OBJECTIVEChronic exercise and obesity both increase intramyocellular triglycerides (IMTGs) despite having opposing effects on insulin sensitivity. We hypothesized that chronically exercise-trained muscle would be characterized by lower skeletal muscle diacylglycerols (DAGs) and ceramides despite higher IMTGs and would account for its higher insulin sensitivity. We also hypothesized that the expression of key skeletal muscle proteins involved in lipid droplet hydrolysis, DAG formation, and fatty-acid partitioning and oxidation would be associated with the lipotoxic phenotype.RESEARCH DESIGN AND METHODSA total of 14 normal-weight, endurance-trained athletes (NWA group) and 7 normal-weight sedentary (NWS group) and 21 obese sedentary (OBS group) volunteers were studied. Insulin sensitivity was assessed by glucose clamps. IMTGs, DAGs, ceramides, and protein expression were measured in muscle biopsies.RESULTSDAG content in the NWA group was approximately twofold higher than in the OBS group and ~50% higher than in the NWS group, corresponding to higher insulin sensitivity. While certain DAG moieties clearly were associated with better insulin sensitivity, other species were not. Ceramide content was higher in insulin-resistant obese muscle. The expression of OXPAT/perilipin-5, adipose triglyceride lipase, and stearoyl-CoA desaturase protein was higher in the NWA group, corresponding to a higher mitochondrial content, proportion of type 1 myocytes, IMTGs, DAGs, and insulin sensitivity.CONCLUSIONSTotal myocellular DAGs were markedly higher in highly trained athletes, corresponding with higher insulin sensitivity, and suggest a more complex role for DAGs in insulin action. Our data also provide additional evidence in humans linking ceramides to insulin resistance. Finally, this study provides novel evidence supporting a role for specific skeletal muscle proteins involved in intramyocellular lipids, mitochondrial oxidative capacity, and insulin resistance.

Dubé JJ, Amati F, Stefanovic-Racic M, Toledo FG, Sauers SE, Goodpaster BH. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited. Am J Physiol Endocrinol Metab 294: E882-E888, 2008. First published March 4, 2008 doi:10.1152/ajpendo.00769.2007.-We previously reported an "athlete's paradox" in which endurance-trained athletes, who possess a high oxidative capacity and enhanced insulin sensitivity, also have higher intramyocellular lipid (IMCL) content. The purpose of this study was to determine whether moderate exercise training would increase IMCL, oxidative capacity of muscle, and insulin sensitivity in previously sedentary overweight to obese, insulin-resistant, older subjects. Twenty-five older (66.4 Ϯ 0.8 yr) obese (BMI ϭ 30.3 Ϯ 0.7 kg/m 2 ) men (n ϭ 9) and women (n ϭ 16) completed a 16-wk moderate but progressive exercise training program. Body weight and fat mass modestly but significantly (P Ͻ 0.01) decreased. Insulin sensitivity, measured using the euglycemic hyperinsulinemic clamp, was increased (21%, P ϭ 0.02), with modest improvements (7%, P ϭ 0.04) in aerobic fitness (V O2peak). Histochemical analyses of IMCL (Oil Red O staining), oxidative capacity [succinate dehydrogenase activity (SDH)], glycogen content, capillary density, and fiber type were performed on skeletal muscle biopsies. Exercise training increased IMCL by 21%. In contrast, diacylglycerol and ceramide, measured by mass spectroscopy, were decreased (n ϭ 13; Ϫ29% and Ϫ24%, respectively, P Ͻ 0.05) with exercise training. SDH (19%), glycogen content (15%), capillary density (7%), and the percentage of type I slow oxidative fibers (from 50.8 to 55.7%), all P Յ 0.05, were increased after exercise. In summary, these results extend the athlete's paradox by demonstrating that chronic exercise in overweight to obese older adults improves insulin sensitivity in conjunction with favorable alterations in lipid partitioning and an enhanced oxidative capacity within muscle. Therefore, several key deleterious effects of aging and/or obesity on the metabolic profile of skeletal muscle can be reversed with only moderate increases in physical activity. insulin sensitivity; aging; diacylglycerol; ceramide SEVERAL STUDIES have demonstrated strong associations between high intramyocellular lipid (IMCL) content and skeletal muscle insulin resistance in obesity (25, 44), aging (11, 42, 45, 52), and type 2 diabetes (T2DM) (31,36, 58). Yet, despite these numerous observations, we (23) described an "athlete's paradox" that has since been confirmed by others (54, 58) in which highly insulin-sensitive, endurance-trained athletes have IMCL content similar to that observed in insulin-resistant obese and T2DM subjects. We (46) later reported that the exercise training-induced increase in IMCL was not limited to young, lean, highly trained athletes; in a group of older (ϳ67 yr), nonobese subjects, moderate aerobic exercise training increased IMCL content concomitant with improved oxidative capacity and overall ...

