Skeletal Muscle Lipid Research Articles

The Effects of BCAAs on Insulin Resistance in Athletes.

The toxic catabolic intermediates of branched chain amino acids can cause insulin resistance, and are involved in different mechanisms in different metabolic tissues. In skeletal muscle, 3-hydroxy-isobutyrate produced by valine promotes skeletal muscle fatty acid uptake, resulting in the accumulation of incompletely oxidized lipids in skeletal muscle, causing skeletal muscle insulin resistance. In the liver, branched-chain α-keto acids decompose in large amounts, promote hepatic gluconeogenesis, and lead to the accumulation of multiple acylcarnitines, which damages the mitochondrial tricarboxylic acid cycle, resulting in the accumulation of incomplete oxidation products, oxidative stress in mitochondria, and hepatic insulin resistance. In adipose tissue, the expression of branched-chain amino acid catabolic enzymes (branched-chain amino acid transaminase, branched-chain α-keto acid dehydrogenase) is reduced, resulting in an increased level of plasma branched-chain amino acids, thereby causing massive decomposition of branched-chain amino acids in tissues such as skeletal muscle and liver, and inducing insulin resistance. However, branched-chain amino acids, as a common nutritional supplement for athletes, do not induce insulin resistance. A possible explanation for this phenomenon is that exercise can enhance the mitochondrial oxidative potential of branched-chain amino acids, alleviate or even eliminate the accumulation of branched-chain amino acid catabolic intermediates, and promotes branched-chain amino acids catabolism into beta-aminoisobutyric acid, increasing plasma beta-aminoisobutyric acid concentration, improving insulin resistance. This article reveals the mechanism of BCAA-induced insulin resistance and the relationship between exercise and BCAAs metabolism, adds a guarantee for the use of BCAAs, and provides a new explanation for the occurrence of diabetes and how exercise improves diabetes.

Transcript profile of skeletal muscle lipid metabolism genes affected by diet in a piglet model of low birth weight.

Dysregulated skeletal muscle metabolism (DSMM) is associated with increased inter- and intramuscular fat deposition in low birth weight (L) individuals. The mechanisms behind DSMM in L individuals are not completely understood but decreased muscle mass and shifts in lipid and carbohydrate utilisation may contribute. Previously, we observed lower fat oxidation in a porcine model of low birth weight. To elucidate the biological activities underpinning this difference microfluidic arrays were used to assess mRNA associated with lipid metabolism in longissimus dorsi (LD) and semitendinosus (ST) skeletal muscle samples from thirty-six female L and normal birth weight (N) pigs. Plasma samples were collected from a sub-population to measure metabolite concentrations. Following overnight fasting, skeletal muscle and plasma samples were collected and the association with birth weight, diet and age was assessed. Reduced dietary fat was associated with decreased LD intermuscular fat deposition and beta-oxidation associated mRNA, in both birth weight groups. Lipid uptake and intramuscular fat deposition associated mRNA was reduced in only L pigs. Abundance of ST mRNA associated with lipolysis, lipid synthesis and transport increased in both birth weight groups. Lipid uptake associated mRNA reduced in only L pigs. These changes were associated with decreased plasma L glucose and N triacylglycerol. Post-dietary fat reduction, LD mRNA associated with lipid synthesis and inter- and intramuscular fat deposition increased in L, whilst beta-oxidation associated mRNA remains elevated for longer in N. In the ST, mRNA associated with lipolysis and intramuscular fat deposition increased in both birth weight groups, however this increase was more significant in L pigs and associated with reduced beta-oxidation. Analysis of muscle lipid metabolism associated mRNA revealed that profile shifts are a consequence of birth weight. Whilst, many of the adaptions to diet and age appear to be similar in birth weight groups, the magnitude of response and individual changes underpin the previously observed lower fat oxidation in L pigs.

