Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice.

Abstract

Adiponectin has emerged as a potential therapy for type 2 diabetes mellitus, but the molecular mechanism by which adiponectin reverses insulin resistance remains unclear. Two weeks of globular adiponectin (gAcrp30) treatment reduced fasting plasma glucose, triglyceride (TAG), and insulin concentrations and reversed whole-body insulin resistance, which could be attributed to both improved insulin-mediated suppression of endogenous glucose production and increased insulin-stimulated glucose uptake in muscle and adipose tissues. These improvements in liver and muscle sensitivity were associated with ∼50% reductions in liver and muscle TAG and plasma membrane (PM)-associated diacylglycerol (DAG) content and occurred independent of reductions in total ceramide content. Reductions of PM DAG content in liver and skeletal muscle were associated with reduced PKCε translocation in liver and reduced PKCθ and PKCε translocation in skeletal muscle resulting in increased insulin-stimulated insulin receptor tyrosine1162 phosphorylation, IRS-1/IRS-2-associated PI3-kinase activity, and Akt-serine phosphorylation. Both gAcrp30 and full-length adiponectin (Acrp30) treatment increased eNOS/AMPK activation in muscle and muscle fatty acid oxidation. gAcrp30 and Acrp30 infusions also increased TAG uptake in epididymal white adipose tissue (eWAT), which could be attributed to increased lipoprotein lipase (LPL) activity. These data suggest that adiponectin and adiponectin-related molecules reverse lipid-induced liver and muscle insulin resistance by reducing ectopic lipid storage in these organs, resulting in decreased plasma membrane sn-1,2-DAG-induced nPKC activity and increased insulin signaling. Adiponectin mediates these effects by both promoting the storage of TAG in eWAT likely through stimulation of LPL as well as by stimulation of AMPK in muscle resulting in increased muscle fat oxidation.

• Authors: Xiruo Li, Dongyan Zhang, Daniel F Vatner, Leigh Goedeke, Sandro M Hirabara, Ye Zhang, Rachel J Perry, Gerald I Shulman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 51 Pg. 32584-32593 (12 22 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 33293421 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 the Author(s). Published by PNAS.

Chemical References

• Adiponectin
• Diglycerides
• Insulin
• Recombinant Proteins
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Protein Kinase C
• AMP-Activated Protein Kinases
• Lipoprotein Lipase

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adiponectin (genetics, metabolism, pharmacology)
• Adipose Tissue, White (drug effects, metabolism)
• Animals
• Diet, High-Fat (adverse effects)
• Diglycerides (metabolism)
• Insulin (metabolism)
• Insulin Resistance (physiology)
• Lipid Metabolism
• Lipoprotein Lipase (metabolism)
• Liver (metabolism)
• Male
• Mice, Inbred C57BL
• Muscle, Skeletal (drug effects, metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Protein Kinase C (metabolism)
• Recombinant Proteins (genetics, metabolism, pharmacology)