RESUMO
The dose-response characteristics of several glucose-utilizing tissues (brain, heart, white adipose tissue, brown adipose tissue, and quadriceps muscle) to a single injection of insulin have been compared in control mice and mice made obese with a single injection of gold thioglucose (GTG). Tissue content of [1-14C]2-deoxyglucose 6-phosphate and blood disappearance rate of [1-14C]2-deoxyglucose (2-DG) were measured at nine different insulin doses and used to calculate rates of 2-DG uptake and phosphorylation in tissues from control and obese mice. The insulin sensitivity of tissues reflected in the ED50 of insulin response varied widely, and brown adipose tissue was the most insulin-sensitive tissue studied. In GTG-obese mice, heart, quadriceps, and brown adipose tissue were insulin resistant (demonstrated by increased ED50), whereas in white adipose tissue, 2-DG phosphorylation was more sensitive to insulin. Brain 2-DG phosphorylation was insulin independent in control and obese animals. The largest decrease in insulin sensitivity in GTG-obese mice was observed in brown adipose tissue. The loss of diet-induced thermogenesis in brown adipose tissue as a result of the hypothalamic lesion in GTG-obese mice could be a major cause of insulin resistance in brown adipose tissue. Because brown adipose tissue can make a major contribution to whole-body glucose utilization, insulin resistance in this tissue may have a significant effect on whole-animal glucose homeostasis in GTG-obese mice.
Assuntos
Aurotioglucose , Desoxiaçúcares/metabolismo , Desoxiglucose/metabolismo , Ouro , Resistência à Insulina , Insulina/farmacologia , Obesidade/induzido quimicamente , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Encéfalo/metabolismo , Radioisótopos de Carbono , Relação Dose-Resposta a Droga , Glucose/metabolismo , Masculino , Camundongos , Músculos/metabolismo , Miocárdio/metabolismo , FosforilaçãoRESUMO
The amount of pyruvate dehydrogenase in the active form (PDHa) was increased 1.7-fold compared with controls in heart muscle of mice 1 week after induction of obesity with a single injection of gold-thioglucose. At 4 weeks post injection, the amount of PDHa was decreased to 32% of control, a value which was observed in later stages of the obesity syndrome. In contrast, liver PDHa was increased and remained at an increased activity during the development of obesity. Despite normal post-prandial serum insulin contents, liver membrane insulin-receptor numbers were decreased 1 week after gold-thioglucose injection, and there was no change in receptor affinity. The decrease in heart PDHa in the obese animals was reversed by a single dose of 2-tetradecylglycidic acid, but this inhibitor of mitochondrial fatty acid oxidation did not affect liver PDHa in these animals. These early and diverse changes in PDHa argue for a multifactorial aetiology in the development of the whole-body insulin resistance seen in older gold-thioglucose-treated obese animals.
Assuntos
Resistência à Insulina , Fígado/enzimologia , Miocárdio/enzimologia , Obesidade/enzimologia , Complexo Piruvato Desidrogenase/metabolismo , Animais , Aurotioglucose , Compostos de Epóxi/farmacologia , Ácidos Graxos/farmacologia , Coração/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Obesidade/induzido quimicamenteRESUMO
The proportion of pyruvate dehydrogenase complex in the active, dephosphorylated form was decreased (compared with lean controls) in heart muscle in gold thioglucose-treated obese hyperinsulinaemic mice, and the extent of enzyme inactivation was significantly linearly correlated with both body weight and body fat content. A single oral dose (25 mg/kg body wt.) of the beta-oxidation inhibitor 2-tetradecylglycidic acid to obese animals restored pyruvate dehydrogenase complex activity to that of lean controls. It is suggested that increased fatty acid oxidation may be a major factor in mediating the phosphorylation and inactivation of pyruvate dehydrogenase complex in mouse heart muscle in obesity, and this may represent an important mechanism in the development and/or expression of insulin resistance in respect of abnormalities of cellular glucose homoeostasis in these animals.