Raspberry supplementation reduces lipid accumulation and improves insulin sensitivity in skeletal muscle of mice fed a high-fat diet

Abstract Raspberry promotes adipose tissue browning and increases lipid oxidation, but its effect on intramyocellular lipid accumulation and insulin sensitivity is unclear. This study aimed to evaluate the protective role of raspberry on high-fat diet (HFD)-induced skeletal muscle lipid accumulation and insulin resistance in mice. Mice were fed a control diet or a HFD diet with or without 5% raspberry for 12 weeks. Dietary raspberry alleviated skeletal muscle inflammatory response by decreasing the expression of pro-inflammatory cytokines and p65 phosphorylation, a key mediator of inflammatory nuclear factor κB (NF-κB) signaling. Meanwhile, raspberry reduced muscle triglyceride content and improved insulin signaling in HFD mice. Raspberry intake increased mitochondrial biogenesis and phosphorylation of AMP-activated protein kinase (AMPK) α impaired due to HFD. Our results suggest that raspberry reduces lipid accumulation and improves insulin sensitivity in skeletal muscle of HFD-fed mice, which is associated with suppressed inflammation and increased mitochondrial biogenesis and AMPKα activity.

Diet and Exercise Training Influence Skeletal Muscle Long-Chain acyl-CoA Synthetases

Long-chain acyl-CoA synthetases (ACSL) are implicated as regulators of oxidation and storage of fatty acids within skeletal muscle; however, to what extent diet and exercise alter skeletal muscle ACSL remains poorly understood. This study aimed to determine the effects of diet and exercise training on skeletal muscle ACSL and to examine relationships between ACSL1 and ACSL6 and fat oxidation and fat storage, respectively. Male C57BL/6J mice consumed a 60% high-fat diet (HFD) for 12 wk to induce obesity compared with low-fat diet (LFD). At week 4, mice began aerobic exercise (EX-Tr) or remained sedentary (SED) for 8 wk. At week 12, the protein abundance of five known ACSL isoforms and mRNA expression for ACSL1 and ACSL6 were measured in gastrocnemius muscle, as was skeletal muscle lipid content. Fat oxidation was measured using metabolic cage indirect calorimetry at week 10. Of the five known ACSL isoforms, four were detected at the protein level. HFD resulted in greater, yet nonsignificant, ACSL1 protein abundance (+18%, P = 0.13 vs LFD), greater ACSL6 (+107%, P < 0.01 vs LFD), and no difference in ACSL4 or ACSL5. Exercise training resulted in greater ACSL6 protein abundance in LFD mice (P = 0.05 LFD EX-Tr vs SED), whereas ACSL4 was lower after exercise training compared with sedentary, regardless of diet. Under fasted conditions, skeletal muscle ACSL1 protein abundance was not related to measures of whole-body fat oxidation. Conversely, skeletal muscle ACSL6 protein abundance was positively correlated with intramyocellular lipid content (P < 0.01, r = 0.22). We present evidence that ACSL isoforms 1, 4, and 6 may undergo regulation by HFD and/or exercise training. We further conclude that increased skeletal muscle ACSL6 may facilitate increased intramyocellular fat storage during HFD-induced obesity.

Transcriptional Regulation of the Bovine Fatty Acid Transport Protein 1 Gene by Krüppel-Like Factors 15.

Simple SummaryThe nutritional value and qualities of beef are enhanced when the unsaturated fatty acid content is increased. Fatty acid transport protein 1 (FATP1), also called SLC27A1, an integral membrane protein that facilitates long-chain fatty acid influx, is involved in the genetic network for oleic acid synthesis in beef. Polymorphisms in bovine SLC27A1 gene are most significantly associated with oleic acid. Its expression exhibits significant positive correlations with bovine intramuscular fat content in the longissimus thoracis muscle. However, the transcription factors that contribute to the control and regulation of its expression have not been characterized extensively. In this study, we determined the tissue distribution of SLC27A1 mRNA and found that bovine SLC27A1 was highly expressed in subcutaneous adipose tissue and the longissimus thoracis muscle. Furthermore, we analyzed the molecular mechanisms involved in SLC27A1 regulation and found that the transcriptional activity of SLC27A1 gene was dependent on KLF15 transcription factor. These results may lead to an enhanced understanding of the regulation of SLC27A1 expression in other models, as well as provide new insights into the regulatory mechanism and biological functions of the SLC27A1 gene in determining the lipid composition in beef.Oleic acid is a major monounsaturated fatty acid, which accounts for about 33% of the fatty acid content in beef and is considered to have the least negative effect on serum cholesterol levels. Fatty acid transport protein 1 (FATP1), an integral membrane protein that facilitates long-chain fatty acid (LCFA) influx, is involved in the genetic network for oleic acid synthesis in beef. Its expression exhibits significant positive correlations with intramuscular fat (IMF) content in the longissimus thoracis. However, the expression mechanism of SLC27A1 or FATP1 is still unclear. To elucidate the molecular mechanisms involved in bovine SLC27A1 regulation, we cloned and characterized the promoter region of SLC27A1. By applying 5′-rapid amplification of cDNA end analysis, we identified two alternative splice variants of this gene. Using a series of 5′ deletion promoter plasmids in luciferase reporter assays, we found that the core promoter was 96 base pairs upstream from the transcription initiation site. Electrophoretic mobility shift assay combined with a site-directed mutation experiment demonstrated that KLF15 binding to the promoter region drives the SLC27A1 transcription. KLF15 plays an essential role in adipogenesis and skeletal muscle lipid flux. Thus, these results might provide further information on the regulatory roles of SLC27A1 gene in mediating the lipid composition in beef.

