Distinct skeletal muscle fiber characteristics and gene expression in diet-sensitive versus diet-resistant obesity

Inter-individual variability in weight gain and loss under energy surfeit and deficit conditions, respectively, are well recognized but poorly understood phenomena. We documented weight loss variability in an intensively supervised clinical weight loss program and assessed skeletal muscle gene expression and phenotypic characteristics related to variable response to a 900 kcal regimen. Matched pairs of healthy, diet-compliant, obese diet-sensitive (ODS) and diet-resistant (ODR) subjects were defined as those in the highest and lowest quintiles for weight loss rate. Physical activity energy expenditure was minimal and comparable. Following program completion and weight stabilization, skeletal muscle biopsies were obtained. Gene expression analysis of rectus femoris and vastus lateralis indicated upregulation of genes and gene sets involved in oxidative phosphorylation and glucose and fatty acid metabolism in ODS compared with ODR. In vastus lateralis, there was a higher proportion of oxidative (type I) fibers in ODS compared with ODR women and lean controls, fiber hypertrophy in ODS compared with ODR women and lean controls, and lower succinate dehydrogenase in oxidative and oxidative-glycolytic fibers in all obese compared with lean subjects. Intramuscular lipid content was generally higher in obese versus lean, and specifically higher in ODS vs. lean women. Altogether, our findings demonstrate differences in muscle gene expression and fiber composition related to clinical weight loss success. Inter-individual variability in weight gain and loss under energy surfeit and deficit conditions, respectively, are well recognized but poorly understood phenomena. We documented weight loss variability in an intensively supervised clinical weight loss program and assessed skeletal muscle gene expression and phenotypic characteristics related to variable response to a 900 kcal regimen. Matched pairs of healthy, diet-compliant, obese diet-sensitive (ODS) and diet-resistant (ODR) subjects were defined as those in the highest and lowest quintiles for weight loss rate. Physical activity energy expenditure was minimal and comparable. Following program completion and weight stabilization, skeletal muscle biopsies were obtained. Gene expression analysis of rectus femoris and vastus lateralis indicated upregulation of genes and gene sets involved in oxidative phosphorylation and glucose and fatty acid metabolism in ODS compared with ODR. In vastus lateralis, there was a higher proportion of oxidative (type I) fibers in ODS compared with ODR women and lean controls, fiber hypertrophy in ODS compared with ODR women and lean controls, and lower succinate dehydrogenase in oxidative and oxidative-glycolytic fibers in all obese compared with lean subjects. Intramuscular lipid content was generally higher in obese versus lean, and specifically higher in ODS vs. lean women. Altogether, our findings demonstrate differences in muscle gene expression and fiber composition related to clinical weight loss success. Obesity is reaching epidemic proportions in developed countries and represents a significant risk factor for cardiovascular disease, diabetes, and cancer (1.Bell C.G. Walley A.J. Froguel P. The genetics of human obesity.Nat. Rev. Genet. 2005; 6: 221-234Crossref PubMed Scopus (490) Google Scholar). Enrolment in clinical and nonclinical obesity treatment programs is unprecedented. Success in obesity treatment programs is highly variable, related in part to compliance and program characteristics (e.g., type and duration of hypocaloric diets, educational components, and/or exercise-associated energy expenditure). While it is generally well accepted that there is substantial inter-individual variability in the susceptibility to weight gain in response to overfeeding (2.Sims E.A. Danforth Jr., E. Horton E.S. Bray G.A. Glennon J.A. Salans L.B. Endocrine and metabolic effects of experimental obesity in man.Recent Prog. Horm. Res. 1973; 29: 457-496PubMed Google Scholar, 3.Bouchard C. Tremblay A. Despres J.P. Nadeau A. Lupien P.J. Theriault G. Dussault J. Moorjani S. Pinault S. Fournier G. The response to long-term overfeeding in identical twins.N. Engl. J. Med. 1990; 322: 1477-1482Crossref PubMed Scopus (1008) Google Scholar), less well understood is the impact of biological factors on weight loss success. However, studies of monozygotic twins have shown greater inter-pair than intra-pair variation in weight loss (4.Bouchard C. Tremblay A. Genetic influences on the response of body fat and fat distribution to positive and negative energy balances in human identical twins.J. Nutr. 1997; 127: 943S-947SCrossref PubMed Google Scholar), consistent with the idea that there are important genetic determinants of weight loss success. We have studied the molecular and cellular determinants of variable weight loss in highly compliant subjects in an intensively supervised and interactive hypocaloric clinical obesity treatment program at the Ottawa Hospital. We previously reported differences in muscle mitochondrial energy inefficiencies between program participants exhibiting high versus low weight loss success (5.Harper M.E. Dent R. Monemdjou S. Bezaire V. Van Wyck L. Wells G. Kavaslar G.N. Gauthier A. Tesson F. McPherson R. Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women.Diabetes. 