Abstract
GPR109A agonists have been used for the treatment of obesity however, the role of GPR109A in regulating aging-associated alterations in lipid metabolism is unknown. In this study we used Gpr109a-/- mice to investigate the effect of aging in the regulation of lipid accumulation. We observed that in mouse and human livers, in addition to Kupffer cells, GPR109A is expressed in hepatocytes. Over 12 months, compared to wild type (WT), Gpr109a-/- mice gained significantly more weight. Food intake and levels of serum lipids were similar among both groups. Compared to age-matched WT mice, 12-months old Gpr109a-/- mice had significantly increased liver weight, hepatic steatosis and serum markers of liver injury. The fatty liver phenotype in Gpr109a-/- mice was associated with increased hepatic expression of lipogenesis genes and decreased expression of lipolysis genes. Gpr109a-/- mice had significantly increased fat tissues, which was associated with significant increase in adipocyte diameter and surface area. Adipose tissue from Gpr109a-/- mice had increased expression of lipogenesis genes; however, expression of lipolytic genes was similar in both groups. Collectively, these results indicate that during aging, GPR109A modulates de novo lipid accumulation in liver and adipose tissue, and its dysregulation can lead to age-associated obesity and hepatic steatosis.
Highlights
Aging is a process of multidimensional organism decline
A number of mechanisms such as increased dietary lipid consumption and hepatic lipid synthesis or decreased lipid catabolism [6,7,8] have been evaluated to explain the impact of aging on the aforementioned conditions several important questions remained unanswered (i.e., is the higher prevalence of Non-alcoholic fatty liver disease (NAFLD) seen in the elderly population a result of physiological changes related to aging or is it a reflection of lifestyle-associated factors? Is aging an actual risk factor for liver diseases, or a merely a bystander? [7])
Wild type (Gpr109a+/+, wild type (WT)) and Gpr109a−/− mice were maintained in our laboratory on a diet of standard rodent chow for 12 months
Summary
Aging is a process of multidimensional organism decline. By 2050, 22% of the world’s population will be greater than 60 years of age [1]. Aging itself is not a disease it is one of the leading risk factors for many debilitating diseases [2, 3] This is not surprising especially given that the liver, a major regulator of metabolic function, is prominently impacted in the aging process. Understating better mechanisms that underlie agerelated liver damage and/or dysfunction such that strategies to protect and preserve this vital metabolic organ can be developed is of paramount importance. This age-associated risk is further magnified in conjunction with obesity. With a goal of improving the current understanding of these topics, in the present study we focused on the Gprotein coupled receptor GPR109A
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