Research on mouse FA metabolism has shown how triglyceride-rich lipoproteins (TRL) are taken up through a sequence of tissue-specific steps, starting within the BAT vasculature. Using the APOE*3-Leiden.CETP mouse model, which expresses human APOE and LDLR and develops atherosclerosis, investigators saw that BAT activation led to increased energy expenditure, decreased plasma triglyceride and cholesterol levels, and reduced atherosclerosis (12, 13). Mouse BAT is also involved in bile acid processing, the metabolism of which is connected directly to the distribution of dietary cholesterol. Cold exposure triggered postprandial TRL uptake in BAT, which accelerated cholesterol delivery to the liver. BAT activation increased synthesis of bile acids, promoting their biliary excretion, and higher bile acid levels in the gut led to an altered microbiome (14).

The possibility that activated BAT could lead to an improved cardiometabolic profile in humans is supported by a very large retrospective study: 134,529 18F-FDG PET/CT scans from 52,487 patients undergoing cancer surveillance, who were categorized as BAT+ and BAT–. Using propensity score matching, the authors showed that the BAT+ patients had comparatively beneficial blood glucose, triglyceride, and HDL values across a range of BMI’s. These patterns were associated with lower prevalence of cardiometabolic diseases, including type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure, and hypertension (15). A smaller, prospective evaluation of human BAT showed similar results: over five years, cold-induced BAT activity correlated with lower levels of cardiovascular risk factors and carotid intima-media thickness, yet higher carotid elasticity (16). A mechanistic explanation came from translational studies showing that cold exposure in mice increased the enzymatic activity of soluble epoxide hydrolases expressed only in mouse BAT and led to the production of the bioactive lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). Injection of 12,13-diHOME in mice acutely activated BAT fuel uptake by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane and FA uptake into brown adipocytes. In addition to improving cold tolerance, 12,13-diHOME lowered serum triglycerides. Support for this process happening in humans came from a clinical trial showing that cold exposure increased the levels of plasma 12,13-diHOME in healthy humans (17).

Bolstering the role of BAT-derived bioactive lipids in cardiometabolic health goes beyond cold exposure. It was shown that a bout of moderate-intensity exercise increased BAT-derived circulating 12,13-diHOME levels in mice of different sexes, ages, and levels of activity. Treatment with 12,13-diHOME increased skeletal muscle FA uptake and oxidation (18). Could chronic BAT activation in humans lead to improved cardiometabolic risk and ultimately clinical endpoints? In addition to the retrospective data supporting this possibility, O’Mara et al. showed that four weeks of mirabegron administration increased serum HDL and total plasma bile acids (6). Therefore, as with improvements in glucose metabolism, chronic activation of human BAT may lead to beneficial cardiometabolic health through the release of bioactive lipids and other adipokines.