2002; 51: 2459-2466Crossref PubMed Scopus (110) Google Scholar). Here, we extend these findings differences in skeletal muscle gene expression and in and metabolic characteristics between of weight loss success in a clinical obesity treatment skeletal muscle energy metabolism are skeletal muscle is a of energy expenditure to the that it for of body weight F. C. E. muscle metabolism is a of energy 1990; PubMed Scopus Google Scholar). the idea that differences in skeletal energy expenditure characteristics variability in weight loss success well However, is consistent with and gene expression studies demonstrate that low oxidative in muscle is of obesity and type and to the J. of in human skeletal muscle in type 2002; 51: PubMed Scopus Google Scholar, A. S. J. P. E. E. genes involved in oxidative phosphorylation are in human Genet. PubMed Scopus Google Scholar, M.E. A.J. S. R. S. R. of genes of oxidative metabolism in with and of and PubMed Scopus Google Scholar, J.A. of to fatty in human skeletal to and obesity and effects of weight J. PubMed Scopus Google Scholar, in skeletal muscle is weight loss in and in lipid PubMed Scopus Google Scholar). In a long-term of obese lower proportions of oxidative (type I) fibers were with a higher of obesity J. distribution weight gain and a 6: PubMed Scopus Google Scholar). J.A. fiber type is with obesity and weight J. 2002; PubMed Scopus Google that weight loss was with proportions of type fibers in rectus have that body energy expenditure is with muscle a to obesity susceptibility F. C. E. muscle metabolism is a of energy 1990; PubMed Scopus Google Scholar). in obesity a lower proportion of type fibers was with risk for high fat obesity compared with J. F. muscle composition in and J. Google Scholar). We have phenotypic and gene expression differences in rectus femoris and vastus lateralis muscle biopsies obese diet-sensitive (ODS) and obese (ODR) subjects in an intensively clinical weight loss findings in the proportion of oxidative fibers and fiber in vastus lateralis muscle of ODS compared with ODR and lean subjects. Obesity and was with muscle mitochondrial gene expression analysis of rectus femoris and vastus lateralis ODR and ODS subjects upregulation of gene sets involved in oxidative phosphorylation and glucose and fatty acid metabolism in ODS compared with ODR. findings factors to weight loss success in The of the Ottawa and the of Ottawa the was all participants of our of with a body of the Ottawa to the of intensively program the for the to weight loss in a weight loss was in the of the 900 kcal We to the of were were women were to weight in our (5.Harper M.E. Dent R. Monemdjou S. Bezaire V. Van Wyck L. Wells G. Kavaslar G.N. Gauthier A. Tesson F. McPherson R. Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women.Diabetes. 2002; 51: 2459-2466Crossref PubMed Scopus (110) Google Scholar), we studied highly compliant women in the Ottawa to is a for response to was to of compliant was subjects the of an weight program with substantial to the In were of the were for than the on there were there was completion of the were on the of of weight of at with with and in and weight were these were in the of weight loss in the of were to and with women in the for the of weight compliance and were as reported in and of weight loss were developed in and on all to at and activity of obese subjects were assessed to weight loss and were at the of at was assessed a with a of defined as an (e.g., and a of defined as a (e.g., the and type of activity energy expenditure in kcal was body and energy expenditure of of women the were in the (ODS) (ODR) of weight loss in the of rectus femoris muscle were between and a and completion of the program and a of at of weight gene expression was rectus femoris muscle of pairs of ODS and ODR women. biopsies of the vastus lateralis muscle were pairs of ODS and ODR women. of muscle fiber type and for mitochondrial a of the vastus lateralis was a an of pairs of ODS and ODR women. was in and were with and were as and to the of and human was ODS and ODR subjects for Gene expression were to a of for all were compared to and were with a in in were for were to in the of genes that between the ODS and ODR the a J. 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E.S. a for expression 2005; PubMed Scopus Google Scholar). the of is of was of was on the with were to the and gene sets with a were to were in the Gene and is of in genes was on vastus lateralis were a and the Following and all were to and as Following all were to analysis with of and was in and to a of in was in a and at was and at Intramuscular lipid content was assessed analysis of were with in for to for with was were to and the and were muscle were the of were content was assessed the succinate dehydrogenase activity in muscle were and activity was a of at was that the was of at the fiber was and with a and a were in the analysis of a for of analysis were the for activity were for on in was for at of and for at were for of analysis to the were at and for type and type fibers P. with type and fibers were as human muscle was with a fibers were with fibers were to the were for type and type was to for type fibers were to of and with to were in and at were at between at at at at at at and sets were to of as was in the and were and to was the and fibers were was to to fiber was as type type type fibers of fibers and were were for and the and the in and were a fibers were were compared with are as characteristics for the of subjects were previously reported (5.Harper M.E. Dent R. Monemdjou S. Bezaire V. Van Wyck L. Wells G. Kavaslar G.N. Gauthier A. Tesson F. McPherson R. Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women.Diabetes. 2002; 51: 2459-2466Crossref PubMed Scopus (110) Google Scholar). of gene we rectus femoris biopsies of pairs of subjects The weight loss in the of was greater for the ODS subjects versus the ODR of subjects for muscle expression at program of 900 kcal weight subjects with The of ODS and ODR subjects were previously (5.Harper M.E. Dent R. Monemdjou S. Bezaire V. Van Wyck L. Wells G. Kavaslar G.N. Gauthier A. Tesson F. McPherson R. Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women.Diabetes. 2002; 51: 2459-2466Crossref PubMed Scopus (110) Google Scholar). in a subjects with The of ODS and ODR subjects were previously (5.Harper M.E. Dent R. Monemdjou S. Bezaire V. 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