RESUMO
The effects of leptin on cocaine- and amphetamine-regulated transcript (CART) and agouti-related protein (AGRP) expression in the hypothalamic arcuate nucleus of obese A(y)/a mice were investigated. CART mRNA expression was upregulated by 41% and AGRP mRNA downregulated by 78% in hyperleptinemic A(y)/a mice relative to levels in lean a/a mice. The mRNA expression of these neuropeptides in either young nonobese A(y)/a mice or rats treated with SHU-9119, a synthetic melanocortin-4 receptor (MC4R) antagonist, did not differ significantly from that in the corresponding controls. After a 72-h fast, which decreased the concentration of serum leptin, CART and AGRP mRNA expression decreased and increased, respectively, in A(y)/a mice. The expression levels of these neuropeptides in leptin-deficient A(y)/a ob/ob double mutants were comparable to those in a/a ob/ob mice. Leptin thus modulates both CART and AGRP mRNA expression in obese A(y)/a mice, whereas leptin signals are blocked at the MCR4R level. Taken together, the present findings indicate that differential expression of these neuropeptides in A(y)/a and ob/ob mice results in dissimilar progression toward obesity.
Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Leptina/sangue , Proteínas do Tecido Nervoso/genética , Obesidade/metabolismo , Proteína Relacionada com Agouti , Animais , Peso Corporal , Insulina/sangue , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Hormônios Estimuladores de Melanócitos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neurotransmissores/genética , Obesidade/genética , Proteínas/genética , RNA Mensageiro/análise , RNA Ribossômico/análise , Ratos , Ratos Wistar , Receptor Tipo 4 de Melanocortina , Receptores de Peptídeos/antagonistas & inibidoresRESUMO
We examined the effects of chronic centrally administered leptin on the glucose metabolism of streptozotocin-induced diabetic (STZ-D) rats, a model for insulin-dependent diabetes mellitus. When 3 microg.rat(-1).day(-1) of leptin was infused into the third ventricle for 6 consecutive days (STZ-LEP), STZ-D rats became completely euglycemic. The effect was not seen when the same dosage was administered s.c. Centrally administered leptin did not affect peripheral insulin levels. The feeding volume of STZ-LEP rats was suppressed to the level of non-STZ-D control rats. No improvement of hyperglycemia was noted when STZ-D rats were pair-fed to match the feeding volume of STZ-LEP rats. Thus, the euglycemia of STZ-LEP rats cannot be due to the decreased feeding volume. In the STZ-D rat, glucokinase mRNA, a marker of glycolysis, is down-regulated whereas glucose-6-phosphatase mRNA, a marker of gluconeogenesis, and glucose transporter (GLUT) 2, which is implicated in the release of glucose from liver, are up-regulated. GLUT4, uncoupling protein (UCP) 1, and UCP3 were down-regulated in brown adipose tissue. These parameters returned to normal upon central infusion of leptin. GLUT4 was not down-regulated in the skeletal muscle of STZ-D rats; however, fatty acid binding protein and carnitine palmitoyltransferase I, markers for utilization and beta-oxidation of fatty acids, were up-regulated and restored when the rats were treated with leptin. The increase and subsequent decrease of fatty acid utilization suggests a decrease of glucose uptake in the skeletal muscle of STZ-D rats, which was restored upon central leptin administration. We conclude that centrally infused leptin does not control serum glucose by regulating feeding volume or elevating peripheral insulin, but by regulating hepatic glucose production, peripheral glucose uptake, and energy expenditure. The present study indicates the possibility of future development of a new class of anti-diabetic agents that act centrally and independent of insulin action.