Lipid emulsion, but not propofol, induces skeletal muscle damage and lipid peroxidation

PurposeProlonged propofol infusion induces skeletal muscle damage. However, it is well known that the lipid emulsion that is the solvent of propofol causes various types of tissue damage via lipid peroxidation, and that propofol, conversely, has an anti-lipid peroxidative effect. The purpose of this study was to determine whether propofol or the lipid emulsion is the cause of muscle damage following prolonged administration.MethodsRats were divided into four groups: NI group (no intervention), Cath group (venous catheter insertion only), Prop group (1% propofol (Maruishi) intravenous infusion at 10 mg/kg/h), and Lipid group (10% Lipofundin® intravenous infusion at 100 mg/kg/h) (n = 10, each group). 1% Propofol (Maruishi) or Lipofundin was infused at 1 mL/kg/h for 72 h. The solvent of 1% propofol (Maruishi) is a 10% lipid emulsion. Lipofundin consists of 50% long-chain triacylglycerols and 50% medium-chain triacylglycerols, similar to the propofol solvent. Plasma concentrations of creatine kinase and myoglobin, superoxide production level, and 4-hydroxynonenal and malondialdehyde expression in the gastrocnemius muscle were evaluated 72 h after the interventions.ResultsPlasma concentrations of creatine kinase and myoglobin in the Lipid group were significantly higher than those in the other three groups. The superoxide production level, and 4-hydroxynonenal and malondialdehyde expression in the Lipid group were also significantly higher than in the other three groups.ConclusionLipofundin induces skeletal muscle damage via lipid peroxidation, and 1% propofol (Maruishi) conversely suppresses the muscle damage via antioxidant effects.

LIPOTOXICIDAD EN MÚSCULO ESQUELÉTICO Y SU RELACIÓN CON LA RESISTENCIA INSULÍNICA. ESTUDIOS EN UN MODELO EXPERIMENTAL DE SÍNDROME METABÓLICO

Introducción: el acúmulo de lípidos en el músculo esquelético se encuentra estrechamente vinculado con el desarrollo de la resistencia insulínica. Esta última cumple un rol patogénico central en el desarrollo de numerosos desórdenes metabólicos incluidos en el síndrome metabólico.Objetivos: analizar algunas vías metabólicas implicadas en el acúmulo de lípidos en el músculo esquelético y su asociación con la resistencia insulínica en un modelo experimental que mimetiza el fenotipo del síndrome metabólico humano.Materiales y métodos: ratas macho Wistar recibieron una dieta control (DC) o una dieta rica en sacarosa (DRS) durante seis meses. Al final del período experimental se analizó en músculo esquelético gastrocnemio: contenido de triglicéridos (TG), acil-CoA de cadena larga y diacilglicerol, actividad enzimática carnitina palmitoil transferasa muscular (M-CPT1, M-CPT2 y M-CPT total) y masa proteica del PPARα, AMPK y AMPKp. Se determinaron los niveles séricos de TG, AGNE, glucosa, insulina, TNFα y adiponectina. La sensibilidad insulínica se midió por la técnica clamp euglucémica-hiperinsulinémica.

