Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model

Abstract

Mitrani P, Srinivasan M, Dodds C, Patel MS. Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model. Am J Physiol Endocrinol Metab 292: E1364 -E1377, 2007. First published January 16, 2007; doi:10.1152/ajpendo.00672.2006.-Exposure to a high-carbohydrate (HC) milk formula during the suckling period results in permanent metabolic programming of hyperinsulinemia in HC rats. Previous studies have shown that hyperinsulinemia in HC rats involves a programmed hyperresponsiveness to glucose. However, the immediate onset and persistence of enhanced insulin secretion throughout life suggests a role for numerous factors that control insulin secretion. Present in vivo and in vitro studies have shown a role for altered autonomic activity, including increased parasympathetic and decreased sympathetic activities, in the maintenance of hyperinsulinemia in 100-day-old HC rats. HC rats were shown to be more sensitive to cholinergic-induced potentiation of glucose-stimulated insulin secretion (GSIS) in response to acetylcholine and showed increased sensitivity to blockade of cholinergic-induced insulin secretion by the muscarinic-type 3 receptor-specific antagonist 4-diphenylacetoxy-Nmethylpiperidine. In addition, HC rats were less sensitive to adrenergic-induced inhibition of insulin secretion by oxymetazoline, whereas treatment with yohimbine resulted in increased GSIS. Furthermore, HC rats showed greater reductions in plasma insulin levels after vagotomy, as well as an attenuation of yohimbine-induced potentiation of GSIS, suggesting that yohimbine-mediated changes are mediated by parasympathetic activity. Changes in autonomic regulation of GSIS are supported by increased mRNA levels of the parasympathetic signaling molecules muscarinic-type 3 receptor, phospholipase C␤1, and protein kinase C-␣ and decreased levels of ␣ 2a-adrenergic receptors in islets from adult HC rats. In conclusion, metabolic programming of hyperinsulinemia throughout adulthood of HC rats involves changes in autonomic activity in response to the HC dietary intervention in the suckling period.high-carbohydrate milk formula; parasympathetic nervous system; and sympathetic nervous system STUDIES OF THE RISING PREVALENCE of obesity, type 2 diabetes mellitus (48), and metabolic syndrome (19) suggest that the origins of these growing epidemics involve an acquired susceptibility to altered nutritional environments during critical periods of early development, including both the fetal and neonatal periods (9,47). This vulnerability manifests as a metabolic programming phenomenon in which a stimulus or insult during critical periods of organogenesis in early life induces permanent alterations in the development and function of affected organs at the cellular, biochemical, and molecular levels to increase the chance of survival in altered nutritional environments (52). These adaptations result in an increased susceptibility to metabolic diseases in adulthood, including obesity, type 2 diabetes mellitus, an...

Metabolic programming effects initiated in the suckling period predisposing for adult-onset obesity cannot be reversed by calorie restriction

“…The metabolic phenotype (body weight, serum hormone levels, insulin secretory capacity of islets, and hypothalamic characteristics) of the HF rats during both the preweaning and postweaning periods was similar to that of the MF rats, which suggests that the development of the HC phenotype was not influenced by the artificial rearing technique employed in our studies (11,16,18,19,30,33,34). Because of the similarity in the phenotype of MF and HF rats, we used only MF rats as control in the present study.…”

“…Although insulin secretion is regulated primarily by circulating glucose concentrations (15), the ANS also controls insulin secretion by islets (2,32). HC islets demonstrated aberrations at both of these levels of regulation of insulin secretion: 1) a leftward shift in the response to glucose (1,29) and 2) an increased PNS activity (increased response to ACh stimulation) and a compromised SNS activity (diminished inhibition by OM) (18,19). Our results indicate that although serum insulin levels were normalized in the adult HC/PF rats, the in vitro insulin secretory capacity of HC/PF islets did not differ from that observed for HC islets.…”

Swimming exercise at weaning improves glycemic control and inhibits the onset of monosodium l-glutamate-obesity in mice

“…While adult (90-day-old) MSG rats are normoglycemic, neonatal MSG adult mice have hyperglycemia (Lucinei Balbo et al 2000, Grassiolli et al 2007. Insulin oversecretion and altered ANS activity have been registered in these MSG-obese rodents (Lucinei Balbo et al 2000, Balbo et al 2002 and in other obese animal models (Campfield et al 1986, Jeanrenaud 1986, Mitrani et al 2007). It has also been shown in our laboratory that MSG-obese mice also have high parasympathetic input and impairment in sympathoadrenal axis activity.…”

Efeito da redução de ninhada sobre as respostas autonômicas e metabólicas de ratos Wistar

“…Estudos apontam ainda que a obesidade está diretamente associada a comorbidades, como a dislipidemia [5][6][7]20,32 . O SNA tem papel fundamental no controle metabólico 23,34 . O equilíbrio do metabolismo corporal prescinde de ações hormonais que são coordenadas entre SNS e SNP 10 .…”

“…O equilíbrio do metabolismo corporal prescinde de ações hormonais que são coordenadas entre SNS e SNP 10 . Ao longo do desenvolvimento, surgem adaptações funcionais necessárias para garantir a manutenção desse controle e evitar alterações do metabolismo 24,34,35 . O hipotálamo de roedores encerra seu desen- volvimento no final do desmame, perdurando por algumas semanas, portanto qualquer evento metabólico adverso nesse período pode comprometer a organização estrutural do sistema nervoso central e determinar alterações funcionais importantes 18 .…”