EPAC1 enhances brown fat growth and beige adipogenesis

TY - JOUR

T1 - EPAC1 enhances brown fat growth and beige adipogenesis

AU - Reverte-Salisa, Laia

AU - Siddig, Sana

AU - Hildebrand, Staffan

AU - Yao, Xi

AU - Zurkovic, Jelena

AU - Jaeckstein, Michelle Y

AU - Heeren, Joerg

AU - Lezoualc'h, Frank

AU - Krahmer, Natalie

AU - Pfeifer, Alexander

N1 - © 2024. The Author(s).

PY - 2024/1

Y1 - 2024/1

N2 - Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show that the cAMP-binding protein EPAC1 is a central regulator of adaptive BAT growth. In vivo, selective pharmacological activation of EPAC1 increases BAT mass and browning of white fat, leading to higher energy expenditure and reduced diet-induced obesity. Mechanistically, EPAC1 coordinates a network of regulators for proliferation specifically in thermogenic adipocytes, but not in white adipocytes. We pinpoint the effects of EPAC1 to PDGFRα-positive preadipocytes, and the loss of EPAC1 in these cells impedes BAT growth and worsens diet-induced obesity. Importantly, EPAC1 activation enhances the proliferation and differentiation of human brown adipocytes and human brown fat organoids. Notably, a coding variant of RAPGEF3 (encoding EPAC1) that is positively correlated with body mass index abolishes noradrenaline-induced proliferation of brown adipocytes. Thus, EPAC1 might be an attractive target to enhance thermogenic adipocyte number and energy expenditure to combat metabolic diseases.

AB - Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show that the cAMP-binding protein EPAC1 is a central regulator of adaptive BAT growth. In vivo, selective pharmacological activation of EPAC1 increases BAT mass and browning of white fat, leading to higher energy expenditure and reduced diet-induced obesity. Mechanistically, EPAC1 coordinates a network of regulators for proliferation specifically in thermogenic adipocytes, but not in white adipocytes. We pinpoint the effects of EPAC1 to PDGFRα-positive preadipocytes, and the loss of EPAC1 in these cells impedes BAT growth and worsens diet-induced obesity. Importantly, EPAC1 activation enhances the proliferation and differentiation of human brown adipocytes and human brown fat organoids. Notably, a coding variant of RAPGEF3 (encoding EPAC1) that is positively correlated with body mass index abolishes noradrenaline-induced proliferation of brown adipocytes. Thus, EPAC1 might be an attractive target to enhance thermogenic adipocyte number and energy expenditure to combat metabolic diseases.

KW - Humans

KW - Adipocytes, Brown/metabolism

KW - Adipogenesis

KW - Adipose Tissue, Brown

KW - Adipose Tissue, White/metabolism

KW - Cell Differentiation

KW - Energy Metabolism

KW - Obesity/metabolism

U2 - 10.1038/s41556-023-01311-9

DO - 10.1038/s41556-023-01311-9

M3 - SCORING: Journal article

C2 - 38195707

VL - 26

SP - 113

EP - 123

JO - NAT CELL BIOL

JF - NAT CELL BIOL

SN - 1465-7392

IS - 1

ER -