Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice

Weight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain.Evidence suggests that this energetic mismatch originates from lean tissue.Although this phenomenon is well documented,the mechanisms have remained elusive.We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss.Wildtype(WT)male C57BL6/N mice were fed with high-fat diet for 10 weeks,followed by a subset of mice that were maintained on the obesogenic diet(OB)or switched to standard chow to promote weight loss(WL)for additional 6 weeks.Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry.Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome.Weight loss promoted~50%increase in the efficiency of oxidative phosphorylation(ATP produced per O_(2) consumed,or P/O)in skeletal muscle.However,Weight loss did not appear to induce significant changes in mitochondrial proteome,nor any changes in respiratory supercomplex formation.Instead,it accelerated the remodeling of mitochondrial cardiolipin(CL)acyl-chains to increase tetralinoleoyl CL(TLCL)content,a species of lipids thought to be functionally critical for the respiratory enzymes.We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain.These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.

Lipid Profile Altered in Phenanthrene Exposed Zebrafish Embryos with Implications for Neurological Development and Early Life Nutritional Status

Lecithotrophic fish embryos rely on finite maternally deposited yolk resources for early development.Toxicant exposure can disrupt the uptake of yolk resources with consequences for development.In this study,we investigate the impacts of altered yolk utilization on fish embryos using the cardiotoxic compound phenanthrene.Zebrafish embryos were exposed to a cardiotoxic concentration of phenanthrene beginning at 6 hpf(hours post-fertilization)until a maximum of 72 hpf.Embryos were stained with Oil Red O to visualize neutral lipids.We then used a nontargeted approach to profile lipids in 24 and 72 hpf embryos after phenanthrene treatment.To assess changes in lipid movement within the embryo,the yolk sac was dissected from the body at 24 and 72 hpf and analyzed separately from the body at 72 hpf.Overall,total metabolites were significantly reduced in the yolk sac,and staining for neutral lipids was reduced in the embryo body at 72 hpf.This result is consistent with significant reductions in triglycerides in both the embryo body and yolk,indicating a limited contribution of impaired cardiac function to lipid mobilization at the dose tested.Additionally,lysophosphatidylcholines and lysophosphatidylethanolamines were significantly increased in the 72 hpf embryo body.Bioinformatic pathway analysis indicated that changes to these lysophospholipids could be linked to a disease model associated with inflammation and neuron demyelination consistent with previously observed injuries to neuronal and eye development in fish embryos and larvae.