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USF1 deficiency activates brown adipose tissue and improves cardiometabolic health
- Source :
- Science Translational Medicine, 8(323)
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
Blood Glucose
Male
030204 cardiovascular system & hematology
Lipoproteins, VLDL
Cardiovascular System
Cohort Studies
Mice
0302 clinical medicine
Adipose Tissue, Brown
Brown adipose tissue
Insulin
2. Zero hunger
Metabolic Syndrome
biology
medicine.diagnostic_test
Thermogenesis
General Medicine
Middle Aged
Lipids
medicine.anatomical_structure
Mitochondrial respiratory chain
Phenotype
Liver
Female
Adult
medicine.medical_specialty
USF1
Carbohydrates
Mice, Transgenic
Polymorphism, Single Nucleotide
03 medical and health sciences
Insulin resistance
Oxygen Consumption
Internal medicine
medicine
Animals
Humans
Gene Silencing
Alleles
Triglycerides
Aged
Cholesterol, HDL
Lipid metabolism
ta3121
medicine.disease
Atherosclerosis
Mice, Inbred C57BL
Lipoprotein Lipase
030104 developmental biology
Endocrinology
Glucose
biology.protein
Upstream Stimulatory Factors
Steatosis
Lipid profile
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Science Translational Medicine, 8(323)
- Accession number :
- edsair.doi.dedup.....c8825a94114d2774164bcd385b116a19