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Characterization of Adult Ghrelin and Ghrelin Receptor Knockout Mice under Positive and Negative Energy Balance

Huffington Center on Aging (Y.S., R.G.S.), Department of Molecular and Cellular Biology (Y.S., R.G.S.); Children’s Nutrition Research Center, Department of Pediatrics (N.F.B.); Division of Endocrinology, Diabetes, and Metabolism (J.M.G.); and Michael E. DeBakey, Houston Veterans Affairs Medical Center (J.M.G.), Department of Medicine (R.G.S.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Roy Smith, Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, M320, Houston, Texas 77030. E-mail: rsmith{at}bcm.tmc.edu.

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 directly regulate energy intake and energy expenditure.