Role of brown fat-derived specialized pro-resolving lipid mediators in inflammation and metabolism

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Project Summary/Abstract Obesity and metabolic syndrome are rapidly growing worldwide, leading to high morbidity and mortality. Fundamental to these pathologies is adipose tissue. Chronic tissue inflammation, especially in adipose tissue, is a crucial feature of obesity and links to systemic insulin resistance and Type 2 diabetes (T2D). Although activation of brown adipose tissue (BAT) can increase energy expenditure and fuel utilization, leading to improvement of insulin sensitivity, little is known about whether the potential insulin-sensitizing effect of BAT is linked to resolution of inflammation. Specialized pro-resolving lipid mediators (SPM), such as the maresins, are novel mediators that resolve inflammation and trigger tissue regeneration. In work in progress, we discovered that activation of BAT by cold significantly reduces inflammation and improves systemic metabolism in obesity. Interestingly, we found that cold exposure selectively increases BAT production of maresins that are produced from ω-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). Based on these exciting findings, we hypothesize that the activation of BAT leads to increased production of maresins that act locally and systemically in resolving inflammation, leading to improved insulin sensitivity in obesity. The objectives of this proposal are to determine the role of maresins in the resolution of inflammation and improvement of insulin sensitivity in response to cold exposure and to investigate the molecular mechanisms mediating cold or β3- adrenergic stimulation-induced maresin biosynthesis. We will determine the role of a potential lipid transporter as well as key enzymes that regulate the maresin production. Completion of the proposed studies will lead to an entirely new understanding of the beneficial effects of BAT activation in obesity and could lead to novel biomimicry-based therapeutic approaches of obesity and T2D.