Mitochondrial fat oxidation is essential for lipid-induced inflammation in skeletal muscle in mice.

Jaycob D Warfel,Randall Mynatt,Estrellita M Bermudez,Tamra M Mendoza,Sujoy Ghosh,Carrie M Elks,Bolormaa Vandanmagsar,Jingying Zhang

doi:10.1038/srep37941

Abstract

Inflammation, lipotoxicity and mitochondrial dysfunction have been implicated in the pathogenesis of obesity-induced insulin resistance and type 2 diabetes. However, how these factors are intertwined in the development of obesity/insulin resistance remains unclear. Here, we examine the role of mitochondrial fat oxidation on lipid-induced inflammation in skeletal muscle. We used skeletal muscle-specific Cpt1b knockout mouse model where the inhibition of mitochondrial fatty acid oxidation results in accumulation of lipid metabolites in muscle and elevated circulating free fatty acids. Gene expression of pro-inflammatory cytokines, chemokines, and cytokine- and members of TLR-signalling pathways were decreased in Cpt1bm−/− muscle. Inflammatory signalling pathways were not activated when evaluated by multiplex and immunoblot analysis. In addition, the inflammatory response to fatty acids was reduced in primary muscle cells derived from Cpt1bm−/− mice. Gene expression of Cd11c, the M1 macrophage marker, was decreased; while Cd206, the M2 macrophage marker, was increased in skeletal muscle of Cpt1bm−/− mice. Finally, expression of pro-inflammatory markers was decreased in white adipose tissue of Cpt1bm−/− mice. We show that the inflammatory response elicited by elevated intracellular lipids in skeletal muscle is repressed in Cpt1bm−/− mice, strongly supporting the hypothesis that mitochondrial processing of fatty acids is essential for the lipid-induction of inflammation in muscle.

Highlights

Carnitine palmitoyltransferase-1 (CPT1) is an enzyme located on the outer mitochondrial membrane that transports long-chain fatty acids into mitochondria for β-oxidation, controlling the rate of mitochondrial fatty acid oxidation (FAO)
Cpt1bm−/− mice have elevated plasma lipids, and accumulation of both intramyocellular lipid (IMCL) and lipotoxic species such as DAG and ceramides, but they have lower fasting insulin and glucose, improved glucose tolerance, and no impairment of insulin signalling in skeletal muscle[23]
We examined whether lipid overload in Cpt1bm−/− mice induced inflammation in skeletal muscle and at the systemic level

Summary

Introduction

Carnitine palmitoyltransferase-1 (CPT1) is an enzyme located on the outer mitochondrial membrane that transports long-chain fatty acids into mitochondria for β-oxidation, controlling the rate of mitochondrial fatty acid oxidation (FAO). The physiological characterization of Cpt1bm−/− mice has revealed many factors associated with obesity and insulin resistance, such as elevated levels of circulating free fatty acids and intramyocellular lipid (IMCL)[23]. Though Cpt1bm−/− mice clearly demonstrate diminished mitochondrial fat oxidation capacity and elevated lipid levels, they do not develop insulin resistance and have attenuated adiposity relative to control mice[23]. Extensive investigation as to the inflammatory status of Cpt1bm−/− mice has not yet been reported. We address whether lipotoxicity and reduced mitochondrial FAO in skeletal muscle contribute to obesity-associated inflammation using Cpt1bm−/− mice. Pro-inflammatory markers, inflammatory sensing, signalling and response are reduced in skeletal muscle, which may contribute to the maintenance of insulin sensitivity of Cpt1bm−/− mice

Methods

Results

Conclusion