Dysferlin deficiency alters lipid metabolism and remodels the skeletal muscle lipidome in mice

Defects in the gene coding for dysferlin, a membrane-associated protein, affect many tissues, including skeletal muscles, with a resultant myopathy called dysferlinopathy. Dysferlinopathy manifests postgrowth with a progressive loss of skeletal muscle function, early intramyocellular lipid accumulation, and a striking later replacement of selective muscles by adipocytes. To better understand the changes underpinning this disease, we assessed whole-body energy homeostasis, skeletal muscle fatty acid metabolism, lipolysis in adipose tissue, and the skeletal muscle lipidome using young adult dysferlin-deficient male BLAJ mice and age-matched C57Bl/6J WT mice. BLAJ mice had increased lean mass and reduced fat mass associated with increased physical activity and increased adipose tissue lipolysis. Skeletal muscle fatty acid metabolism was remodeled in BLAJ mice, characterized by a partitioning of fatty acids toward storage rather than oxidation. Lipidomic analysis identified marked changes in almost all lipid classes examined in the skeletal muscle of BLAJ mice, including sphingolipids, phospholipids, cholesterol, and most glycerolipids but, surprisingly, not triacylglycerol. These observations indicate that an early manifestation of dysferlin deficiency is the reprogramming of skeletal muscle and adipose tissue lipid metabolism, which is likely to contribute to the progressive adverse histopathology in dysferlinopathies.

EPA and DHA elicit distinct transcriptional responses to high-fat feeding in skeletal muscle and liver.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert numerous beneficial biological effects and attenuate diet-induced insulin resistance in rodent models. In the present study, the independent, tissue-specific effects of two nutritionally relevant n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were characterized in the context of a high-fat diet (HFD). EPA and DHA supplementation (3.2% of total fat) in 6-mo-old male C57BL/6 mice fed an HFD (60% fat) partially mitigated reductions in insulin sensitivity. At 5 wk, the area above the curve below baseline glucose following an intraperitoneal insulin tolerance test was 54.5% lower in HFD than control, whereas HFD + EPA and HFD + DHA showed 27.6% and 17.1% reductions, respectively. At 10 wk, HFD increased mitochondrial oxidative capacity supported by lipid and carbohydrate-based substrates in both liver and skeletal muscle (P < 0.05), with little effect of EPA or DHA supplementation. Whole genome transcriptomic analyses revealed HFD-induced transcriptional changes indicative of inflammation and fibrosis in both liver and muscle. Gene set enrichment analyses indicated a downregulation of transcripts associated with extracellular matrix in muscle (family-wise error rate P < 0.01) and liver (P = 0.04) and in transcripts associated with inflammation in muscle (P = 0.03) in HFD + DHA compared with HFD alone. In contrast, EPA appeared to potentiate some proinflammatory effects of the HFD. In the skeletal muscle, DHA increased the expression of stress-responsive genes, whereas EPA upregulated the expression of transcripts related to cell cycle. Therefore, although both EPA and DHA supplementation during HFD partially preserve insulin signaling, they modulate distinct processes, highlighting their unique biological effects in the context of obesity.

NUTRIGENOMICS AS A TOOL IN THE PREVENTION OF LIPOTOXICITY: THE CASE OF SOY PROTEIN.

Obesity is associated with an increase of several metabolic disorders leading to the development of diseases such as type 2 diabetes and cardiovascular disease. This is due in part to the ectopic accumulation of triglycerides in organs that are non-adipose tissues, leading to lipotoxicity. Particularly, in the liver, the accumulation of lipids, mainly of triglycerides, leads to the formation of fatty liver. The accumulation of lipids in skeletal muscle and pancreas associates with insulin resistance and a decrease in insulin secretion, respectively. In addition, it has been suggested that dysbiosis of the gut microbiota can contribute to the process of lipid accumulation in non-adipose tissues, especially in the liver. The aim of the present review is to highlight the mechanisms associated with the development of lipotoxicity, and how with the advances in nutrigenomics, it is now possible to understand the molecular mechanisms by which some nutrients can attenuate the ectopic accumulation of triglycerides in non-adipose tissues. Particularly, we emphasize research conducted on the molecular mechanisms of action of soy protein and some of its isoflavones, and how these can reduce lipotoxicity by preventing the accumulation of lipids in the liver, skeletal muscle, and pancreas, as well as their role on the gut microbiota to attenuate the development of fatty liver. Thus, nutrigenomics is opening new dietary strategies based on several functional foods that can be used to ameliorate the pathologies associated with lipotoxicity.

Dietary Linoleic Acid Targets Skeletal Muscle to Impact Energy Metabolism (P08-124-19)

ObjectivesInvestigate the impact of dietary linoleic acid (LA) on whole-body energy metabolism, fatty acid uptake, oxylipin metabolites, and energy production machinery in skeletal muscle. MethodsMice were fed modified AIN-93 M diets containing 6% wt of LA or palmitic acid (PA) for 5 weeks. To address energy balance, grip strength, blood glucose, and body composition were measured weekly and indirect calorimetry was performed after 4.5 weeks of diet. To address skeletal muscle architecture, cross-sectional area was quantified in quadriceps. To determine the effect of LA diet on skeletal muscle lipids, fatty acid composition was measured in quadriceps using GC. Targeted lipidomics using LC-MS/MS was utilized to measure LA-derived oxylipins in mitochondria isolated from gastrocnemius. ResultsNo difference in food intake, body weight, blood glucose, or body composition were observed between diet groups. Mice fed the LA diet exhibited higher heat production and lower respiratory exchange ratio, independent of ambulatory activity compared to mice fed the PA diet. Cross sectional area analysis in quadriceps muscle revealed that mice fed the LA diet had smaller muscle fibers compared to mice fed the PA diet. The LA diet increased LA level in quadriceps. Using hierarchal cluster analysis, we identified several unique patterns of oxylipins that impact insulin sensitivity and may be associated with increased mitochondrial capacity. Mice fed the LA diet exhibited a three-fold increase of oxylipin metabolites 9- and 13-HODE, and 12,13-diHOME. ConclusionsMice fed a diet fortified in LA have increased LA in skeletal muscle, changes to skeletal muscle architecture, favorable changes to whole body energy metabolism, and increases in LA-derived oxylipins in skeletal muscle mitochondria. Our discovery that LA generates 9-HODE and 13-HODE in muscle mitochondria suggests that downstream pathways, including PPARg transactivation, may be linked with effects on muscle energy metabolism. Funding SourcesFunding was provided by the National Institutes of Health (NIH) R21CA185140, Ohio Agriculture Research and Development Center and the Carol S. Kennedy Professorship. DBS is supported by the Center for Muscle Health and Neuromuscular Disorders Predoctoral Research Fellowship.

290-OR: High-Intensity Interval Training and Moderate-Intensity Continuous Training Induce Similar Modifications to Factors Regulating Skeletal Muscle Lipolysis

Abnormalities in muscle lipid metabolism in obesity have been linked to insulin resistance. Exercise training alters skeletal muscle lipid abundance and localization, but the direct effects of exercise training (independent of weight loss) on skeletal muscle lipolytic proteins are not clearly understood, and data are lacking regarding influence of training intensity on factors regulating muscle lipid metabolism in obesity. Our aim was to examine the effects of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) on skeletal muscle lipolytic proteins in obese humans. Eighteen sedentary, obese adults completed 12 weeks (4 sessions weekly) of either HIIT (10 x 1 min at 90% HRmax, 1 min recovery; n=8) or MICT (45 min at 70% HRmax; n=10). Muscle biopsies (vastus lateralis) were collected before and after training. Subjects maintained body weight and fat mass and the post-training biopsy occurred 3 days after the final exercise session. Both exercise training programs increased aerobic capacity (VO2max) by ~10% (p=0.003), with no significant difference between HIIT and MICT. In muscle samples, hormone-sensitive lipase (HSL) protein abundance increased ~2-fold after training in HIIT (P&amp;lt;0.05), but not MICT. Training did not affect muscle abundance of adipose triglyceride lipase (ATGL) in either group but interestingly, the abundance of both CGI-58 (a positive regulator of ATGL lipolytic activity) and G0S2 (a negative regulator of ATGL lipolytic activity) increased ~15-20% after training (p&amp;lt;0.02), with no difference between HIIT and MICT. In summary, HIIT and MICT result in similar modifications to lipolytic proteins in skeletal muscle, although our findings suggest that HIIT may be a more potent stimulus for increasing HSL abundance. Future work is needed to determine if the concomitant increases in protein abundance of CGI-58 and G0S2 with training may improve lipid handling in obesity. Disclosure B.J. Ryan: None. M.W. Schleh: None. P. Varshney: None. A. Ludzki: None. J.B. Gillen: None. K. Foug: None. B.D. Carr: None. J.F. Horowitz: Research Support; Self; American Diabetes Association. Funding National Institutes of Health (R01DK077966, P30DK089503, T32DK007245); Canadian Institutes of Health Research (DFS146190)

Phenotypic characterization of a novel type 2 diabetes animal model in a SHANXI MU colony of Chinese hamsters.

