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Impaired Central Insulin Response in Aged Wistar Rats: Role of Adiposity

Facultad de Ciencias de la Salud (M.G.-S.F., T.F.-A., M.R.), Universidad Rey Juan Carlos, Alcorcón, 28922 Madrid, Spain; Centro de Biología Molecular Severo Ochoa (A.J.D.S., J.M.C.), Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Cientificas, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain; and Área de Bioquímica (A.A., C.A.), Centro Regional de Investigaciones Biomédicas (CRIB), Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, 13003 Ciudad Real, Spain

Address all correspondence and requests for reprints to: Manuel Ros Pérez, Ph.D., Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. Atenas s/n, Alcorcón, 28922 Madrid, Spain. E-mail: manuel.ros{at}urjc.es.

Insulin, like leptin, is considered as a lipostatic signal acting at a central level. Aging and age-associated adiposity have been related to the development of leptin resistance in Wistar rats. In the present article, hypothalamic insulin response during aging has been studied in Wistar rats. Thus, the effects of intracerebroventricular infusion of insulin during a week on food intake and body weight as well as insulin signal transduction after acute intracerebroventricular insulin administration have been studied in 3-, 8-, and 24-month-old rats. To explore the possible role of age-associated adiposity, these experiments were also performed in 8- and 24-month-old rats after 3 months of food restriction to reduce visceral adiposity index to values below those of young animals. Intracerebroventricular administration of insulin during a week was more efficient at reducing food intake and body weight in 3-month-old rats than in 8- and 24-month-old rats. Hypothalamic insulin-stimulated insulin receptor, GSK3, AKT, and p70S6K phosphorylation decreased with aging. Insulin receptor and IRS-2 phosphoserine was increased in 24-month-old rats. Food restriction improved both insulin responsiveness and insulin signaling. These data suggest that Wistar rats develop hypothalamic insulin resistance with aging. This can be explained by alterations of the signal transduction pathway. The fact that food restriction improves central insulin response and signal transduction points to the age-associated adiposity as a key player in the development of central insulin resistance.