Adiponectin Corrects High-Fat Diet–Induced Disturbances in Muscle Metabolomic Profile and Whole-Body Glucose Homeostasis

Abstract

We provide here a detailed and comprehensive analysis of skeletal muscle metabolomic profiles in response to adiponectin in adiponectin knockout (AdKO) mice after high-fat–diet (HFD) feeding. Hyperinsulinemic-euglycemic clamp studies showed that adiponectin administration corrected HFD-induced defects in post/basal insulin stimulated Rd and insulin signaling in skeletal muscle. Lipidomic profiling of skeletal muscle from HFD-fed mice indicated elevated triacylglycerol and diacylglycerol species (16:0–18:1, 18:1, and 18:0–18:2) as well as acetyl coA, all of which were mitigated by adiponectin. HFD induced elevated levels of various ceramides, but these were not significantly altered by adiponectin. Adiponectin corrected the altered branched-chain amino acid metabolism caused by HFD and corrected increases across a range of glycerolipids, fatty acids, and various lysolipids. Adiponectin also reversed induction of the pentose phosphate pathway by HFD. Analysis of muscle mitochondrial structure indicated that adiponectin treatment corrected HFD-induced pathological changes. In summary, we show an unbiased comprehensive metabolomic profile of skeletal muscle from AdKO mice subjected to HFD with or without adiponectin and relate these to changes in whole-body glucose handling, insulin signaling, and mitochondrial structure and function. Our data revealed a key signature of relatively normalized muscle metabolism across multiple metabolic pathways with adiponectin supplementation under the HFD condition.

Adiponectin Stimulates Autophagy and Reduces Oxidative Stress to Enhance Insulin Sensitivity During High-Fat Diet Feeding in Mice

“…Here, we used WT and Ad-KO (with and without adiponectin replenishment) mice fed chow or HFD. We previously validated that HFD-fed Ad-KO mice developed skeletal muscle insulin resistance and glucose intolerance and that replenishment of adiponectin corrected these defects (17). We also conducted a metabolomic profiling analysis and found that adiponectin alleviated HFD-induced changes in metabolites such as several diacylglycerol species, branched-chain amino acids, and various lysolipids (17).…”

“…Animals were fed a regular chow diet or 60% HFD as we described (17). HFD Ad-KO animals received saline or adiponectin (3 mg/g body weight) twice daily for 1 and 2 weeks for the 2-week and 6-week diet groups, respectively, by intraperitoneal injection.…”

“…HFD Ad-KO animals received saline or adiponectin (3 mg/g body weight) twice daily for 1 and 2 weeks for the 2-week and 6-week diet groups, respectively, by intraperitoneal injection. Glucose tolerance tests (GTT) and clamp studies were performed as we described (17).…”

“…All tissue and cell samples were prepared as we described before (17), and primary antibodies were used at 1:1,000 dilutions. Membranes were washed four times in 13 wash buffer for 15 min each at room temperature and incubated with appropriate horseradish peroxidase-coupled secondary antibody (1:10,000) for 1 h. Membranes were washed five times in 13 wash buffer for 10 min each and proteins visualized using enhanced chemiluminescence.…”

Adipokines and insulin action

“…34,84,85 Loss of adiponectin in vivo in mice is associated with a reduction in fatty acid oxidation and consequently increased levels of plasma and tissue ceramide and diacylglycerol both postulated to inhibit insulin signaling. 33,86,87 Rats fed high-fat diets rapidly develop adiponectin resistance, measured as a reduction in adiponectin induced fatty acid oxidation, and show impaired phosphorylation of the crucial insulin signaling proteins Akt and AS160 in muscle resulting in impaired GLUT4 vesicular translocation in skeletal muscle, characteristic of insulin resistance. 88 Besides having clear beneficial effects on insulin action in peripheral tissues, most notably in liver, adiponectin also targets the β cells of the pancreas.…”