Intramyocellular Lipid Levels Research Articles

Therapeutic effect of hybrid training of voluntary and electrical muscle contractions in middle-aged obese women with nonalcoholic fatty liver disease: a pilot trial.

BackgroundExercise training is an effective therapy for nonalcoholic fatty liver disease (NAFLD). Hybrid training (HYB) of voluntary and electrical muscle contractions was developed to prevent disuse atrophy during space flight. HYB can be applied to obtain a strength training effect accompanying articular movement. In this pilot study, we aimed to investigate the therapeutic efficacy of HYB in NAFLD.MethodsA total of 15 middle-aged obese women with NAFLD who had no improvement in serum alanine aminotransferase levels and/or liver fat deposition after 12 weeks of lifestyle counseling participated in an HYB program. HYB of the quadriceps and hamstrings was conducted for 20 minutes twice a week for 24 weeks.ResultsNAFLD patients showed attenuated intramyocellular lipid levels in the quadriceps after the HYB intervention (−15.5%). Levels of leptin (−17.4%), tumor necrosis factor-α (−23.2%), and interleukin-6 (−30.5%) were also decreased after the intervention. HYB led to a significant body weight reduction (−4.7%), which in turn was associated with a significant decrease in serum alanine aminotransferase (−35.8%), gamma-glutamyl transpeptidase (−21.6%), ferritin (−16.0%), oxidative stress (−17.8%) levels, and insulin resistance values (−2.7%).ConclusionIn NAFLD, HYB exerts an antiobesity effect and attenuates liver dysfunction and insulin resistance in association with an increase in muscle strength and a decrease in ectopic muscle fat. Therefore, HYB has great potential as a new type of exercise therapy for liver disease in patients with NAFLD.

Effect of ankle flexion on the quantification of MRS for intramyocellular lipids of the tibialis anterior and the medial gastrocnemius.

Muscle proton magnetic resonance spectroscopy (MRS) has been developed for non-invasive measurement of intramyocellular lipid (IMCL) levels. The majority of previous studies measuring IMCL with MRS have been performed on the calf muscle. The appearance of muscle MRS is influenced by bulk magnetic susceptibility and residual dipolar couplings, which depend on the angle between the muscle fibers and the main magnetic field. Our objective in this study was to evaluate the effect of ankle flexion and of the pennation angle on IMCL quantification in the calf muscle using proton MRS. The subjects comprised ten healthy male volunteers. In proton MRS, the ankle flexion angle was changed, and the pennation angle was measured from the tibialis anterior (TA) and the medial gastrocnemius (MG), respectively. We considered the relationship between the quantification of IMCL with (1)H MRS and the pennation angle by ankle flexion angle. The pennation angle of the TA and MG changed with the ankle flexion angle. The IMCL on the TA decreased significantly with plantar flexion (p<0.05). However, the IMCL on the MG demonstrated no significant difference. The MR spectrum and IMCL quantitation changed with the pennation angle. Therefore, when spectra of individual subjects in longitudinal studies or between subjects are compared in cross-sectional studies, the foot position or calf muscle orientation must be considered.

Association between expression of FABPpm in skeletal muscle and insulin sensitivity in intramyocellular lipid-accumulated nonobese men.

