Lipid-mediated muscle insulin resistance: different fat, different pathways?

Area of Science:

• Metabolic Physiology
• Molecular Biology
• Endocrinology

Background:

• Excessive dietary fat intake and lipolysis lead to increased lipid availability, contributing to impaired insulin sensitivity.
• Lipid intermediates, including diacylglycerols (DAG) and ceramides (CER), are implicated in the development of insulin resistance.
• Specific lipid metabolites can interfere with key signaling pathways regulating glucose metabolism and insulin action.

Purpose of the Study:

• To review the mechanisms by which lipid metabolites affect insulin action in skeletal muscle.
• To analyze the role of DAG and CER in lipid-induced insulin resistance in humans and rodents.
• To highlight recent findings on specific lipid species and their impact on insulin sensitivity.

Main Methods:

• Literature review of studies investigating lipid metabolites and insulin resistance.
• Analysis of data from human and rodent models, including athletes.
• Focus on molecular mechanisms involving protein kinase C (PKC) and insulin receptor substrate 1 (IRS1) phosphorylation.

Main Results:

• Diacylglycerols (DAG) activate novel protein kinase C (PKC) isoforms, leading to inhibitory serine phosphorylation of insulin receptor substrate 1 (IRS1).
• Ceramides (CER), activated via Toll-like receptor 4 (TLR4), induce pro-inflammatory pathways and inhibit Akt phosphorylation.
• Inhibition of glucosylceramide and ganglioside synthesis improves insulin sensitivity and IRS1 phosphorylation.
• Incomplete fat oxidation increases acylcarnitines (ACC), promoting pro-inflammatory pathways.
• Specific membrane and cytosolic C18:2 DAG activate PKCθ, inducing acute and chronic insulin resistance in humans.

Conclusions:

• Both DAG and CER are associated with insulin resistance, but their causal relevance may depend on subcellular localization and specific populations.
• Recent evidence implicates specific lipid species, such as C18:2 DAG, in activating PKCθ and driving insulin resistance.
• Understanding the precise roles of individual lipid metabolites is crucial for developing targeted interventions against insulin resistance.