SummaryWith the increasing prevalence of obesity, research has focused on the molecular mechanism(s) linking obesity and skeletal muscle insulin resistance. Metabolic alterations within muscle, such as changes in the cellular location of fatty acid transporter proteins, decreased mitochondrial enzyme activity, and defects in mitochondrial morphology, likely contribute to obesity and insulin resistance. These defects are thought to play a role in the reduced skeletal muscle fatty acid oxidation and increased intramuscular lipid (IMCL) accumulation that is apparent with obesity and other insulin-resistant states such as type 2 diabetes. Intramuscular triacylglycerol does not appear to be a ubiquitous marker of insulin resistance, although specific IMCL intermediates such as long-chain fatty acyl-CoAs, ceramide, and diacylglycerol may inhibit insulin signal transduction. In this review, we will briefly summarize the defects in skeletal muscle lipid metabolism associated with obesity, and discuss the proposed mechanisms by which these defects may contribute to insulin resistance.
IUBMBIUBMB Life, 61(1): [47][48][49][50][51][52][53][54][55] 2009
Cultured myocytes from severely obese women express perturbations in FA metabolism and insulin signaling reminiscent of those observed in vivo. The obesity phenotype can be recapitulated in muscle cells from lean subjects via exposure to excess lipid, but not by overexpressing the FAT/CD36 FA transporter.
OBJECTIVETo determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α).RESEARCH DESIGN AND METHODSFAO was studied in HSkMC from lean (BMI 22.4 ± 0.9 kg/m2; N = 12) and extremely obese (45.3 ± 1.4 kg/m2; N = 9) subjects. Recombinant adenovirus was used to increase HSkMC PGC-1α expression (3.5- and 8.0-fold), followed by assessment of mitochondrial content (mtDNA and cytochrome C oxidase IV [COXIV]), complete (14CO2 production from labeled oleate), and incomplete (acid soluble metabolites [ASM]) FAO, and glycerolipid synthesis.RESULTSObesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([14C]ASM production/14CO2), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (−27%), COXIV (−35%), and mitochondrial transcription factor (mtTFA) (−43%) protein levels. PGC-1α overexpression increased (P < 0.05) FAO, mtDNA, COXIV, mtTFA, and fatty acid incorporation into triacylglycerol in both lean and obese groups. Perturbations in FAO, triacylglycerol synthesis, mtDNA, COXIV, and mtTFA in obese compared with lean HSkMC persisted despite PGC-1α overexpression. When adjusted for mtDNA and COXIV content, FAO was equivalent between lean and obese groups.CONCLUSIONReduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1α protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1α abundance.
Supplemental Digital Content is Available in the Text.
The TRIAL-STIM randomised controlled trial found no evidence that a spinal cord stimulation screening trial strategy provides superior patient outcomes compared to a no trial screening approach.
Given the apparent importance of triggers in attaining and maintaining asthma control, empirical research concerning optimal trigger management is needed. Results demonstrate that asthma triggers are similar across continents, suggesting a global checklist of triggers for use in research and clinical practice would be feasible.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.