Intramyocellular lipid (IMCL) accumulation is observed in both insulin-resistant subjects and insulin-sensitive endurance athletes (athlete's paradox). We hypothesized that the expression pattern of fatty acid transporters may influence oxidative capacity and determine the association between IMCL and insulin resistance. The objective of the study was to investigate the muscle expression of fatty acid transporters and their function related to insulin sensitivity in IMCL-accumulated subjects. The study subjects were 36 nonobese healthy men. Their IMCL levels were measured by (1)H-magnetic resonance spectroscopy, and their insulin sensitivity was evaluated by steady-state glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp. Gene expression levels in the vastus lateralis were evaluated by quantitative RT-PCR. We compared the clinical phenotypes and the expression levels of genes involved in lipid metabolism in skeletal muscle between IMCL-accumulated high-GIR (H-GIR) subjects (n = 8) and low-GIR subjects (n = 9). The functions of candidate fatty acid transporters were determined by in vitro analyses. Compared with the low-GIR group, body fat was lower and maximum oxygen uptake was higher in the H-GIR group. Several lipid oxidation genes in muscle were up-regulated in the H-GIR group, and this was associated with increased expression of higher plasma membrane-associated fatty acid-binding protein (FABPpm) and decreased expression of fatty acid transport protein (FATP)-1. Overexpression of FABPpm in C2C12 myotubes increased fatty acid oxidation coupled with the elevated expression of genes related to fatty acid oxidation. These changes were not observed in FATP1-overexpressed myotubes. Differences in the gene expression of fatty acid transporters may, at least in part, affect insulin sensitivity in IMCL-accumulated nonobese men.

Differences in extramyocellular lipid and physical function in older adults with sufficient and insufficient vitamin D status (260.2)

The metabolic role of extramyocellular lipid (EMCL) has yet to be elucidated. An inverse relationship between EMCL and physical function, and EMCL and vitamin D status has been described in vitamin D‐deficiency (25(OH)D &lt; 20 ng/mL). The purpose of this study was to assess differences in muscle lipid and physical function in community dwelling elderly with vitamin D insufficiency (25(OH)D 蠄 30 ng/mL) compared to vitamin D levels that may promote extra‐skeletal health (25(OH)D 蠅 40 ng/mL). 25(OH)D and four square step test (FSST) were assessed in 21 adults aged 65 to 83 years. Gastrocnemius IMCL and EMCL were measured with magnetic resonance spectroscopy and fat ratio segmentation, respectively. Mean body mass index (BMI) was 26.9±0.9 kg/m2. Mean EMCL was 20.2±0.9% with a range of 11.8 to 25.9% and intramyocellular lipid (IMCL) to water ratio was 0.5±0.06. Participants who were vitamin D insufficient (23.9±1.1 ng/mL) had significant higher levels of lateral gastrocnemius EMCL and slower FSST times compared to vitamin D replete (54.7±3 ng/mL) (p&lt;0.05). IMCL, BMI, age, and activity levels were not significantly different between vitamin D groups. These data suggest that vitamin D status 蠄 30 ng/mL may contribute to EMCL accumulation and impaired physical function independent of activity and body mass. A vitamin D status higher than what is normally deemed as sufficient may be needed to measure muscle function.Grant Funding Source: Partially sponsored by NIH CTSA UL1TR000117.

Dietary lipids do not contribute to the higher hepatic triglyceride levels of fructose‐ compared to glucose‐fed mice

Fructose consumption has been associated with the surge in obesity and dyslipidemia. This may be mediated by the fructose effects on hepatic lipids and ATP levels. Fructose metabolism provides carbons for de novo lipogenesis (DNL) and stimulates enterocyte secretion of apoB48. Thus, fructose-induced hepatic triglyceride (HTG) accumulation can be attributed to both DNL stimulation and dietary lipid absorption. The aim of this study was to assess the effects of fructose diet on HTG and ATP content and the contributions of dietary lipids and DNL to HTG. Measurements were performed in vivo in mice by magnetic resonance imaging (MRI) and novel magnetic resonance spectroscopy (MRS) approaches. Abdominal adipose tissue volume and intramyocellular lipid levels were comparable between 8-wk fructose- and glucose-fed mice. HTG levels were ∼1.5-fold higher in fructose-fed than in glucose-fed mice (P<0.05). Metabolic flux analysis by (13)C and (2)H MRS showed that this was not due to dietary lipid absorption, but due to DNL stimulation. The contribution of oral lipids to HTG was, after 5 h, 1.60 ± 0.23% for fructose and 2.16 ± 0.35% for glucose diets (P=0.26), whereas that of DNL was higher in fructose than in glucose diets (2.55±0.51 vs.1.13±0.24%, P=0.01). Hepatic energy status, assessed by (31)P MRS, was similar for fructose- and glucose-fed mice. Fructose-induced HTG accumulation is better explained by DNL and not by dietary lipid uptake, while not compromising ATP homeostasis.

