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

Aging Cell

Ligen Lin¹  Pradip K. Saha²  Xiaojun Ma¹  Iyabo O. Henshaw¹  Longjiang Shao⁴  Benny H. J. Chang²  Eric D. Buras²  Qiang Tong¹  Lawrence Chan²  Owen P. McGuinness³ 

[1] USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA;Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA;Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicines, Nashville, TN 37232, USA;Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA

关键词: aging;    ghrelin;    growth hormone secretagogue receptor;    insulin resistance;    obesity;    thermogenesis;   

DOI  :  10.1111/j.1474-9726.2011.00740.x

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

Unknown   
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland