RESUMO
Increases in adiposity trigger metabolic and inflammatory changes that interfere with insulin action in peripheral tissues, culminating in beta cell failure and overt diabetes. We found that the cAMP Response Element Binding protein (CREB) is activated in adipose cells under obese conditions, where it promotes insulin resistance by triggering expression of the transcriptional repressor ATF3 and thereby downregulating expression of the adipokine hormone adiponectin as well as the insulin-sensitive glucose transporter 4 (GLUT4). Transgenic mice expressing a dominant-negative CREB transgene in adipocytes displayed increased whole-body insulin sensitivity in the contexts of diet-induced and genetic obesity, and they were protected from the development of hepatic steatosis and adipose tissue inflammation. These results indicate that adipocyte CREB provides an early signal in the progression to type 2 diabetes.
Assuntos
Adipócitos/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Resistência à Insulina/fisiologia , Obesidade/fisiopatologia , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Adenilato Quinase/metabolismo , Adipócitos/citologia , Adipócitos/patologia , Adiponectina/metabolismo , Animais , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Progressão da Doença , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Gluconeogênese/fisiologia , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Obesos , Camundongos Transgênicos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismoRESUMO
The KAP-2 protein that binds to the H-box (CCTACC) element in the bean CHS15 chalcone synthase promoter was purified, and internal peptide sequence used to design primers leading to the cloning of KAP-2 from bean (Phaseolus vulgaris) and barrel medic (Medicago truncatula). KAP-2 shares sequence similarity to the large subunit of mammalian Ku autoantigen, a protein proposed to be involved in control of DNA recombination and transcription. KAP-2 sequences were present in genomic DNA from a range of legumes, and a related protein is found in Arabidopsis thaliana. Recombinant KAP-2 expressed in insect cells showed the same binding specificity for the CHS15 H-box as the protein purified from bean cell extracts. In vitro transcription assays confirmed that KAP-2 stimulates transcription from a promoter harboring the H-box cis element.