An evaluation of early cardiometabolic risk factors in children and adolescents with Turner syndrome

Turner syndrome (TS) confers increased lifetime risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors and measures of subcutaneous, visceral adipose tissue and intra-myocellular lipid between young TS girls and an age- and BMI-standard deviation scores (SDS)-matched healthy female cohort. A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. Nineteen TS and 17 control girls (13.7 ± 2.5 vs 12.7 ± 3.4 years of age, respectively, P = 0.30). Multiple-sample oral glucose tolerance test with measurement of fasting insulin, LDL, HDL, triglycerides, adiponectin and highly sensitive C-reactive protein (hsCRP) was performed. Subcutaneous adipose tissue, visceral adipose tissue intramyocellular lipid levels evaluated by magnetic resonance techniques. Insulin secretion (IS), sensitivity (Si) and the insulin secretion-sensitivity index (ISSI-2) were calculated from oral glucose tolerance test data. Five TS and no controls had impaired fasting glucose or impaired glucose tolerance; none had type 2 diabetes mellitus. Insulin sensitivity and insulin secretion were similar between groups; ISSI-2 was lower in TS (923.5 ± 307.3 vs 659.1 ± 387.3; P = 0.03). TS girls had higher blood pressure (82.5 ± 13.6 vs 73.5 ± 5.5 mmHg; P = 0.0146), waist circumference (76.0 ± 11.8 vs 65.9 ± 9.7; P = 0.0087) and subcutaneous adipose tissue (135.6 ± 88.6 vs 69.3 ± 59.9; P = 0.01) than controls. Visceral adipose tissue, intramyocellular lipid levels and adiponectin were not different between groups. TS girls also had higher triglycerides (1.1 ± 0.6 vs 0.7 ± 0.3; P = 0.003), total cholesterol (4.4 ± 0.7 vs 3.9 ± 0.4; P = 0.02) and hsCRP (2.0 ± 1.9 vs 0.8 ± 0.3; P = 0.01). TS girls exhibit more cardiometabolic risk factors and reduced beta cell function compared with age- and BMI-SDS-matched girls. Increased awareness of early risk of type 2 diabetes mellitus and hypertension in TS girls is needed.

A Palaeolithic‐type diet causes strong tissue‐specific effects on ectopic fat deposition in obese postmenopausal women

Ectopic fat accumulation in liver and skeletal muscle may be an essential link between abdominal obesity, insulin resistance and increased risk of cardiovascular disease after menopause. We hypothesized that a diet containing a relatively high content of protein and unsaturated fat [mainly monounsaturated fatty acids (MUFAs)] but limited carbohydrates and saturated fat would reduce lipid content in liver and muscle and increase insulin sensitivity in postmenopausal women. Ten healthy, nonsmoking postmenopausal women with a body mass index (BMI) >27 (28-35) kg m(-2) were included in the study. Participants were instructed to consume an ad libitum Palaeolithic-type diet intended to provide approximately 30 energy percentage (E%) protein, 40 E% fat (mainly MUFAs) and 30 E% carbohydrate. Intramyocellular lipid (IMCL) levels in calf muscles and liver triglyceride levels were quantified using proton magnetic resonance spectroscopy ((1) H-MRS) before and 5 weeks after dietary intervention. Insulin sensitivity was estimated by homoeostasis model assessment (HOMA) indices and the euglycaemic hyperinsulinaemic clamp technique. Mean energy intake decreased by 25% with a weight loss of 4.5 kg. BMI, waist and hip circumference, waist/hip ratio and abdominal sagittal diameter also decreased significantly, as did diastolic blood pressure (mean -7 mmHg), levels of fasting serum glucose, cholesterol, triglycerides, LDL/HDL cholesterol, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1), urinary C-peptide and HOMA indices. Whole-body insulin sensitivity did not change. Liver triglyceride levels decreased by 49%, whereas IMCL levels in skeletal muscle were not significantly altered. A modified Palaeolithic-type diet has strong and tissue-specific effects on ectopic lipid deposition in postmenopausal women.

