Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport

Abstract

Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE*3-Leiden.CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

“…This browning of WAT has been linked to decreased adiposity in rodents and humans . In addition, it has been demonstrated in rodents that thermogenic stimulation promotes HDL‐cholesterol clearance in mice . Our results reveal the physiological relevance of these processes controlling whole‐body metabolism and obesity in p107 KO mice.…”

“…In this setting, the higher uptake in WAT could be caused by an enhancement of lipolysis and lipid β‐oxidation. In this regard, it has been demonstrated that BAT activity controls plasma levels of TGs by selective uptake of TRL‐derived fatty acids and the metabolic activity of thermogenesis in adipocytes is linked to high‐density lipoprotein (HDL) metabolism, which may also explain the lipid phenotype to some extent. The higher thermogenic activity in BAT and WAT is in agreement with the higher levels of protein markers of the thermogenic program in BAT, such as UCP‐1, PRDM16, and PCG1alfa; and the up‐regulation of UCP‐1 in WAT.…”

Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism

“…To resupply fuels for cold-induced energy expenditure, lipolysis is activated in WAT, and genetic blockade of adipose tissue lipolysis blocks BAT thermogenic function (Haemmerle et al, 2006; Schreiber et al, 2017), highlighting both the role of BAT lipolysis and the role of WAT as a fuel source for BAT during cold challenge. In addition to the high levels of glucose BAT takes up in response to cold (Chondronikola et al, 2014; Cooney et al, 1985; Orava et al, 2011), it also takes up lipid and cholesterol when activated (Bartelt et al, 2011, 2017; Berbée et al, 2015). …”

Novel Aspects of Follistatin/Transforming Growth Factor-β (TGF-β) Signaling in Adipose Tissue Metabolism: Implications in Metabolic Health

“…In both these reports, the beneficial metabolic effects were claimed to result from enlarged muscle mass following inactivation of functional Mst in LDLR −/− mice. Several recent reports have provided strong evidence suggesting that brown fat activation could reduce hypercholesterolemia and protect from atherosclerosis development [70][71][72]. Therefore, it is possible that observed beneficial effects of Mst inactivation in LDLR −/− background could be mediated at least in part via adipose browning.…”