Adiponectin has emerged as an antidiabetic adipokine, and a potential therapy to treat type 2 diabetes. However, the mechanism by which adiponectin improves insulin sensitivity remains unclear. To address this question, we examined the effects of a 2-week continuous infusion of globular adiponectin (gAcrp30) or saline (CON) on glucose and lipid metabolism in a high fat diet fed (HFD) mouse model. Whole-body and tissue-specific insulin action was assessed by a hyperinsulinemic-euglycemic clamp (HEC). gAcrp30-treated mice displayed reduced fasting plasma glucose and insulin concentrations (both P<0.05 vs. CON) and increased glucose infusion rate (14 vs. 22 mg/(kg-min), P<0.001) during the HEC reflecting increased whole-body insulin-sensitivity. Increased insulin sensitivity could be attributed to reduced endogenous glucose production (16.7 vs.14.2 mg/(kg-min), P<0.05), increased glucose uptake in muscle (191 vs. 285 nmol/(kg-min), p=0.006) and adipose tissues (BAT: 112 vs. 217, WAT: 11 vs. 22 nmol/(kg-min), both P<0.05) during the HEC. These improvements in liver and muscle insulin sensitivity were associated with ∼50% reductions in liver and muscle triglyceride (TAG) and ∼40% diacylglycerol (DAG) (both P<0.01 vs. CON) content but no changes in hepatic ceramide content. Reduced tissue TAG/DAG content occurred independent of changes in WAT lipolysis, hepatic AMPK activation, ACC phosphorylation or mitochondrial oxidation. Reduced tissue DAG content was associated with decreased PKCε activation in liver and PKCθ activation in muscle and increased insulin signaling in liver, muscle and white adipose tissue.

Conclusion: Taken together these data support the hypothesis that adiponectin improves insulin sensitivity in liver and muscle of HFD fed mice by reducing ectopic lipid (DAG) content in these tissues leading to decreased nPKC activity and increased insulin signaling, and contrary to prior studies, is independent of changes in hepatic ceramide content.


X. Li: None. D. Zhang: None. R.J. Perry: Research Support; Self; AstraZeneca. D.F. Vatner: None. L. Goedeke: None. Y. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V.


American Heart Association (19PRE34380268); National Institutes of Health (R01DK116774)

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