Deletion of CD73 promotes dyslipidemia and intramyocellular lipid accumulation in muscle of mice

Context: CD73 converts extracellular AMP to adenosine which is well known to inhibit lipolysis. It is unknown, however, whether adenosine formed directly by CD73 is functionally relevant in this process. Objective: We therefore explored the effect of CD73-derived adenosine on body fat of aged mice. Results: In lean mice, extracellular adenosine formation by adipocytes is dependent on CD73. High fat diet down-regulates the expression of CD73 in wildtype mice similar to ob/ob mice. Transgenic mice chronically lacking CD73 (CD73−/−) gain significantly less body weight and show decreased superficial white fat content as well as increased serum free fatty acids and triglycerides. In addition, intramyocellular lipid levels are significantly increased. This phenotype is accompanied by an increase in blood glucose and serum insulin levels although insulin secretion and the level of insulin degrading enzyme are unaltered. Additionally, insulin-induced Akt phosphorylation is reduced in skeletal muscle of CD73−/− mice. Conclusion: CD73-derived adenosine is functionally involved in body fat homeostasis.

PS5 - 29. Increased intramyocellular lipid storage capacity is associated with lower fasting-induced insulin resistance

Obesity is associated with increased lipid supply to skeletal muscle. However, high intramyocellular lipid (IMCL) levels do not necessarily result in impaired insulin signaling. Lipid droplet coat proteins modulate IMCL metabolism.

Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice

Excessive ectopic lipid deposition contributes to impaired insulin action in peripheral tissues and is considered an important link between obesity and type 2 diabetes mellitus. Acetyl-CoA carboxylase 2 (ACC2) is a key regulatory enzyme controlling skeletal muscle mitochondrial fatty acid oxidation; inhibition of ACC2 results in enhanced oxidation of lipids. Several mouse models lacking functional ACC2 have been reported in the literature. However, the phenotypes of the different models are inconclusive with respect to glucose homeostasis and protection from diet-induced obesity. Here, we studied the effects of pharmacological inhibition of ACC2 using as a selective inhibitor the S enantiomer of compound 9c ([S]-9c). Selectivity was confirmed in biochemical assays using purified human ACC1 and ACC2. (S)-9c significantly increased fatty acid oxidation in isolated extensor digitorum longus muscle from different mouse models (EC(50) 226 nmol/l). Accordingly, short-term treatment of mice with (S)-9c decreased malonyl-CoA levels in skeletal muscle and concomitantly reduced intramyocellular lipid levels. Treatment of db/db mice for 70 days with (S)-9c (10 and 30 mg/kg, by oral gavage) resulted in improved oral glucose tolerance (AUC -36%, p < 0.05), enhanced skeletal muscle 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake, as well as lowered prandial glucose (-31%, p < 0.01) and HbA(1c) (-0.7%, p < 0.05). Body weight, liver triacylglycerol, plasma insulin and pancreatic insulin content were unaffected by the treatment. In conclusion, the ACC2-selective inhibitor (S)-9c revealed glucose-lowering effects in a mouse model of diabetes mellitus.

