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

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.

Blood cytokine patterns suggest a modest inflammation phenotype in subjects with long‐chain fatty acid oxidation disorders

“…), and genetic ablation of muscle CPT1b (Warfel et al. ) tends to rescue or normalize cell stress‐inflammation phenotypes that accompany inefficient β ‐oxidation or experimental provision of LCFA. These observations highlight excessive LCACs as potential lipotoxins; however, mismatched LCFA availability relative to mitochondrial fatty acid oxidation would increase cellular concentrations of many other lipid derivatives upstream of CPT1, and alter non‐lipid metabolite pools as well.…”

“…CPT1b‐/‐ mice were protected from muscle inflammation under modest fat feeding; in addition, CPT1b‐/‐ myotubes grown in the presence of 500 μ mol/L palmitate plus carnitine displayed >90% lower TNF α and IL6 mRNA levels compared to wild‐type cells (Warfel et al. ).…”

Reduced Fat Oxidation During Exercise in Post-Menopausal Overweight-Obese Women with Higher Lipid Accumulation Product Index

“…CRP levels are a clinically relevant marker of subclinical inflammation in obesity and related to metabolic pathways that induces atherosclerosis and diabetes [1]. Moreover, inflammatory cytokines reduces the oxidative capacity of mitochondrial enzymes which favors the accumulation of lipids derivate in peripheral tissue and the lipotoxicity in obesity [29]. In vitro studies revealed that the accumulation of lipid intermediates in peripheral tissues, mainly muscle tissue, leads to low fat oxidation and altered fatty acid metabolism through increased inflammatory pathway [30].…”

Resveratrol alleviates obesity-induced skeletal muscle inflammation via decreasing M1 macrophage polarization and increasing the regulatory T cell population

“…in the initiation of the inflammatory processes 30,31 . TLR-2 and TLR-4 activation leads to inflammatory cytokine production such as TNF-α and IL-6 [32][33][34] .…”