USF1 deficiency activates brown adipose tissue and improves cardiometabolic health

Abstract

USF1 (upstream stimulatory factor 1) is a transcription factor associated with familial combined hyperlipidemia and coronary artery disease in humans. However, whether USF1 is beneficial or detrimental to cardiometabolic health has not been addressed. By inactivating USF1 in mice, we demonstrate protection against diet-induced dyslipidemia, obesity, insulin resistance, hepatic steatosis, and atherosclerosis. The favorable plasma lipid profile, including increased high-density lipoprotein cholesterol and decreased triglycerides, was coupled with increased energy expenditure due to activation of brown adipose tissue (BAT). Usf1 inactivation directs triglycerides from the circulation to BAT for combustion via a lipoprotein lipase-dependent mechanism, thus enhancing plasma triglyceride clearance. Mice lacking Usf1 displayed increased BAT-facilitated, diet-induced thermogenesis with up-regulation of mitochondrial respiratory chain complexes, as well as increased BAT activity even at thermoneutrality and after BAT sympathectomy. A direct effect of USF1 on BAT activation was demonstrated by an amplified adrenergic response in brown adipocytes after Usf1 silencing, and by augmented norepinephrine-induced thermogenesis in mice lacking Usf1. In humans, individuals carrying SNP (single-nucleotide polymorphism) alleles that reduced USF1 mRNA expression also displayed a beneficial cardiometabolic profile, featuring improved insulin sensitivity, a favorable lipid profile, and reduced atherosclerosis. Our findings identify a new molecular link between lipid metabolism and energy expenditure, and point to the potential of USF1 as a therapeutic target for cardiometabolic disease.

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood

“…Changes in thermogenesis are known to affect metabolic responses in animals and humans 19, 46, 47 . Therefore, we next examined glucose tolerance in Ldlr −/− and Apoe −/− mice fed a cholesterol-enriched diet housed at 22°C and 30°C ambient temperatures.…”

Regulation of visceral and epicardial adipose tissue for preventing cardiovascular injuries associated to obesity and diabetes

“…Laurila et al demonstrated that lacking upstream stimulatory factor 1 (USF1) activated BAT in obese/T2DM mice, and promoted protection against dyslipidaemia, obesity, insulin resistance, and atherosclerosis. These data were also confirmed in subjects carrying a mutation in USF1 [82]. Also, steroid glycosides as ginsenoside Rb1 improved glucose and lipid metabolisms and reduced body weight in obese animals by up-regulating PRDM-16, PGC1α, and UCP-1 expression and WAT browning [83].…”

“…Interestingly, high-fat diets stimulated browning capacity of WAT in the retroperitoneal depot by stimulating UCP-1 and CIDE-A (cell death-inducing DFFA-like effector-A) expression, likely, as a compensation mechanism [81]. Also, micro-RNAs such as miR-26, miR-27, mir-30, miR-34a, miR-106b, miR-133, miR-155, miR-193-365, miR-196 and miR-378 have been involved in the control of bAT and BAT formation and function in mice [82]. …”

Brown Adipose Tissue: an Update on Recent Findings

“…Findings from mouse models demonstrate that cold-activated BAT can effectively clear plasma triglycerides [48–50] and may even mitigate hypercholesterinemia and suppress the formation of atherosclerotic plaque [51, 52, 49]. One study demonstrated a retardation of atherosclerotic plaque growth with only 8 weeks of cold exposure [53]; however, this may have been the result of rapid exposure instead of gradual acclimation.…”