RESUMO
Adipose tissue takes up glucose and releases lactate, thereby contributing significantly to systemic glucose and lactate homeostasis. This implies the necessity of upregulation of net acid and lactate flux capacity during adipocyte differentiation and function. However, the regulation of lactate- and acid/base transporters in adipocytes is poorly understood. Here, we tested the hypothesis that adipocyte thermogenesis, browning and differentiation are associated with an upregulation of plasma membrane lactate and acid/base transport capacity that in turn is important for adipocyte metabolism. The mRNA and protein levels of the lactate-H+ transporter MCT1 and the Na+,HCO3- cotransporter NBCe1 were upregulated in mouse interscapular brown and inguinal white adipose tissue upon cold induction of thermogenesis and browning. MCT1, MCT4, and NBCe1 were furthermore strongly upregulated at the mRNA and protein level upon differentiation of cultured pre-adipocytes. Adipocyte differentiation was accompanied by increased plasma membrane lactate flux capacity, which was reduced by MCT inhibition and by MCT1 knockdown. Finally, in differentiated brown adipocytes, glycolysis (assessed as ECAR), and after noradrenergic stimulation also oxidative metabolism (OCR), was decreased by MCT inhibition. We suggest that upregulation of MCT1- and MCT4-mediated lactate flux capacity and NBCe1-mediated HCO3-/pH homeostasis are important for the physiological function of mature adipocytes.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Adipócitos/citologia , Adipogenia/genética , Adipogenia/fisiologia , Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Animais , Células HEK293 , Humanos , Isoproterenol , Camundongos , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Simportadores de Sódio-Bicarbonato/genética , Simportadores de Sódio-Bicarbonato/metabolismo , Simportadores/genéticaRESUMO
Both common forms of diabetes have an inflammatory pathogenesis in which immune and metabolic factors converge on interleukin-1ß as a key mediator of insulin resistance and ß-cell failure. In addition to improving insulin resistance and preventing ß-cell inflammatory damage, there is evidence of genetic association between diabetes and histone deacetylases (HDACs); and HDAC inhibitors (HDACi) promote ß-cell development, proliferation, differentiation and function and positively affect late diabetic microvascular complications. Here we review this evidence and propose that there is a strong rationale for preclinical studies and clinical trials with the aim of testing the utility of HDACi as a novel therapy for diabetes.
