Metabolomic profiling in liver of adiponectin knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action

Abstract

Adiponectin mediates antidiabetic effects via increasing hepatic insulin sensitivity and direct metabolic effects. In this study we conducted a comprehensive and unbiased metabolomic profiling of liver tissue from adiponectin knockout (AdKO) mice, with and without adiponectin supplementation, fed high fat diet (HFD) to derive insight into the mechanisms and consequences of insulin resistance. Hepatic lipid accumulation and insulin resistance induced by HFD were reduced by adiponectin. HFD significantly altered levels of 147 metabolites and bioinformatic analysis indicated that one of the most striking changes was the profile of increased lysophospholipids. These changes were largely corrected by adiponectin, at least in part via direct regulation of phospholipase A2 (PLA2) as palmitate-induced PLA2 activation was attenuated by adiponectin in primary hepatocytes. Notable decreases in several glycerolipids after HFD were reversed by adiponectin which also corrected elevations in several diacyglycerol and ceramide species. Our data also indicate that stimulation of ω-oxidation of fatty acids by HFD is enhanced by adiponectin. In conclusion, this metabolomic profiling approach in AdKO mice identified important targets of adiponectin action, including PLA2 to regulate lysophospholipid metabolism and ω-oxidation of fatty acids.