Blunted hypothalamic neuropeptide gene expression in response to fasting, but preservation of feeding responses to AgRP in aging male Brown Norway rats

Abstract

Aging mammals lose the ability to maintain energy balance, exhibiting decreased appetite (anorexia) and impaired ability to maintain body weight. To determine the contribution of hypothalamic neuropeptides, two experiments were performed in male Brown Norway rats. To assess the hypothalamic neuropeptide response to food deprivation, young (Y; 4 mo old), middle-aged (M; 13 mo), and old (O; 25 mo) rats were either ad libitum fed or fasted for 72 h (n = 10/group) and killed. Hypothalamic levels of agouti-related peptide (AgRP), proopiomelanocortin (POMC), and cocaine-amphetamine-regulated transcript (CART) mRNA were assessed by in situ hybridization. With aging, arcuate AgRP gene expression decreased and CART mRNA increased, but POMC mRNA did not change. Fasting-induced changes in gene expression of all neuropeptides studied were attenuated with aging. To test the food intake response to appetite-stimulating neuropeptides, Y, M, O, and very old (VO; 33 mo) rats (n = 4-8/group) received one intracerebroventricular injection of each of three treatments: 0.1 nmol AgRP, 2.34 nmol NPY, and saline control. AgRP increased food intake of all groups by 10-20%, compared with saline, and this effect persisted up to 7 days after injection. VO animals were more sensitive to the effects of AgRP than younger animals. In contrast, NPY increased food intake more in Y than in older animals and its effects did not last >24 h. We conclude that the mechanisms by which arcuate nucleus neurons influence appetite are differentially affected by age and speculate that the melanocortin system may be a useful target for treatment of the anorexia of aging.

Mechanisms of the anorexia of aging—a review

“…Its anorexigenic activity results from the inhibition of NPY neurons. Results for agerelated changes are inconclusive: some authors reported increased CART mRNA expression ( Wolden-Hanson et al 2004), while others found no changes (Kappeler et al 2003). As shown by Sohn et al, testosterone may lower hypothalamic CART mRNA levels (Bender et al 2014).…”

“…Results of studies on changes in NPY secretion with aging are inconclusive. NPY mRNA expression declines with aging in rats ( Wolden-Hanson et al 2004) and older rats show altered feeding responses to NPY (Blanton et al 2001). It has been found that aging decreased the feeding and drinking effects of NPY in rats (Pich et al 1992), but not in mice (Morley et al 1987).…”

“…Animal studies indicate that the expression of AgRP is decreased in older rats (Lin et al 2014). Other authors found that fasting-induced changes in gene expression of AgRP is attenuated with aging, but older animals are more sensitive to the effects of AgRP than younger animals ( Wolden-Hanson et al 2004). No data for aging-related changes in AgRP levels are available for humans.…”

Stability of CART peptide expression in the nucleus accumbens in aging

“…CART peptide expression is stable through adulthood hypothalamic expressions of numerous orexigenic neuropeptides such as npy, agRp and orexins were changed during aging, however, expression of the anorexigenic neuropeptide pomC was similar in young and old animals [13,14,26,28,34]. in the arcuate nucleus of aging animals, decrease of npy expression was detected, which coincided by an increase of CaRt expression [34].…”

“…decreased expression of agouti-related peptide (agRp) and neuropeptide y (npy) genes was demonstrated in the hypothalamic arcuate nucleus with the age, and very old animals have shown increased sensitivity for agRp compared to younger animals [34]. in contrast, npy had a stronger effect on food intake in younger rats than in aged animals [2,8].…”