Abstract
Objective: Lipoic Acid Synthase (LASY) was recently shown to play a critical role in inflammation, mitochondrial function and insulin resistance. In this study using a pharmacological inducer of LASY as a tool, we studied the effects of LASY induction in vivo in rodent models of obesity and type 2 diabetes. Methods: We identified a small molecule that increases LASY mRNA and lipoic acid levels in vitro. Effect of the inducer (compound 1) on body weight, food intake, energy expenditure and metabolic parameters was studied in rodent models of genetic and diet-induced obesity. Results: Compound 1 was identified as a transcriptional inducer of LASY. In vitro, compound 1 increased LASY mRNA expression, mitochondrial lipoic acid levels and improved mitochondrial function in cultured skeletal muscle cells. LASY mRNA and lipoic acid levels were significantly increased in skeletal muscle and adipose tissue of animals treated with compound 1. In genetic and diet-induced rodent models of obesity, treatment with compound 1 significantly reduced body weight gain and fat mass without changes in food intake. Whole-animal calorimetry revealed that compound 1-treated animals had a significant increase in energy expenditure over vehicle control. Compound 1 treatment was also accompanied by improvements in plasma metabolic parameters and increase in lean mass. Conclusion: Our data suggests that the benefical effects of compound 1 are mediated by increase in mitochondrial lipoic acid levels, although general effects on mitochondrial function cannot be ruled out. These results establish the in vivo relevance of LASY induction and show the potential of a peripheral mediated approach for achieving many of the desired effects in treating obesity. Future studies focusing on the mechanism(s) by which compound 1 exerts its beneficial effects will help to reveal if these benefits are specific to LASY induction or are due to non-specific effects on mitochondrial function.
Highlights
Obesity is the result of an imbalance between energy intake and expenditure
Since Lipoic acid synthase (LASY) is the key enzyme in the generation of endogenous lipoic acid (LA), we studied Lipoic acid (LA) levels associated with pyruvate dehydrogenase complex (PDC)
Compound 1 decreases insulin resistance in DIO mice: We studied the effect of compound 1 on insulin resistance (IR) in the DIO mouse model by homeostasis model assessment (HOMA) method using the formula indicated in the Research Methods and Procedures and the legend for (Figure 4H)
Summary
Obesity is the result of an imbalance between energy intake and expenditure. It plays a causal role in the metabolic syndrome which encompasses various risk factors such as insulin resistance, type 2 diabetes, dyslipidemia, hypertension and cardiovascular dysfunction. Lipoic acid (LA), a short chain fatty acid, is a potent endogenous antioxidant that functions as a cofactor of major mitochondrial enzyme complexes such as the pyruvate dehydrogenase complex (PDC) and the alpha-ketoglutarate dehydrogenase complex (KDH). Both LA and its reduced form, dihydrolipoic acid (DHLA) have powerful antioxidant properties, and can regenerate other antioxidants such as vitamin C, vitamin E and glutathione [3]. Supplementation with LA has been shown to have numerous therapeutic benefits, including amelioration of insulin resistance in rodent models [4,5] and in human studies [6] Many of these therapeutic benefits are likely mediated by its powerful antioxidant function. Defects in LA biosynthesis in humans results in a fatal mitochondrial disease, as observed recently in ten infants who were found to have a point mutation in a protein, NFU1, Received June 22, 2012; Accepted July 23, 2012; Published July 28, 2012
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