title: 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.
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland. Department of Medical Genetics, University of Helsinki, Helsinki FI-00014, Finland. Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00251, Finland. pirkka-pekka.laurila@thl.fi matti.jauhiainen@thl.fi.
authors.forename: Pirkka-Pekka
authors.initials: PP
authors.lastname: Laurila
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland. Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00251, Finland. Minerva Foundation Institute for Medical Research, Helsinki FI-00290, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Soronen
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden 2333 ZA, Netherlands. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Kooijman
authors.affiliation: Molecular Neurology, Research Programs Unit, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Forsström
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden 2333 ZA, Netherlands. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, Netherlands.
authors.forename: Mariëtte R
authors.initials: MR
authors.lastname: Boon
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland. Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00251, Finland.
authors.forename: Ida
authors.initials: I
authors.lastname: Surakka
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland.
authors.forename: Essi
authors.initials: E
authors.lastname: Kaiharju
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden 2333 ZA, Netherlands. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden 2333 ZA, Netherlands.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Coomans
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZA, Netherlands.
authors.forename: Sjoerd A A
authors.initials: SA
authors.lastname: Van Den Berg
authors.affiliation: Turku PET Centre, University of Turku and Turku University Hospital, Turku FI-20520, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Autio
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland. Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00251, Finland.
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Sarin
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland. Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00251, Finland. Computational Medicine, Institute of Health Sciences, University of Oulu and Oulu University Hospital, Oulu FI-90014, Finland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland. Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00251, Finland. Hjelt Institute, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Emmi
authors.initials: E
authors.lastname: Tikkanen
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland. Molecular Neurology, Research Programs Unit, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Manninen
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Metso
authors.affiliation: Wihuri Research Institute, Helsinki FI-00290, Finland.
authors.forename: Reija
authors.initials: R
authors.lastname: Silvennoinen
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland.
authors.forename: Krista
authors.initials: K
authors.lastname: Merikanto
authors.affiliation: Wihuri Research Institute, Helsinki FI-00290, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Ruuth
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki FI-00290, Finland.
authors.forename: Julia
authors.initials: J
authors.lastname: Perttilä
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu FI-90014, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Mäkelä
authors.affiliation: Hiroshima University, Hiroshima 730-0053, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Isomi
authors.affiliation: Institute of Dentistry, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Anita M
authors.initials: AM
authors.lastname: Tuomainen
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Tikka
authors.affiliation: Experimental MRI Laboratory, Department of Neurology, Helsinki University Central Hospital, Helsinki FI-00290, Finland.
authors.forename: Usama Abo
authors.initials: UA
authors.lastname: Ramadan
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, and Tampere University School of Medicine, Tampere FI-33014, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Seppälä
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, and Tampere University School of Medicine, Tampere FI-33014, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: Department of Health, National Institute for Health and Welfare, Helsinki FI-00271, Finland. Folkhälsan Research Centre, Helsinki FI-00251, Finland. Unit of General Practice, Helsinki University Central Hospital, Helsinki FI-00290, Finland. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: Department of Health, National Institute for Health and Welfare, Helsinki FI-00271, Finland.
authors.forename: Aki
authors.initials: A
authors.lastname: Havulinna
authors.affiliation: Department of Health, National Institute for Health and Welfare, Helsinki FI-00271, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, and Tampere University School of Medicine, Tampere FI-33014, Finland.
authors.forename: Pekka J
authors.initials: PJ
authors.lastname: Karhunen
authors.affiliation: Department of Health, National Institute for Health and Welfare, Helsinki FI-00271, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland.
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland.
authors.forename: Christian
authors.initials: C
authors.lastname: Ehnholm
authors.affiliation: Wihuri Research Institute, Helsinki FI-00290, Finland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Lee-Rueckert
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden 2333 ZA, Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.affiliation: Turku PET Centre, University of Turku and Turku University Hospital, Turku FI-20520, Finland. Turku Center for Disease Modeling, University of Turku, Turku FI-20520, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Roivainen
authors.affiliation: Diabetes and Obesity Research Program, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.affiliation: Institute of Biomedicine, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Mervaala
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
authors.affiliation: Department of Genetics and Physiology, University of Oulu, Oulu FI-90014, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Hohtola
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki FI-00290, Finland.
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland. Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00251, Finland. Hjelt Institute, University of Helsinki, Helsinki FI-00014, Finland. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Wihuri Research Institute, Helsinki FI-00290, Finland.
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden 2333 ZA, Netherlands. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, Netherlands.
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.affiliation: Molecular Neurology, Research Programs Unit, University of Helsinki, Helsinki FI-00014, Finland. Department of Neurology, Helsinki University Central Hospital, Helsinki FI-00290, Finland. Neuroscience Center, University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.affiliation: Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki FI-00251, Finland. pirkka-pekka.laurila@thl.fi matti.jauhiainen@thl.fi.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002241:Carbohydrates / Q000737:chemistry; D002319:Cardiovascular System; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008071:Lipoprotein Lipase / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D010101:Oxygen Consumption; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D022722:Thermogenesis; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D051720:Upstream Stimulatory Factors / Q000172:deficiency* / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D002241:Carbohydrates; D008076:Cholesterol, HDL; D007328:Insulin; D008055:Lipids; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; D008071:Lipoprotein Lipase; D005947:Glucose