Metabolic Inflexibility with Obesity and the Effects of Fenofibrate on Skeletal Muscle Fatty Acid Oxidation

Abstract

This study was designed to investigate mechanisms of lipid metabolic inflexibility in human obesity and the ability of fenofibrate (FENO) to increase skeletal muscle fatty acid oxidation (FAO) in primary human skeletal muscle cell cultures (HSkMC) exhibiting metabolic inflexibility. HSkMC from 10 lean and 10 obese, insulin resistant subjects were treated with excess fatty acid for 24 h (24hFA) to gauge lipid-related metabolic flexibility. Metabolically inflexible HSkMC from obese individuals were then treated with 24hFA in combination with FENO to determine effectiveness for increasing FAO. Mitochondrial enzyme activity and FAO were measured in skeletal muscle from subjects with prediabetes (n=11) before and after 10 weeks of fenofibrate in vivo. 24hFA increased FAO to a greater extent in HSkMC from lean versus obese subjects (+49% vs. +9%, for lean vs. obese, respectively; p<0.05) indicating metabolic inflexibility with obesity. Metabolic inflexibility was not observed for measures of cellular respiration in permeabilized cells using carbohydrate substrate. Fenofibrate co-incubation with 24hFA, increased FAO in a subset of HSkMC from metabolically inflexible, obese subjects (p<0.05), which was eliminated by PPARα antagonist. In vivo, fenofibrate treatment increased skeletal muscle FAO in a subset of subjects with prediabetes but did not affect gene transcription or mitochondrial enzyme activity. Lipid metabolic inflexibility observed in HSkMC from obese subjects is not due to differences in electron transport flux, but rather upstream decrements in lipid metabolism. Fenofibrate increases the capacity for FAO in human skeletal muscle cells, though its role in skeletal muscle metabolism in vivo remains unclear.

Lipoprotein Lipase Is a Feature of Alternatively-Activated Microglia and May Facilitate Lipid Uptake in the CNS During Demyelination

“…Fatty Acid Oxidation (FAO) assays were performed as described with limited modifications (Boyle et al, 2017 ). Control and LPL KD BV-2 microglia were incubated at 37°C in sealed 24-well plates containing differentiation media containing 0.25 μCi/ml [ 14 C]oleate and 0.25 μCi/ml [ 14 C]palmitate (PerkinElmer Life Sciences, Waltham, MA, USA), with 200 μM, 1:1 “cold” oleate:palmitate.…”

Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation in mesenchymal stem cells from human infants

“…Following 21 d of myogenesis, cells were fixed with 4% formaldehyde and stained for ORO neutral lipid content, as described [4] . 14 C-labeled fatty acid oxidation (FAO) was measured using 200 μM oleate and palmitate (2:1 ratio) with 1 mM carnitine, as described [18] . This method measures both complete oxidation of fatty acids to CO 2 and incomplete oxidation of fatty acids as determined by acid soluble metabolites (ASM)s. FAO is the sum of these component measures.…”

Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease

“…Besides adipocyte metabolic dysfunction, skeletal muscle mitochondrial capacity and β -oxidation are reduced. Specifically, upregulation of PPAR α and its downstream targets in response to high-fat feeding are defective ( 142 ). Excess calories are then stored in peripheral fat depots as triglyceride; when these depots reach their maximum capacity and fail to expand, fat accumulates in ectopic depots, including skeletal muscle and the liver.…”

“…Fenofibrate improves FAO in primary human skeletal muscle cell cultures from obese and insulin resistant subjects. In vitro and in animal models, PPAR α activation increased expression of PDK and CPT1 ( 142 ). In insulin-deficient mice, bezafibrate improves impaired glucose metabolism by augmenting hepatic mitochondrial performance [reviewed in Komen and Thorburn ( 255 )], suppressing hepatic inflammatory pathways, and improving insulin sensitivity ( 271 ).…”