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Cell ; 184(13): 3502-3518.e33, 2021 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-34048700

RESUMEN

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.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Receptor de Androstano Constitutivo/metabolismo , Lipólisis , Receptores Acoplados a Proteínas G/metabolismo , Termogénesis , Adipocitos/metabolismo , Animales , Células COS , Células Cultivadas , Chlorocebus aethiops , Frío , Grasas de la Dieta/farmacología , Humanos , Ratones Endogámicos C57BL , Fenotipo , Receptores Acoplados a Proteínas G/genética , Transducción de Señal , Sistema Nervioso Simpático/metabolismo , Transcripción Genética
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