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 m...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.展开更多
基金This research is supported by NIH DK107397,DK127979,GM144613,AG074535,AG067186(to K.F.),AG065993(to A.C.),DK091317(to M.J.L.)Department of Defense W81XWH-19-1-0213(to K.H.F-W)+2 种基金American Heart Association 18PRE33960491(to A.R.P.V.),19PRE34380991(to J.M.J.),and 915674(P.S.)Larry H.&Gail Miller Family Foundation(to P.J.F.)University of Utah Metabolomics Core Facility is supported by S10 OD016232,S10 OD021505,and U54 DK110858.
文摘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.
