The role of endocannabinoid receptor activity in young and aged rats with high-fat feeding

Two-thirds of adult Americans are overweight or obese, which increases the risk of developing other serious diseases. Leptin is a hormone produced in adipose tissue that acts within the hypothalamus to increase energy expenditure and decrease food intake. In contrast, endocannabinoids are produced on-demand and act on central cannabinoid-1 (CB1) receptors to stimulate food intake and fat storage. This dissertation examined leptin and CB1 antagonist responses in both young adult and aged rats with or without high-fat (HF) feeding in order to better understand the dysregulation of these two signaling systems in the aged and/or obese state.;First, we demonstrated that all aged rats, as opposed to only some young adult rats, are susceptible to the detrimental effects of a HF diet. When given ad libitum access to a HF diet, aged rats display exacerbated hyperphagia and body weight gain, characterized by a disproportionate gain in fat versus lean mass. Additionally, we demonstrated that young adult rats display dose-dependent reductions in food intake and body weight in response to peripheral leptin infusions while aged rats remain completely unresponsive to the exogenous leptin.;Next, we showed that daily i.p. administration of AM251, a CB1 antagonist, reduced the intake of the highly palatable HF diet to a greater extent than normal chow during short-term exposure do the diets. AM251 stimulated greater anorectic responses, characterized by decreases in caloric intake and body weight gain, in aged rats, and this effect was further enhanced with short-term HF feeding. In accordance with the decrease in body weight, AM251 treatment induced a reduction in adiposity and serum leptin levels in young adult and aged rats. However, AM251 was unable to change the palatability or preference of the diets tested.;After characterizing AM251 responsiveness during short-term diet exposure, we investigated responsiveness after long-term exposure. Again, AM251 induced greater anorectic effects with age and HF-feeding, measured by increased sensitivity and maximal efficacy. These results appeared to be related to the diet and established obesity as well as the development of leptin resistance. Further studies are needed to confirm the connections between leptin resistance and the dysregulation of the endocannabinoid signaling system that is believed to occur in aged and/or obese states.