The ability of adipose tissue to dispose of circulating fatty acids (FA) by oxidation or storage as triglyceride (TG) has important metabolic and clinical implications, by preventing the accumulation of potentially harmful FA metabolites in other organs, such as the liver and muscle. Peroxisomes integrate lipid storage and removal since FA can be conjugated with dihydroxyacetone phosphate (DHAP) to synthesize various lipids or be shuttled into oxidative pathways, either beta or alpha oxidation. We and others have reported that peroxisomes play important roles in regulating adipogenesis and adipocyte FA metabolism. Our current application aims to understand the metabolic functions of peroxisomes in adipocytes with a focus on the little studied alpha oxidation pathway. Based on our observation of the increased peroxisomes during adipogenesis and the pro- lipogenic effects of alpha oxidation, we hypothesize that limited peroxisomal alpha oxidation will decrease FA into lipid storage and increase mitochondrial FA oxidation in adipocytes.
Aim 1 seeks to determine functions of peroxisomes in adipogenesis and in FA metabolism in primary adipocytes with manipulated alpha oxidation. FA alpha oxidation activities and levels of enzymes involved in peroxisomal functions in adipose tissues from obese mice and mice resistant to diet-induced obesity (CD36 null and SCD-1 null) will also be determined.
Aim 2 will examine mechanisms responsible for the metabolic effects of peroxisomal FA alpha oxidation. Metabolic fates of exogenous and endogenous alpha hydroxylated FA enantiomers will be studied to understand specific cellular pathways contributing to its effects on FA metabolism. Peroxisomal and mitochondrial remodeling and biogenesis and their association with lipid droplets will be explored in primary adipocytes with inhibited or enhanced peroxisomal FA alpha oxidation.
In aim 3, we will evaluate contribution of adipocyte peroxisomal alpha oxidation to adiposity and insulin sensitivity using transgenic mouse models with altered peroxisomal FA alpha oxidation and in mice treated with the FA alpha oxidation inhibitor oxythiamine. Proteins involved in and lipid species resulting from peroxisomal FA metabolism in adipose tissues from lean and obese people and from obese people after weight loss will also be evaluated. The studies outlined in this proposal will provide new information regarding the role of peroxisomes in regulating adipocyte lipid and energy metabolism, which could provide novel insights into the pathophysiology of obesity-related metabolic diseases.
Obesity and diabetes are affecting an alarming proportion of the population in industrialized nations. We will study a new pathway regulating fat cell fatty aci oxidation and fat expansion. Our study will gain significant insights into the etiology of obesity and diabetes and will aid in the discovery of novel targets for treatment of these metabolic diseases.
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