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

Abstract

Adiponectin mediates anti-diabetic effects via increasing hepatic insulin sensitivity and direct metabolic effects. In the present study, we conducted a comprehensive and unbiased metabolomic profiling of liver tissue from AdKO (adiponectin-knockout) mice, with and without adiponectin supplementation, fed on an HFD (high-fat diet) to derive insight into the mechanisms and consequences of insulin resistance. Hepatic lipid accumulation and insulin resistance induced by the HFD were reduced by adiponectin. The 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 PLA2 (phospholipase A2) as palmitate-induced PLA2 activation was attenuated by adiponectin in primary hepatocytes. Notable decreases in several glycerolipids after the 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 the 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.

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

“…Adiponectin mediates its antidiabetic effects in part by increasing hepatic insulin sensitivity and by preventing hepatic lipid accumulation. APNko mice on a high-fat diet develop hepatic lipid accumulation and insulin resistance, an effect that was reversed by adiponectin supplementation (43). In line with these data, we found that APNko mice challenged with DHT have increased liver lipid content, while normal or elevated adiponectin levels protect against fatty liver in DHT-exposed mice.…”

“…Liver triglyceride content did not correlate with serum triglyceride levels in APNko-DHT mice, while APNtg mice had lower circulating triglycerides. There may be multiple protective effects of adiponectin on hepatic steatosis and hypertriglyceridemia, including direct action on the liver, improved capacity for safe deposition of excess nutrients in the s.c. fat compartment, and an increased metabolic activity in BAT (16,17,(42)(43)(44).…”

Metabolomic and lipidomic analysis of the effect of pioglitazone on hepatic steatosis in a rat model of obese Type 2 diabetes

“…First, we determined the expression of genes involved in de novo lipogenesis. Pioglitazone down‐regulated expression of sterol regulatory element‐binding protein 1c (SREBP1c), the master regulator of lipogenesis, and stearoyl‐CoA desaturase‐1 (SCD1), key enzymes for the synthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids (Liu et al ., ). Gene expression of liver X receptor α and diglyceride acyltransferase 1 and 2, all of which are related to hepatic de novo lipogenesis, was decreased or trended lower in pioglitazone‐treated groups compared with control groups respectively.…”

“…palmitic acid and stearic acid) and MUFA (e.g. palmitoleic acid and oleic acid) were positively affected by a high‐fat diet (Kim et al ., ; Liu et al ., ). In our study, we observed that pioglitazone decreased palmitic acid and stearic acid, which suggests its role as a mediator of lipotoxicity.…”

The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications

“…Previously, Nawrocki and colleagues demonstrated that adiponectin-deficient mice lost hepatic insulin sensitivity and response to PPAR- γ , indicating that adiponectin contributes to PPAR- γ -mediated improvements in glucose tolerance [80]. A recent metabolomic profiling of adiponectin-deficient mice indicated that lysophospholipid metabolism and ω -oxidation of fatty acids are directly regulated by adiponectin [81]. These findings suggest that adiponectin can be an anti-inflammatory protein with therapeutic potential to ameliorate symptoms of metabolic syndrome and NASH.…”