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

Abstract

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 paper, 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 detection 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 of 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. GHS-R antagonists may be a new means of combating obesity by shifting the energy balance from obesogenesis to thermogenesis.

Effects of peripheral administration of ghrelin antagonist [D-Lys<sup>3</sup>]-GHRP-6 on growth performance and blood biochemical indices in broiler chickens

“…Furthermore, the results reported in this study, as shown in Table 2, are in agreement with those of Lin et al (2011) who reported less food intake in mice with ablation of ghrelin receptor. Nevertheless, the results observed in this study with respect to decreased feed intake in chickens, given in Table 2, contradict those of Vizcarra et al (2012), who studied active immunization of ghrelin in turkeys.…”

“…They maintained that changes in glycemic control attributed to infusion of GHS-R antagonist might cause less food intake and weight gain (Asakawa et al, 2003). In another study, Lin et al (2011) mentioned that ablation of ghrelin receptor may cause less food intake and reduce adiposity in mice. In a study on growing pigs (Vizcarra et al, 2007), after active immunization against ghrelin, reduced feed intake (mild anorexia) and body weight gain were observed.…”

“…Asakawa et al (2003) argued that continuous injection of [D-Lys 3 ]-GHRP-6 (200 ng, every 12 h for 6 days) in rats resulted in considerable decreases in serum glucose level and moderate decrease in total cholesterol. Lin et al (2011) maintained that the ablation of ghrelin receptor led to a hypoglycemic effect in old rats.…”

Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARγ signaling pathway

“…Recent studies suggest alternative pathways for lipid metabolism involving peripheral actions of ghrelin. The presence of functional GHSR1a has been demonstrated in adipocytes by pharmacological, physiological, and genetic studies (16,17). Both GHSR1a-dependent and GHSR1a-independent mechanisms have been reported to mediate the effects of ghrelin on adipogenesis and lipid metabolism in adipocytes (6,18).…”

Obesity and related consequences to ageing

“…It has been shown that BAT exerts anti-type 2 diabetic effects associated with improvements of dyslipidemia and insulin secretion (de Souza et al 1997;Peirce and Vidal-Puig 2013). Moreover, recent studies on rodents have showed that caloric restriction postpones the age-related decline in BAT mitochondrial function (Valle et al 2008) and ghrelin ablation in older individuals prevents age-associated decline in UCP1 gene expression (Lin et al 2011). Therefore, it may be possible to prevent the age-related decrease BAT content and in consequence decelerate age-related fat mass accumulation and development of diabetes.…”