Metabolic Profiling of Serum Reveals Significant Changes in Lipid and Amino Acid Metabolism in A Lipodystrophy Mouse Model

Abstract

ObjectiveAdipose tissue serves as not only an energy reservoir to store excess energy in form of triglyceride but also as an important endocrine organ producing adipokines such as leptin and adiponectin. Lipodystrophy, characterized by abnormal or degeneration of adipose tissue, leads to metabolic diseases including hypertriglyceridemia, insulin resistance, and hepatic steatosis. Lipotoxicity is known as a major driver for the metabolic dysregulation in lipodystrophy, however, which specific lipid species and/or other factors contributes to the disease progression is not well characterized. In this study, we employed untargeted metabolomics to identify small metabolites that are altered in a lipodystrophy mouse model.MethodsWe have recently generated the lipodystrophy mouse model by which adipocyte mouse double minute 2 homolog (Mdm2) is deleted by Cre‐loxP approach. Circulating metabolites were measured and compared in the serum of adipocyte‐specific Mdm2 knockout mice at 3‐week (Before lipodystrophy development) and 12‐week old (After lipodystrophy development) with age‐matched wild‐type mice, using an untargeted metabolomics profiling by LC‐MS. Data were explored using principal component analysis and statistical analysis.ResultsOur untargeted metabolomics profiling had successfully identified and quantified more than 300 circulating metabolites in the serum samples. The results promptly point towards a significant increase in metabolites groups including carnitine and amino acids in the lipodystrophy mouse mice. During the development of lipodystrophy, serum level of phosphatidylcholines species (PC) was significantly reduced whereas increased serum sphingolipid species (including sphingosine and sphinganine) were observed in Mdm2 knockout mice is positively associated with insulin resistance. The high rate of incomplete fatty acid oxidation and accumulation of acylcarnitine metabolites may indicate the damage of skeletal muscle due to an excessive fatty‐acid metabolites supply in the lipodystrophy mice.ConclusionTogether, these data show that metabolic diseases in lipodystrophy mice is associated with the alteration of metabolites supply to other tissues. Moreover, the utilization of lipodystrophy model in investigating the mechanisms of novel therapeutic targets of metabolic disease via maintaining normal adipose tissue functions was demonstrated.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.