Herniated lumbar discs were making spontaneously increased amounts of matrix metalloproteinases, nitric oxide, prostaglandin E2, and interleukin-6. These products may be involved intimately in the biochemistry of disc degeneration and the pathophysiology of radiculopathy. Their exact roles certainly need further investigation, but their mere presence implicates biochemical processes in intervertebral disc degeneration.

nondiabetic patients following RYGB surgery are typically quite modest compared with the presurgery condition (3). Moreover, there appear to be 2 discrete periods of improvement. The first is immediately after surgery, at which time hepatic, but not peripheral, S I improves in response to acute energy restriction (4-6), while greater, protracted weight loss appears to be more strongly associated with improved peripheral S I (7,8). Even with significant weight loss 1 year following RYBG surgery, peripheral S I is still low compared with that of lean metabolically healthy individuals (3,5,6,9).Exercise is considered a cornerstone for obesity treatment, and while it is not generally viewed to cause substantial body weight reduction (10), it can potently improve peripheral S I and glucose control (11-13) and can reduce the risk of T2D and cardiovascular disease (14,15). There is general consensus that even a single session of moderate intensity exercise can induce an improvement in S I (16). There is also evidence that exercise can BACKGROUND. Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (S I ) in obese patients. Regular exercise can also improve S I in obese individuals; however, it is unknown whether exercise and RYGB surgery-induced weight loss would additively improve S I and other cardiometabolic factors. METHODS.We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1-3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included S I and glucose effectiveness (S G ), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO 2 peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week).RESULTS. 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). S I improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min -1 /μU/ml, P = 0.18 for Δ, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive S I improvement (PP: CON vs. EX; +1.57 vs. +2.69 min

Aims/hypothesis Intramyocellular lipids, including diacylglycerol (DAG) and ceramides, have been linked to insulin resistance. This randomised repeated-measures study examined the effects of diet-induced weight loss (DIWL) and aerobic exercise (EX) on insulin sensitivity and intramyocellular triacylglycerol (IMTG), DAG and ceramide. Methods Sixteen overweight to obese adults (BMI 30.6±0.8; 67.2±4.0 years of age) with either impaired fasting glucose, or impaired glucose tolerance completed one of two lifestyle interventions: DIWL (n=8) or EX (n=8). Insulin sensitivity was determined using hyperinsulinaemic–euglycaemic clamps. Intramyocellular lipids were measured in muscle biopsies using histochemistry and tandem mass spectrometry. Results Insulin sensitivity was improved with DIWL (20.6± 4.7%) and EX (19.2±12.9%). Body weight and body fat were decreased by both interventions, with greater decreases in DIWL compared with EX.Muscle glycogen, IMTG content and oxidative capacity were all significantly (p<0.05) decreased with DIWL and increased with EX. There were decreases in DAG with DIWL (−12.4±14.6%) and EX (−40.9±12.0%). Ceramide decreased with EX (−33.7± 11.2%), but not with DIWL. Dihydroceramide was decreased with both interventions. Sphingosine was decreased only with EX. Changes in total DAG, total ceramides and other sphingolipids did not correlate with changes in glucose disposal. Stearoyl-coenzyme A desaturase 1 (SCD1) content was decreased with DIWL (−19.5± 8.5%, p<0.05), but increased with EX (19.6±7.4%, p<0.05). Diacylglycerol acyltransferase 1 (DGAT1) was unchanged with the interventions. Conclusions/interpretation Diet-induced weight loss and exercise training both improved insulin resistance and decreased DAG, while only exercise decreased ceramides, despite the interventions having different effects on IMTG. These alterations may be mediated through differential changes in skeletal muscle capacity for oxidation and triacylglycerol synthesis.