RESUMO
Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of ß-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.
Assuntos
Tecido Adiposo Marrom/metabolismo , Receptor Constitutivo de Androstano/metabolismo , Lipólise , Receptores Acoplados a Proteínas G/metabolismo , Termogênese , Adipócitos/metabolismo , Animais , Células COS , Células Cultivadas , Chlorocebus aethiops , Temperatura Baixa , Gorduras na Dieta/farmacologia , Humanos , Camundongos Endogâmicos C57BL , Fenótipo , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Sistema Nervoso Simpático/metabolismo , Transcrição GênicaRESUMO
Thermogenic fat expends energy during cold for temperature homeostasis, and its activity regulates nutrient metabolism and insulin sensitivity. We measured cold-activated lipid landscapes in circulation and in adipose tissue by MS/MSALL shotgun lipidomics. We created an interactive online viewer to visualize the changes of specific lipid species in response to cold. In adipose tissue, among the approximately 1,600 lipid species profiled, we identified the biosynthetic pathway of the mitochondrial phospholipid cardiolipin as coordinately activated in brown and beige fat by cold in wild-type and transgenic mice with enhanced browning of white fat. Together, these data provide a comprehensive lipid bio-signature of thermogenic fat activation in circulation and tissue and suggest pathways regulated by cold exposure.