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United States Department of Agriculture

Agricultural Research Service

Research Project: MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF OBESITY DEVELOPMENT IN CHILDREN

Location: Children's Nutrition Research Center

Title: Abalation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues)

Author
item Lin, Ligan
item Saha, Pradip
item Ma, Xiaojun
item Henshaw, Iyabo
item Shao, Longjiang
item Chang, Benny H.
item Buras, Ericd
item Tong, Qiang
item Chan, Lawrence
item Mcguinness, Owen
item Sun, Yuxiang

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.

Last Modified: 8/24/2016
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