Attenuation of age-related declines in glucagon-mediated signal transduction in rat liver by exercise training

Abstract

This study investigated alterations in glucagon receptor-mediated signal transduction in rat livers from 7- to 25-mo-old animals and examined the effects of exercise training on ameliorating these changes. Sixty-six young (4 mo), middle-aged (12 mo), and old (22 mo) male Fischer 344 rats were divided into sedentary and trained (treadmill running) groups. Isolated hepatic membranes were combined with [(125)I-Tyr(10)]monoiodoglucagon and nine concentrations of glucagon to determine maximal binding capacity (B(max)) and dissociation constant (K(d)). No alterations were found in B(max) among groups; however, middle-aged trained animals had significantly higher glucagon affinity (lower K(d); 21.1 +/- 1.8 nM) than did their untrained counterparts (50.2 +/- 7.1 nM). Second messenger studies were performed by measuring adenylyl cyclase (AC) specific activity under basal conditions and with four pharmacological stimulations to assess changes in receptor-dependent, G protein-dependent, and AC catalyst-dependent cAMP production. Age-related declines were observed in the old animals under all five conditions. Training resulted in increased cAMP production in the old animals when AC was directly stimulated by forskolin. Stimulatory G protein (G(s)) content was reduced with age in the sedentary group; however, training offset this decline. We conclude that age-related declines in glucagon signaling capacity and responsiveness may be attributed, in part, to declines in intrinsic AC activity and changes in G protein [inhibitory G protein (G(i))/G(s)] ratios. These age-related changes occur in the absence of alterations in glucagon receptor content and appear to involve both G protein- and AC-related changes. Endurance training was able to significantly offset these declines through restoration of the G(i)/G(s) ratio and AC activity.

Alterations of epinephrine-induced gluconeogenesis in aging

“…The catecholamine challenge in aged individuals shows deteriorated response (Morgan et al, 1983;Mabry et al, 1995;Podolin et al, 1996;Marker et al, 1998;Podolin et al, 2001). A deterioration of the catecholamine response with aging was suggested to be due to an Epinephrine induced PEPCK and PGC-1α expressions differ in young and old rat primary hepatocytes.…”

The Characteristics of Hepatic Gsα-cAMP Axis in HSHF Diet-Fed Obese Insulin Resistance Rats and Genetic Diabetic Mice

“…Consistent with the previous report by Charbonneau et al 29) Gsα, GlucR and ADRB 2 levels in liver were decreased by HFD diet. We speculated that HSHF-diet or aging could accelerate the desensitization and destruction of the hepatic Gsα-cAMP signal axis, resulting in decreased HGP, 13,[30][31][32][33] and these reduced hepatic Gsα-cAMP signal axis would finally strengthen IR and was able to cause hepatic steatosis. 29,33) This different tendency of hepatic Gsα-cAMP signal axis in progressing of IR also indicated that it is critical to select a suitable animal model in the research on different signaling molecules in IR.…”

“…Interestingly, Podolin et al reported that the reduction of Gsα protein was concurrent with a decrease of intracellular cAMP production with age, which may account for age-related declines in hepatic gluconeogenesis in older animals and humans. 13,14) Although many reports focused on the role of Gsα deficiency in glucose metabolism, less attention had been paid on the dynamic characterizatics of hepatic Gsα-cAMP signal axis in the process from IR to T2DM, which are important to understand the pathophysiological mechanism of hepatic IR and may also contribute to the prevention and treatment of diabe-tes. Thus, the changing characterizatics of hepatic Gsα-cAMP signal axis were studied in chronic high-sugar-high-fat (HSHF) diet-fed obese Wistar rats and diabetic db/db mice.…”

Treinamento de natação na intensidade do limiar anaeróbio melhora a aptidão funcional de ratos idosos

“…Por outro lado, a realização crônica de exercícios físicos mostra-se como uma importante intervenção não farmacoló-gica no tratamento e prevenção de diversas disfunções (3) , reduzindo os fatores de risco associados ao envelhecimento e resultando em aumento da qualidade e expectativa de vida (4) .…”

“…A prática de atividade física diminui o número de internações, doenças cardíacas, diabetes e hipertensão (10,12,13) , previne o risco de quedas (14) , além de proporcionar bem-estar psicológico fundamental para melhor qualidade de vida (15) . Alguns estudos, por utilizarem-se de manipulações invasivas durante exercício físico, têm sido realizados em modelo animal, envolvendo a natação (9,16) e a corrida como forma de exercício, em ratos (3,17) . A determinação da intensidade de exercício em ratos permite simular condições de estresse físico observadas em humanos, visando o melhor acompanhamento das alterações sistêmicas decorrentes do exercício agudo e crônico.…”