Metabolic manifestations of polycystic ovary syndrome in nonobese adolescents: retinol-binding protein 4 and ectopic fat deposition

To determine whether nonobese adolescents with polycystic ovary syndrome (PCOS) have higher levels of retinol-binding protein 4 (RBP4) and ectopic fat than controls and whether RBP4 and ectopic fat correlate with comorbidities of metabolic disease. Cross-sectional case-control study. Pediatric clinical research center based in a quaternary care medical center. Twenty-four nonobese adolescents between the ages of 13 and 21 years, 13 with PCOS and 11 controls. Measurement of RBP4, insulin resistance, lipids, and body composition. Retinol-binding protein 4, reproductive and adrenal hormones, insulin resistance, intrahepatic and intramyocellular lipid levels, and visceral adipose tissue. Adolescents with PCOS had higher intrahepatic lipid content and a statistical trend for higher RBP4 compared with controls. Retinol-binding protein 4 correlated with body fat, triglycerides, insulin resistance, and androgens but not intrahepatic lipid content; however, when adjusted for body fat, the correlation between RBP4 and triglycerides weakened to a statistical trend and was no longer statistically significant for the other measures. This small preliminary study of nonobese adolescent girls suggests that RBP4 may be involved in the dyslipidemia associated with PCOS and that there may be an independent relationship between RBP4 and triglycerides but not between RBP4 and insulin resistance. Although intrahepatic lipid content was higher in PCOS, it did not correlate with RBP4, triglycerides, or insulin resistance.

Influence of foot orientation on the appearance and quantification of 1H magnetic resonance muscle spectra obtained from the soleus and the vastus lateralis.

Muscle (1)H magnetic resonance spectroscopy noninvasively measures intramyocellular lipid levels, which correlate with obesity, insulin resistance, and type 2 diabetes. The appearance of muscle magnetic resonance spectra is influenced by bulk magnetic susceptibility and residual dipolar couplings which depend on the angle between the muscle fibers and the main magnetic field. This study used a 4 T magnet to examine the influence of foot orientation on the appearance and quantification of muscle magnetic resonance spectra from the soleus and the vastus lateralis. For each individual, intramyocellular lipid, extramyocellular lipid, and creatine concentrations were quantified in the soleus and the vastus lateralis during one session. Foot orientation was found to influence the appearance of muscle spectra from the soleus but not from the vastus lateralis. It was concluded that quantifying intramyocellular lipid by the standard LCModel using a water reference may be more appropriate than using a creatine reference in the presence of residual dipolar couplings.

Skeletal muscle 1H MRSI before and after prolonged exercise. I. muscle specific depletion of intramyocellular lipids

Aim of the study was to determine distribution and depletion patterns of intramyocellular lipids (IMCL) in leg muscles before and after two types of standardized endurance exercise. ¹H-magnetic resonance spectroscopic imaging was performed (1) in the thigh of eight-trained cyclists after exercising on an ergometer for 3 h at 52 ± 8% of maximal speed and (2) in the lower leg of eight-trained runners after exercising on a treadmill for 3 h at 49 ± 3% of maximal workload. Pre-exercise IMCL contents were reduced postexercise in 11 out of 13 investigated upper and lower leg muscles (P < 0.015 for all). A strong linear correlation with a slope of ∼0.5 between pre-exercise IMCL content and IMCL depletion was found. IMCL depletion differed strongly between muscles. Absolute and also relative IMCL reduction was significantly higher in muscles with predominantly slow fibers compared to those with fast fibers. Creatine levels and fiber orientation were stable and unchanged after exercise, while trimethyl-ammonium groups increased. This is presented in the accompanying paper. In conclusion, a systematic comparison of metabolic changes in cross sections of the upper and lower leg was performed. The results imply that pre-exercise IMCL levels determine the degree of IMCL depletion after exercise.

Proton magnetic resonance spectroscopy shows lower intramyocellular lipid accumulation in middle-aged subjects predisposed to familial longevity

