RESUMO
The metabolic syndrome is a worldwide problem mainly caused by obesity. FTO was found to be a obesity-risk gene in humans and FTO deficiency in mice led to reduction in adipose tissue. Thus, FTO is an important factor for the development of obesity. Leptin-deficient mice are a well characterized model for analysing the metabolic syndrome. To determine the relevance of FTO for the development of the metabolic syndrome we analysed different parameters in combined homozygous deficient mice (Lep(ob/ob);Fto(-/-)). Lep(ob/ob);Fto(-/-) mice showed an improvement in analysed hallmarks of the metabolic syndrome in comparison to leptin-deficient mice wild type or heterozygous for Fto. Lep(ob/ob);Fto(-/-) mice did not develop hyperglycaemia and showed an improved glucose tolerance. Furthermore, extension of beta-cell mass was prevented in Lep(ob/ob);Fto(-/-)mice and accumulation of ectopic fat in the liver was reduced. In conclusion this study demonstrates that FTO deficiency has a protective effect not only on the development of obesity but also on the metabolic syndrome. Thus, FTO plays an important role in the development of metabolic disorders and is an interesting target for therapeutic agents.
Assuntos
Síndrome Metabólica/genética , Oxigenases de Função Mista/genética , Oxo-Ácido-Liases/genética , Tecido Adiposo/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Animais , Peso Corporal/genética , Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Predisposição Genética para Doença , Hepatócitos/metabolismo , Hiperglicemia/genética , Hiperglicemia/metabolismo , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Leptina/deficiência , Leptina/genética , Metabolismo dos Lipídeos , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Camundongos KnockoutRESUMO
CONTEXT: CD73 converts extracellular AMP to adenosine which is well known to inhibit lipolysis. It is unknown, however, whether adenosine formed directly by CD73 is functionally relevant in this process. OBJECTIVE: We therefore explored the effect of CD73-derived adenosine on body fat of aged mice. RESULTS: In lean mice, extracellular adenosine formation by adipocytes is dependent on CD73. High fat diet down-regulates the expression of CD73 in wildtype mice similar to ob/ob mice. Transgenic mice chronically lacking CD73 (CD73(-/-)) gain significantly less body weight and show decreased superficial white fat content as well as increased serum free fatty acids and triglycerides. In addition, intramyocellular lipid levels are significantly increased. This phenotype is accompanied by an increase in blood glucose and serum insulin levels although insulin secretion and the level of insulin degrading enzyme are unaltered. Additionally, insulin-induced Akt phosphorylation is reduced in skeletal muscle of CD73(-/-) mice. CONCLUSION: CD73-derived adenosine is functionally involved in body fat homeostasis.