Location: Children's Nutrition Research CenterTitle: Abalation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues Author
|Chang, Benny H.|
Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/17/2011
Publication Date: 11/14/2011
Citation: Lin, L., Saha, P.K., Ma, X., Henshaw, I.O., Shao, L., Chang, B.J., Buras, E., Tong, Q., Chan, L., Mcguinness, O.P., Sun, Y. 2011. Abalation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and borwn adipose tissues. Aging Cell. 10(6):996-1010. Interpretive Summary: Aging is associated with increased fat deposition in white fat, and impaired heat-generating ability in brown fat; both contribute to increased incidences of obesity and type 2 diabetes. Ghrelin is the only known circulating hormone which promotes fat deposition. In this study, we show that deletion of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) improves the response to insulin during aging. We discovered that GHS-R plays an important role in heat-production during aging, and ablation of GHS-R improves aging-associated obesity and responsiveness to insulin by reducing fat deposition and increasing heat production. GHS-R blockers thus may be a new means of combating obesity by shifting the energy balance from fat-generation to heat-generation.
Technical Abstract: Aging is associated with increased adiposity in white adipose tissues and impaired thermogenesis in brown adipose tissues; both contribute to increased incidences of obesity and type 2 diabetes. Ghrelin is the only known circulating orexigenic hormone that promotes adiposity. In this study, we show that ablation of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) improves insulin sensitivity during aging. Compared to wild-type (WT) mice, old Ghsr(-/-) mice have reduced fat and preserve a healthier lipid profile. Old Ghsr(-/-) mice also exhibit elevated energy expenditure and resting metabolic rate, yet have similar food intake and locomotor activity. While GHS-R expression in white and brown adipose tissues was below the detectable level in the young mice, GHS-R expression was readily detectable in visceral white fat and interscapular brown fat of the old mice. Gene expression profiles reveal that Ghsr ablation reduced glucose/lipid uptake and lipogenesis in white adipose tissues but increased thermogenic capacity in brown adipose tissues. Ghsr ablation prevents age-associated decline in thermogenic gene expression of uncoupling protein 1 (UCP1). Cell culture studies in brown adipocytes further demonstrate that ghrelin suppresses the expression of adipogenic and thermogenic genes, while GHS-R antagonist abolishes ghrelin's effects and increases UCP1 expression. Hence, GHS-R plays an important role in thermogenic impairment during aging. Ghsr ablation improves aging-associated obesity and insulin resistance by reducing adiposity and increasing thermogenesis. Growth hormone secretagogue receptor antagonists may be a new means of combating obesity by shifting the energy balance from obesogenesis to thermogenesis.