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.

Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age.

Exercise training or higher levels of physical activity are known to exert anti-inflammatory effects. CD14+CD16+ monocytes are potent producers of inflammatory proteins, and elevated levels of these "inflammatory" monocytes have been implicated in disease development. Little is known about the influence of exercise training on this cell population. On the basis of their physical activity pattern, male and female subjects, 65-80 years old, were assigned to a physically active (PA; n=15) or inactive (PI; n=15) group. The PI group performed 12 weeks (3 days/week) of endurance (20 min at 70-80% heart-rate reserve) and resistance exercise training (eight exercises, two sets at 70-80% of one repetition maximum). Subjects in the PA group maintained their habitual activity level. Flow cytometry was used to determine monocyte phenotype and monocyte TLR4 expression. ELISAs were used to measure whole blood, LPS-stimulated TNF-alpha production, and serum C-reactive protein (CRP). At baseline, the PA group had a lower percentage of CD14+CD16+ monocytes and lower unstimulated production of TNF-alpha than the PI group. CD14+CD16+ monocyte percentage and 1 ng/ml LPS-stimulated TNF-alpha production were reduced after the PI group underwent 12 weeks of exercise training. PI subjects also had higher TLR4 expression on classical monocytes, but there were no significant exercise training-induced changes in monocyte TLR4 expression. The PA group had significantly lower serum CRP than the PI group. Physical activity was associated with lower CD14+CD16+ monocyte percentage and LPS-stimulated TNF-alpha production. Exercise training-induced reductions in CD14+CD16+ monocytes may contribute to the anti-inflammatory effects of exercise training.

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.

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

Intramyocellular lipid (IMCL) is predominantly stored as intramuscular triglyceride (IMTG) in lipid droplets and is utilized as metabolic fuel during physical exercise. IMTG is also implicated in muscle insulin resistance (IR) in type 2 diabetes. However, it has become apparent that lipid moieties such as ceramide and diacylglycerol are the likely culprits of IR. This article reviews current knowledge of IMCL-mediated IR and important areas of investigation, including myocellular lipid transport and lipid droplet proteins. Several crucial questions remain unanswered, such as the identity of specific ceramide and diacylglycerol species that mediate IR in human muscle and their subcellular location. Quantitative lipidomics and proteomics of targeted subcellular organelles will help to better define the mechanisms underlying pathological IMCL accumulation and IR.

These results support the use of combined aerobic/resistance training as a modality to reduce the risk of cardiovascular disease development as defined by a decrease in serum CRP concentration in healthy humans.

Circulating factors released from tissues during exercise have been hypothesized to mediate some of the health benefits of regular physical activity. Lipokines are circulating lipid species that have recently been reported to affect metabolism in response to cold. Here, lipidomics analysis revealed that a bout of moderate-intensity exercise causes a pronounced increase in the circulating lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) in male, female, young, old, sedentary, and active human subjects. In mice, both a single bout of exercise and exercise training increased circulating 12,13-diHOME and surgical removal of brown adipose tissue (BAT) negated the increase in 12,13-diHOME, suggesting that BAT is the tissue source for exercise-stimulated 12,13-diHOME. Acute 12,13-diHOME treatment of mice in vivo increased skeletal muscle fatty acid uptake and oxidation, but not glucose uptake. These data reveal that lipokines are novel exercise-stimulated circulating factors that may contribute to the metabolic changes that occur with physical exercise.