Hypothalamic Melanocortin System in the Regulation of the Energy Homeostasis: Studies in Aging Rats and in SHR Animals

Abstract

Obesity, as a common risk factor for numerous diseases became in the last decades a major epidemiological and general healthcare challenge in Western countries. While middle-aged populations tend to become obese, old age is rather characterized by anorexia and consequent loss of active tissues (muscle) leading to sarcopenia. As both trends are also observed in other mammals common endogenous regulatory alterations may contribute to their development. As similar trends were also observed in male laboratory mice and rats, the idea arises that changes observed in humans and other mammals may share their biological background. Moreover, due to the current obesogenic environment, young adult populations and even children show increasing incidence of obesity leading to an early onset of cardiometabolic syndrome and a rise in premature mortality. Although these are well-known epidemiological observations, our knowledge on its neurobiological background is still insufficient. The main goal of this Ph.D. research program was to gain deeper insight into the hypothalamic control of energy homeostasis. As the hypothalamic melanocortin (MC) system is a major central regulator of the energy homeostasis, we hypothesized that age-related shifts in the balance of melanocortins play an important role in long-term trends of body weight (BW) during the course of aging (i.e. middle-aged obesity and aging anorexia). We analyzed the age-related changes in the effects and endogenous activity of the MC system using in vivo [i.e. measurement of BW, food intake (FI) and metabolic rate (MR), body composition (BC)] and in vitro (i.e. qRT-PCR and immunohistochemistry) techniques on hypothalamic samples of male Wistar rats of different age-groups. The MC system influences via activation of the sympathetic nervous system not only the energy homeostasis but also the blood pressure (BP) regulation. The strong interaction between these two homeostatic systems was observed in spontaneously hypertensive rats (SHR). They have high sympathetic tone and progressive hypertension. Chronic calorie-restriction was able to prevent their hypertension. Their FI and BW are lower than in normotensive controls, even on a high-fat diet, suggesting a dysregulation of energy homeostasis in these animals. Therefore, we hypothesized that the dysregulation of the hypothalamic MC system may contribute both to the development of hypertension and altered energy homeostasis in SHR. As a part of this Ph.D. project the activity of the MC system of SHR was compared with that of Wistar rats in order to understand how the dysregulation of the MC system contributes to the characteristic phenotype of SHR rats.