RESUMO
Protein kinase R (PKR) has previously been suggested to mediate many of the deleterious consequences of a high-fat diet (HFD). However, previous studies have observed substantial phenotypic variability when examining the metabolic consequences of PKR deletion. Accordingly, herein, we have re-examined the role of PKR in the development of obesity and its associated metabolic complications in vivo as well as its putative lipid-sensing role in vitro. Here we show that the deletion of PKR does not affect HFD-induced obesity, hepatic steatosis or glucose metabolism, and only modestly affects adipose tissue inflammation. Treatment with the saturated fatty acid palmitate in vitro induced comparable levels of inflammation in WT and PKR KO macrophages, demonstrating that PKR is not necessary for the sensing of pro-inflammatory lipids. These results challenge the proposed role for PKR in obesity, its associated metabolic complications and its role in lipid-induced inflammation.
Assuntos
Dieta Hiperlipídica , Fígado Gorduroso/genética , Inflamação/genética , Macrófagos/metabolismo , Obesidade/genética , RNA Mensageiro/metabolismo , eIF-2 Quinase/genética , Tecido Adiposo Branco/metabolismo , Animais , Composição Corporal , Antígenos CD11/genética , Complexo CD3/genética , Proteínas de Ligação ao Cálcio , Quimiocina CCL2/genética , Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Citometria de Fluxo , Perfilação da Expressão Gênica , Teste de Tolerância a Glucose , Immunoblotting , Inflamação/metabolismo , Insulina/sangue , Cadeias alfa de Integrinas/genética , Interferon gama/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Leucócitos , Fígado/metabolismo , Fígado/patologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Palmitatos/farmacologia , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas G , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Obesity is now recognised as a low grade, chronic inflammatory disease that is linked to a myriad of disorders including cancer, cardiovascular disease and type 2 diabetes (T2D). With respect to T2D, work in the last decade has revealed that cells of the immune system are recruited to white adipose tissue beds (WAT), where they can secrete cytokines to modulate metabolism within WAT. As many of these cytokines are known to impair insulin action, blocking the recruitment of immune cells has been purported to have therapeutic utility for the treatment of obesity-induced T2D. As inflammation is critical for host defence, and energy consuming in nature, the blockade of inflammatory processes may, however, result in unwanted complications. In this review, we outline the immunological changes that occur within the WAT with respect to systemic glucose homeostasis. In particular, we focus on the role of major immune cell types in regulating nutrient homeostasis and potential initiating stimuli for WAT inflammation.
Assuntos
Tecido Adiposo/metabolismo , Metabolismo dos Carboidratos/fisiologia , Glucose/metabolismo , Inflamação/metabolismo , Obesidade/metabolismo , Tecido Adiposo/patologia , Animais , Humanos , Inflamação/patologia , Obesidade/patologiaRESUMO
Obesity and type 2 diabetes are now the most prevalent metabolic diseases in the Western world and the development of new strategies to treat these metabolic diseases is most warranted. Obesity results in a state of chronic low-grade inflammation in metabolically active tissues such as the liver, adipose tissue, brain and skeletal muscle. Work in our laboratory has focussed on the role of the cytokine interleukin-6 (IL)-6 and other IL-6-like cytokines that signal through the gp130 receptor complex. We have focussed on the role of blocking IL-6 trans-signalling to prevent inflammation on the one hand, and activating membrane-bound signalling to promote insulin sensitivity on the other hand. Since the cloning of the IL-6 gene nearly 30 years ago, a pattern has emerged associating IL-6 with a number of diseases associated with inflammation including rheumatoid arthritis (RA), Crohn's disease and several cancers. Accordingly, tocilizumab, an IL-6 receptor-inhibiting monoclonal antibody, is now useful for the treatment of RA. However, this may not be the most optimal strategy to block inflammation associated with IL-6 and may result in unwanted side effects that, paradoxically, could actually promote metabolic disease.
