Endocrine Abstracts

Activated brown adipose tissue (BAT) combusts high amounts of intracellular lipids into heat. In the past few years, we have investigated the consequences of BAT activation for lipid metabolism and cardiometabolic health. Initially, we showed that South Asians, a population characterized by dyslipidemia and prone to develop type 2 diabetes and cardiovascular disease compared to white Caucasians, have low BAT activity correlating with low energy expenditure (Lancet Diab Endocrinol 2014). In search for pharmacological strategies to activate BAT, we then set out to understand the physiology of BAT. Using preclinical models we elucidated that BAT activation enhances selective uptake of lipoprotein-triglyceride-derived fatty acids by BAT thereby generating lipoprotein remnants that are taken up by the liver (J Lipid Res 2015; Circ Res 2016). Next, we discovered novel pharmacological targets that modulate BAT activity with respect to uptake of plasma triglyceride-derived fatty acids, both directly (e.g. AMPK, BMP7R, CB1R, USF-1) and via neural control (e.g. MC4R, GLP-1R, ADRB3) and showed that BAT activation improves dyslipidemia and hyperglycemia and reduces type 2 diabetes and atherosclerosis (e.g. FASEB J 2014; Diabetes 2014; Nat Commun 2015; Sci Transl Med 2016). Recently, we also demonstrated that disruption of the central biological clock predisposes to adiposity by reduced sympathetic outflow to BAT (PNAS USA 2015) and we identified a strong circadian rhythm in the uptake of plasma lipids by BAT, explaining a circadian rhythm in postprandial lipid responses as well as plasma lipid levels (unpublished). Based on these collective data, we recently started (timed) human intervention studies in prediabetic individuals from South Asian vs white Caucasians origin aimed to activate BAT activity and to improve cardiometabolic health.