability contributes to the decrease in HGP. Lipidomic analysis revealed that HE3286 treatment reduced liver cholesterol and triglyceride content, leading to a feedback elevation of LDL receptor and HMG-CoA reductase expression. Accordingly, HE3286 treatment markedly decreased total serum cholesterol. In conclusion, HE3286 is a novel anti-inflammatory compound, which displays both glucose-lowering and cholesterol-lowering effects. Copyright © 2010 the American Physiological Society. Source

Oh D.Y.,University of California at San Diego | Walenta E.,University of California at San Diego | Akiyama T.E.,Merck And Co. | Lagakos W.S.,University of California at San Diego | And 18 more authors.
Nature Medicine

It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future. © 2014 Nature America, Inc. Source

Lee Y.S.,University of California at San Diego | Kim J.-W.,University of California at San Diego | Osborne O.,University of California at San Diego | Oh D.Y.,University of California at San Diego | And 11 more authors.

Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance. © 2014 Elsevier Inc. Source

Agency: Department of Defense | Branch: Army | Program: STTR | Phase: Phase II | Award Amount: 749.93K | Year: 2007

This Phase II STTR award for evaluation of combat and civilian personnel for optimum performance will establish metabolic biomarkers that assess the health and predict the performance success of individual personnel. Seventy subjects reflecting the spectrum of normal human physiological boundaries will be sampled before and after a defined set of physical tests and their serum analyzed using a metabolite analysis platform. The metabolites measured have been demonstrated to respond to physical performance include the comprehensive distribution of energetic lipids, eicosanoids, acylcarnitines, and amino acids. The database of metabolites measured from these subjects will be analyzed by a bioinformatic toolset to identify metabolic pathways distinguishing the performance and exhaustion outcomes. This study will identify a set of metabolic pathway intermediates whose measured abundance before an event are predictive of future performance and a set of metabolites taken after an event that serve as biomarkers of extent of physical exertion, metabolic damage and stress. The resulting knowledge of specific biochemical pathways relating to performance and metabolic damage and the identities of molecules whose abundances are diagnostically predictive of performance will provide the military objective, measurable criteria for recruitment training, mission selection, dietary management and improvement of individual soldier health and performance.

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