Direct and macrophage-mediated actions of fatty acids causing insulin resistance in muscle cells

Abstract

Obesity is associated with insulin resistance and increased risk for developing type 2 diabetes. Enlarged adipocytes develop resistance to the anti-lipolytic action of insulin. Elevated levels of fatty acids in the plasma and interstitial fluids lead to whole-body insulin resistance by disrupting normal insulin-regulated glucose uptake and glycogen storage in skeletal muscle. A new understanding has been cultivated in the past 5 to 10 years that adipocytes and macrophages (resident or bone marrow-derived) in adipose tissue of obese animals and humans are activated in a pro-inflammatory capacity and secrete insulin resistance-inducing factors. However, only recently have fatty acids themselves been identified as agents that engage toll-like receptors of the innate immunity systems of macrophages, adipocytes and muscle cells to trigger pro-inflammatory responses. This review summarizes our observations that fatty acids evoke the release of pro-inflammatory factors from macrophages that consequently induce insulin resistance in muscle cells.

Keywords::

• Skeletal muscle cells
• macrophages
• palmitate
• glucose uptake
• insulin resistance

Acknowledgements

Work from the Klip lab summarized in this review was supported by a grant from the Canadian Diabetes Association. V.S. was supported by a fellowship from the Research Training Centre at The Hospital for Sick Children and from the Alberta Heritage Foundation for Medical Research (AHFMR) and Tomorrow’s Research Cardiovascular Health Professionals (TORCH). J.D.S. was supported by a fellowship from NSERC and a supplement from the Canadian Diabetes Association. M.C.S. was supported by the Division of Endocrinology, The Hospital for Sick Children.

Declaration of interest: The authors report no conflict of interest.