USF1 deficiency activates brown adipose tissue and improves cardiometabolic health

Pirkka-Pekka Laurila; Jarkko Soronen; Sander Kooijman; Saara Forsström; Mariëtte R Boon; Ida Surakka; Essi Kaiharju; Claudia P Coomans; Sjoerd A A Van Den Berg; Anu Autio; Antti-Pekka Sarin; Johannes Kettunen; Emmi Tikkanen; Tuula Manninen; Jari Metso; Reija Silvennoinen; Krista Merikanto; Maija Ruuth; Julia Perttilä; Anne Mäkelä; Ayaka Isomi; Anita M Tuomainen; Anna Tikka; Usama Abo Ramadan; Ilkka Seppälä; Terho Lehtimäki; Johan Eriksson; Aki Havulinna; Antti Jula; Pekka J Karhunen; Veikko Salomaa; Markus Perola; Christian Ehnholm; Miriam Lee-Rueckert; Miranda Van Eck; Anne Roivainen; Marja-Riitta Taskinen; Leena Peltonen; Eero Mervaala; Anu Jalanko; Esa Hohtola; Vesa M Olkkonen; Samuli Ripatti; Petri T Kovanen; Patrick C N Rensen; Anu Suomalainen; Matti Jauhiainen

doi:10.1126/scitranslmed.aad0015

USF1 deficiency activates brown adipose tissue and improves cardiometabolic health

Pirkka-Pekka Laurila^*, Jarkko Soronen, Sander Kooijman, Saara Forsström, Mariëtte R Boon, Ida Surakka, Essi Kaiharju, Claudia P Coomans, Sjoerd A A Van Den Berg, Anu Autio, Antti-Pekka Sarin, Johannes Kettunen, Emmi Tikkanen, Tuula Manninen, Jari Metso, Reija Silvennoinen, Krista Merikanto, Maija Ruuth, Julia Perttilä, Anne MäkeläAyaka Isomi, Anita M Tuomainen, Anna Tikka, Usama Abo Ramadan, Ilkka Seppälä, Terho Lehtimäki, Johan Eriksson, Aki Havulinna, Antti Jula, Pekka J Karhunen, Veikko Salomaa, Markus Perola, Christian Ehnholm, Miriam Lee-Rueckert, Miranda Van Eck, Anne Roivainen, Marja-Riitta Taskinen, Leena Peltonen, Eero Mervaala, Anu Jalanko, Esa Hohtola, Vesa M Olkkonen, Samuli Ripatti, Petri T Kovanen, Patrick C N Rensen, Anu Suomalainen, Matti Jauhiainen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

59 Citations (Scopus)

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.

Original language	English
Pages (from-to)	323ra13
Journal	Science Translational Medicine
Volume	8
Issue number	323
DOIs	https://doi.org/10.1126/scitranslmed.aad0015
Publication status	Published - 27 Jan 2016
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/scitranslmed.aad0015

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Laurila, P.-P., Soronen, J., Kooijman, S., Forsström, S., Boon, M. R., Surakka, I., Kaiharju, E., Coomans, C. P., Van Den Berg, S. A. A., Autio, A., Sarin, A.-P., Kettunen, J., Tikkanen, E., Manninen, T., Metso, J., Silvennoinen, R., Merikanto, K., Ruuth, M., Perttilä, J., ... Jauhiainen, M. (2016). USF1 deficiency activates brown adipose tissue and improves cardiometabolic health. Science Translational Medicine, 8(323), 323ra13. https://doi.org/10.1126/scitranslmed.aad0015

@article{f4ea9d4bd3284564a558e4d4b9a816a9,

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.",

author = "Pirkka-Pekka Laurila and Jarkko Soronen and Sander Kooijman and Saara Forsstr{\"o}m and Boon, {Mari{\"e}tte R} and Ida Surakka and Essi Kaiharju and Coomans, {Claudia P} and {Van Den Berg}, {Sjoerd A A} and Anu Autio and Antti-Pekka Sarin and Johannes Kettunen and Emmi Tikkanen and Tuula Manninen and Jari Metso and Reija Silvennoinen and Krista Merikanto and Maija Ruuth and Julia Perttil{\"a} and Anne M{\"a}kel{\"a} and Ayaka Isomi and Tuomainen, {Anita M} and Anna Tikka and Ramadan, {Usama Abo} and Ilkka Sepp{\"a}l{\"a} and Terho Lehtim{\"a}ki and Johan Eriksson and Aki Havulinna and Antti Jula and Karhunen, {Pekka J} and Veikko Salomaa and Markus Perola and Christian Ehnholm and Miriam Lee-Rueckert and {Van Eck}, Miranda and Anne Roivainen and Marja-Riitta Taskinen and Leena Peltonen and Eero Mervaala and Anu Jalanko and Esa Hohtola and Olkkonen, {Vesa M} and Samuli Ripatti and Kovanen, {Petri T} and Rensen, {Patrick C N} and Anu Suomalainen and Matti Jauhiainen",