Families predisposed to longevity show enhanced glucose tolerance and skeletal muscle insulin sensitivity compared with controls, independent of body composition and physical activity. Intramyocellular lipid (IMCL) accumulation in skeletal muscle has been associated with insulin resistance. Here, we assessed whether subjects enriched for familial longevity have lower IMCL levels. We determined IMCL levels in 48 subjects from the Leiden Longevity Study, comprising 24 offspring of nonagenarian siblings and 24 partners thereof as control subjects. IMCL levels were assessed noninvasively using short echo time proton magnetic resonance spectroscopy ((1)H-MRS) of the tibialis anterior muscle with a 7 Tesla human MR scanner. IMCL levels were calculated relative to the total creatine (tCr) CH3 signal. Physical activity was assessed using the International Physical Activity Questionnaire (IPAQ). After correction for age, sex, BMI, and physical activity, offspring of long-lived nonagenarian siblings tended to show lower IMCL levels compared with controls (IMCL/tCr: 3.1 ± 0.5 vs. 4.5 ± 0.5, respectively, P = 0.051). In a pairwise comparison, this difference reached statistical significance (P = 0.038). We conclude that offspring of nonagenarian siblings predisposed to longevity show lower IMCL levels compared with environmentally matched control subjects. Future research should focus on assessing what mechanisms may explain the lower IMCL levels in familial longevity.

PS5 - 28. Pioglitazone treatment improves muscle oxidative capacity and lowers muscle lipid content in diabetic rats

Pioglitazone is a PPAR- agonist that redirects lipids from ectopic sites into subcutaneous adipose tissue and is hypothesized to improve mitochondrial function in skeletal muscle. This study assessed whether the insulin-sensitizing effect of pioglitazone is accompanied by improved skeletal muscle mitochondrial function and intramyocellular lipid (IMCL) levels in Zucker diabetic fatty rats using 31P and 1H magnetic resonance spectroscopy (MRS).

PS14 - 71. Increased intramyocellular lipids, but normal muscular mitochondrial oxidative capacity in adipose triglyceride lipase deficient mice

Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme of triglyceride hydrolysis and is mainly expressed in adipocytes and myocytes, thus ATGL-KO mice show abnormal triglyceride accumulation in those tissues. Intramyocellular lipids (IMCL) are often used as biomarker of insulin resistance and type 2 diabetes, potentially reflecting lipotoxic effects on mitochondrial function. Whether IMCL accumulation per se has adverse effects on mitochondria is unclear. Therefore, we assessed IMCL levels and mitochondrial oxidative capacity of ATGL-KO mice in vivo with 1HMRS and gated-dynamic-31PMRS of contracting calf-muscles.

Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation on Energy Metabolism and Metabolic Profile in Obese Humans

Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 healthy, obese men with placebo and 150mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.

Insulin Resistance in Non-Obese Subjects Is Associated with Activation of the JNK Pathway and Impaired Insulin Signaling in Skeletal Muscle

BackgroundThe pathogenesis of insulin resistance in the absence of obesity is unknown. In obesity, multiple stress kinases have been identified that impair the insulin signaling pathway via serine phosphorylation of key second messenger proteins. These stress kinases are activated through various mechanisms related to lipid oversupply locally in insulin target tissues and in various adipose depots.Methodology/Principal FindingsTo explore whether specific stress kinases that have been implicated in the insulin resistance of obesity are potentially contributing to insulin resistance in non-obese individuals, twenty healthy, non-obese, normoglycemic subjects identified as insulin sensitive or resistant were studied. Vastus lateralis muscle biopsies obtained during euglycemic, hyperinsulinemic clamp were evaluated for insulin signaling and for activation of stress kinase pathways. Total and regional adipose stores and intramyocellular lipids (IMCL) were assessed by DXA, MRI and 1H-MRS. In muscle of resistant subjects, phosphorylation of JNK was increased (1.36±0.23 vs. 0.78±0.10 OD units, P<0.05), while there was no evidence for activation of p38 MAPK or IKKβ. IRS-1 serine phosphorylation was increased (1.30±0.09 vs. 0.22±0.03 OD units, P<0.005) while insulin-stimulated tyrosine phosphorylation decreased (10.97±0.95 vs. 0.89±0.50 OD units, P<0.005). IMCL levels were twice as high in insulin resistant subjects (3.26±0.48 vs. 1.58±0.35% H2O peak, P<0.05), who also displayed increased total fat and abdominal fat when compared to insulin sensitive controls.ConclusionsThis is the first report demonstrating that insulin resistance in non-obese, normoglycemic subjects is associated with activation of the JNK pathway related to increased IMCL and higher total body and abdominal adipose stores. While JNK activation is consistent with a primary impact of muscle lipid accumulation on metabolic stress, further work is necessary to determine the relative contributions of the various mediators of impaired insulin signaling in this population.

