EBI2 is a negative modulator of adipose tissue activity

Abstract

Weight-related diseases are common and often fatal conditions characterized by an imbalance between energy intake and energy expenditure. Obesity and weight gain related diseases such as type 2-diabetes have reached in the last decades pandemic levels. Importantly, excessive weight loss characterizes a broad spectrum of pathological conditions, from cancer cachexia to anorexia-nervosa.<br /> Adipose tissue activity is positively regulated by Gαs-coupled receptors such as β3-adrenergic receptors, causing an intracellular increase of cAMP and the following stimulation of lipolysis and energy expenditure. Oppositely, activation of Gαi-coupled receptors causes inhibition of cAMP production and lipolysis. Among Gαi-coupled receptors, the Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) was found to be highly expressed on adipocytes and adipose tissues; however, its possible role in regulating energy expenditure and adipose tissue function has not been investigated so far. In this study, the effect of EBI2 and its ligand 7α,25-dihydroxycholesterol (7α,25-OHC) was studied on adipocytes, adipose tissue and whole-body metabolism.<br /> EBI2 stimulation was able to potently decrease activation of brown adipocytes, decreasing intracellular cAMP levels and counteracting norepinephrine-induced lipolysis. In vivo, EBI2 deletion increased energy expenditure in response to an acute cold stimulus. EBI2 acute activation following in vivo injection of 7α,25-OHC potently influenced the energy expenditure in mice, dramatically decreasing oxygen consumption. The data on the long-term effects of EBI2 loss or stimulation are less clear, and require further studies.<br /> Thus, EBI2 is involved in regulating acutely adipose tissue activity and energy expenditure, and in the long term in the development of type 2-diabetes.