title: Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues.
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.
authors: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Ligen
authors: L
authors: Lin
authors: Pradip K
authors: PK
authors: Saha
authors: Xiaojun
authors: X
authors: Ma
authors: Iyabo O
authors: IO
authors: Henshaw
authors: Longjiang
authors: L
authors: Shao
authors: Benny H J
authors: BH
authors: Chang
authors: Eric D
authors: ED
authors: Buras
authors: Qiang
authors: Q
authors: Tong
authors: Lawrence
authors: L
authors: Chan
authors: Owen P
authors: OP
authors: McGuinness
authors: Yuxiang
authors: Y
authors: Sun
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D050154:Adiposity / Q000235:genetics; D000375:Aging / Q000235:genetics*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D022722:Thermogenesis / Q000502:physiology; D000071256:Uncoupling Protein 1
chemical_list: D054439:Ghrelin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D054440:Receptors, Ghrelin; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1