Longitudinal evaluation of intramyocellular lipids (IMCLs) in tibialis anterior muscle of ob/ob and ob/+ control mice using a cryogenic surface coil at 9.4 T

Insulin resistance is a central feature of type II diabetes and is associated with alterations in skeletal muscle lipid metabolism, which manifest themselves, in part, in increased intramyocellular lipid (IMCL) accumulation. The objective of this study was to assess noninvasively the levels of IMCL longitudinally in the tibialis anterior muscle of Lep(ob) /Lep(ob) (ob/ob) mice, a genetic model of obesity and mild diabetes, and Lep(ob) /+ (ob/+) heterozygous control animals, using (1) H MRS at 9.4 T. The use of a cryogenic surface coil transceiver leads to significant increases in sensitivity. Method implementation included the assessment of the reproducibility and spatial heterogeneity of the IMCL signal and the determination of T(2) relaxation times, as IMCL levels were expressed relative to the total creatine signal, and therefore the signal ratios had to be corrected for differences in T(2) relaxation. IMCL levels were found to be significantly higher in ob/ob mice relative to ob/+ heterozygous control mice that do not develop disease. An increase in IMCL levels was observed for ob/ob mice until weeks 16/17; after this time point, IMCL levels decreased again, reaching final levels that were slightly higher than the initial values. These noninvasively detected alterations in skeletal muscle lipid metabolism in ob/ob mice were accompanied by a transient increase in plasma insulin concentrations. This study indicates that IMCL may be reliably assessed in mouse tibialis anterior muscle using a cryogenic surface coil, implying that (1) H MRS at 9.4 T represents a useful technology for the noninvasive measurement of changes in lipid metabolism in the skeletal muscle that accompany obesity.

Determinants of intramyocellular lipid accumulation after dietary fat loading in non-obese men.

Aims/Introduction: Accumulation of intramyocellular lipid (IMCL) is associated with insulin resistance. However, the factors affecting the change in IMCL remain to be elucidated. The aim of the present study was to determine the factors that influence the change in IMCL level after high-fat loading. The study subjects were 37 non-obese men. Each subject consumed a high-fat diet for 3 days after a normal-fat diet for 3 days. After each diet program, IMCL levels in the tibialis anterior (TA-IMCL) and soleus (SOL-IMCL) were measured by proton magnetic resonance spectroscopy. Glucose infusion rate (GIR) was evaluated by euglycemic hyperinsulinemic clamp as an index of peripheral insulin sensitivity. The high-fat diet significantly increased TA-IMCL and SOL-IMCL by ∼30 and ∼20%, respectively (P < 0.05), whereas it did not significantly alter GIR. The increase in SOL-IMCL, but not in TA-IMCL, negatively correlated with serum high molecular weight (HMW)-adiponectin (r = -0.36, P < 0.05) and HMW-/total-adiponectin ratio (r = -0.46, P < 0.05). Although high-fat diet-related changes in SOL-IMCL showed high inter-individual variations, in subjects doing exercise, changes in SOL-IMCL (r = 0.55, P < 0.05) and TA-IMCL (r = 0.61, P < 0.05) positively correlated with daily physical activity level. In contrast, in sedentary subjects, changes in SOL-IMCL (r = -0.50, P < 0.01) and TA-IMCL (r = -0.48, P < 0.05) negatively correlated with daily physical activity. HMW-adiponectin and daily physical activity are determinants of IMCL accumulation by a high-fat diet. Intriguingly, the effect of daily physical activity on the change in IMCL depends on the level of regular exercise. (J Diabetes Invest,doi: 10.1111/j.2040-1124.2010.00091.x, 2011).