Ghrelin receptor regulates appetite and satiety during aging in mice by regulating meal frequency and portion size but not total food intake

Aging is often associated with overweight and obesity. There exists a long-standing debate about whether meal pattern also contributes to the development of obesity. The orexigenic hormone ghrelin regulates appetite and satiety by activating its receptor, growth hormone secretagogue receptor (GHS-R). In mice, circulating ghrelin concentrations and brain GHS-R expression were shown to increase with aging. To assess whether GHS-R regulates feeding pattern during aging, we studied meal patterns for the following cohorts of male mice fed a normal unpurified diet: 1) 3-4 mo, young wild-type (WT) mice; 2) 3-4 mo, young Ghsr-null (Ghsr(-/-)) mice; 3) 12-14 mo, middle-aged WT (WT-M) mice; 4) 12-14 mo, middle-aged Ghsr(-/-) (Ghsr(-/-)-M) mice; 5) 24-26 mo, old WT (WT-O) mice; and 6) 24-26 mo, old Ghsr(-/-) (Ghsr(-/-)-O) mice. Although the total daily food intake of Ghsr(-/-) mice was similar to that of WT controls, Ghsr(-/-)-M and Ghsr(-/-)-O mice had 9% (P = 0.07) and 16% (P < 0.05) less body weight compared with WT-M and WT-O mice, respectively, primarily due to reduced fat mass (P < 0.05, WT-M vs. Ghsr(-/-)-M and WT-O vs. Ghsr(-/-)-O). Intriguingly, Ghsr(-/-)-M mice ate larger meals (on average, Ghsr(-/-)-M mice ate 0.117 g/meal and WT-M mice ate 0.080 g/meal; P < 0.01) and took a longer time to eat (Ghsr(-/-)-M, 196.0 s and WT-M, 128.9 s; P < 0.01), but ate less frequently (Ghsr(-/-)-M, 31.0 times/d and WT-M, 42.3 times/d; P < 0.05) than WT-M controls. In addition, we found that expression of hypothalamic orexigenic peptides, neuropeptide Y (NPY) and agouti-related peptide (AgRP), was relatively lower in aged WT mice (P = 0.09 for NPY and P = 0.06 for AgRP), but anorexic peptide pro-opiomelanocortin (POMC) expression remained unchanged between the WT age groups. Interestingly, old Ghsr(-/-) mice had greater hypothalamic NPY expression (102% higher; P < 0.05) and AgRP expression (P = 0.07) but significantly lower POMC expression (P < 0.05) when compared with age-matched WT-O controls. Thus, our results indicate that GHS-R plays an important role in the regulation of meal pattern and that GHS-R ablation may modulate feeding behavior through the regulation of hypothalamic neuropeptides. Our results collectively suggest that ghrelin receptor antagonism may have a beneficial effect on metabolism during aging.