Submitted to: Endocrinology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 11/15/2007
Publication Date: 2/1/2008
Citation: Sun, Y., Butte, N.F., Garcia, J.M., Smith, R.G. 2008. Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. Endocrinology. 149(2):843-850. Interpretive Summary: The roles of the hormone ghrelin and its receptor, growth hormone secretagogue receptor, in the regulation of energy regulation were investigated using congenic (N10) adult ghrelin-/- and Ghsr-/- mice. Energy expenditure and fuel utilization were measured using calorimetry under conditions of positive and negative energy balance. Positive energy balance was achieved by 35% high fat diet feeding and negative energy balance by 50% caloric restriction. Changes in body weight and energy expenditure were not different between the two strains of mice. Under caloric restriction, weight loss was identical but blood glucose levels were significantly lower in the congenic ghrelin-/- and Ghsr-/- mice compared to wild type mice. We detected a modest decrease in RQ in our congenic adult ghrelin-/- compared to ghrelin+/+ mice fed a normal diet, but not when fed a high fat diet. We conclude that adult congenic ghrelin-/- and Ghsr-/- mice are not resistant to obesity, but are deficient in maintaining glucose levels under negative energy balance. The main role of ghrelin seems to be in the regulation of glucose sensing and insulin sensitivity, rather than energy regulation.
Technical Abstract: Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R) are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and negative (caloric restriction) energy balance. In contrast to results from young N2 mutant mice, changes in body weight and energy expenditure are not clearly distinguishable across genotypes. Although respiratory quotient was lower in mice fed a high-fat diet, no differences were evident between littermate wild-type and null genotypes. With normal chow, a modest decrease trend in respiratory quotient was detected in ghrelin(-/-) mice but not in Ghsr(-/-) mice. Under caloric restriction, the weight loss of ghrelin(-/-) and Ghsr(-/-) mice was identical to wild-type littermates, but blood glucose levels were significantly lower. We conclude that adult congenic ghrelin(-/-) and Ghsr(-/-) mice are not resistant to diet-induced obesity, but under conditions of negative energy balance show impairment in maintaining glucose homeostasis. These results support our hypothesis that the primary metabolic function of ghrelin in adult mice is to modulate glucose sensing and insulin sensitivity, rather than to directly regulate energy intake and energy expenditure.