note = "Copyright {\textcopyright} 2016, American Association for the Advancement of Science.",

year = "2016",

month = jan,

day = "27",

doi = "10.1126/scitranslmed.aad0015",

language = "English",

volume = "8",

pages = "323ra13",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

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Laurila, P-P, Soronen, J, Kooijman, S, Forsström, S, Boon, MR, Surakka, I, Kaiharju, E, Coomans, CP, Van Den Berg, SAA, Autio, A, Sarin, A-P, Kettunen, J, Tikkanen, E, Manninen, T, Metso, J, Silvennoinen, R, Merikanto, K, Ruuth, M, Perttilä, J, Mäkelä, A, Isomi, A, Tuomainen, AM, Tikka, A, Ramadan, UA, Seppälä, I, Lehtimäki, T, Eriksson, J, Havulinna, A, Jula, A, Karhunen, PJ, Salomaa, V, Perola, M, Ehnholm, C, Lee-Rueckert, M, Van Eck, M, Roivainen, A, Taskinen, M-R, Peltonen, L, Mervaala, E, Jalanko, A, Hohtola, E, Olkkonen, VM, Ripatti, S, Kovanen, PT, Rensen, PCN, Suomalainen, A & Jauhiainen, M 2016, 'USF1 deficiency activates brown adipose tissue and improves cardiometabolic health', Science Translational Medicine, vol. 8, no. 323, pp. 323ra13. https://doi.org/10.1126/scitranslmed.aad0015

TY - JOUR

T1 - USF1 deficiency activates brown adipose tissue and improves cardiometabolic health

AU - Laurila, Pirkka-Pekka

AU - Soronen, Jarkko

AU - Kooijman, Sander

AU - Forsström, Saara

AU - Boon, Mariëtte R

AU - Surakka, Ida

AU - Kaiharju, Essi

AU - Coomans, Claudia P

AU - Van Den Berg, Sjoerd A A

AU - Autio, Anu

AU - Sarin, Antti-Pekka

AU - Kettunen, Johannes

AU - Tikkanen, Emmi

AU - Manninen, Tuula

AU - Metso, Jari

AU - Silvennoinen, Reija

AU - Merikanto, Krista

AU - Ruuth, Maija

AU - Perttilä, Julia

AU - Mäkelä, Anne

AU - Isomi, Ayaka

AU - Tuomainen, Anita M

AU - Tikka, Anna

AU - Ramadan, Usama Abo

AU - Seppälä, Ilkka

AU - Lehtimäki, Terho

AU - Eriksson, Johan

AU - Havulinna, Aki

AU - Jula, Antti

AU - Karhunen, Pekka J

AU - Salomaa, Veikko

AU - Perola, Markus

AU - Ehnholm, Christian

AU - Lee-Rueckert, Miriam

AU - Van Eck, Miranda

AU - Roivainen, Anne

AU - Taskinen, Marja-Riitta

AU - Peltonen, Leena

AU - Mervaala, Eero

AU - Jalanko, Anu

AU - Hohtola, Esa

AU - Olkkonen, Vesa M

AU - Ripatti, Samuli

AU - Kovanen, Petri T

AU - Rensen, Patrick C N

AU - Suomalainen, Anu

AU - Jauhiainen, Matti

PY - 2016/1/27

Y1 - 2016/1/27

N2 - 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.

AB - 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.

U2 - 10.1126/scitranslmed.aad0015

DO - 10.1126/scitranslmed.aad0015

M3 - Article

C2 - 26819196

SN - 1946-6234

VL - 8

SP - 323ra13

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 323

ER -

USF1 deficiency activates brown adipose tissue and improves cardiometabolic health

Abstract

Bibliographical note

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