Developing animal models for human diseases is critical for studying complex diseases such as type 2 diabetes mellitus (T2DM). Since inbred colonies of Chinese hamsters tend toward spontaneous development of diabetes, we investigated them as a possible model. We regarded individuals with fasting blood glucose (FBG) higher than 6.0 mmol/L and post-prandial blood glucose (PBG) higher than 7.0 mmol/L as diabetic based on the mean and 95% frequency distribution values of FBG and PBG. Diabetic hamsters were characterized based on metabolic profiles, histopathological features, and changes in the expression of genes involved in glucose and lipid metabolism. Metabolic analyses showed that diabetic hamsters exhibited mild hyperglycemia, hypertriglyceridemia, glucose intolerance, and insulin resistance. Histopathological analysis revealed that cell nuclei migrated inward in skeletal muscle and obvious partial liver lipid deposition and focal necrosis was found. We additionally observed mild injury, atrophy, and occasional vacuolization in islet cells. Changes in the expression of several genes related to glucose and lipid metabolism were observed. Decreased expression of adiponectin and GLUT4 and increased expression of PPARγ, Akt, and leptin was observed in skeletal muscle. Decreased expression of adiponectin with increased expression of PPARγ and leptin was observed in the liver. These results indicate that we have established a spontaneous diabetic hamster line that closely mimics human T2DM, which may hold potential for further research on the pathogenesis and treatment of this disease.

SUN-LB006 Skeletal Muscle Krüppel-Like Factor 15 and PPARd Cooperate to Regulate Skeletal Muscle Lipid Metabolism

Skeletal muscle lipid metabolism significantly modulates systemic metabolic status; unsurprisingly, aberrant skeletal muscle nutrient handling is closely associated with metabolic diseases. The mechanisms underlying skeletal muscle regulation of lipid metabolism remain to be fully elucidated. Previous studies have shown that mice deficient in nuclear receptor PPARδ suffer from deranged skeletal muscle lipid handling; a similar phenotype is observed in mice deficient in the transcription factor Krüppel-like factor 15 (KLF15). Preliminary data support the existence of KLF15-PPARδ cooperativity in regulating skeletal muscle lipid metabolism, and thus we sought to 1) define the metabolic role of skeletal muscle specific KLF15; and 2) elucidate the molecular basis of KLF15-PPARδ interaction and impact on skeletal muscle lipid metabolism. We generated a skeletal muscle specific KLF15 knockout (K15-SKO) mouse and characterized the metabolic phenotype of this animal. K15-SKO mice have increased body weight and fat mass, elevated circulating free-fatty acids and triglyceride, insulin insensitivity, and glucose intolerance compared to controls. Importantly, K15-SKO mice demonstrated decreased skeletal muscle expression of a number of lipid flux genes, many of which are targets of PPARδ. To determine the necessity of KLF15 for PPARδ-mediated gene expression, we depleted KLF15 in C2C12 cells and looked at a number of PPARδ targets. The expression levels of Fatp1, Cpt1b, and Scl25a20 were attenuated - this response was unchanged in the presence or absence of GW501516 (GW), a PPARδ agonist. We used Seahorse cell metabolism analyzer to assess fatty acid oxidation and observed that knockdown of KLF15 reduces GW induction of palmitate oxygen consumption rates. We conducted co-transfection studies and determined that KLF15 and PPARδ act synergistically on the Fatp1 promoter. Co-immunoprecipitation studies confirmed physical interaction between KLF15 and PPARδ. Finally, control and K15-SKO mice were gavaged with GW for 10 days, and K15-SKO animals demonstrated attenuated induction of a number of PPARδ targets in skeletal muscle. Taken together, these data suggest that skeletal muscle specific KLF15 is critical in the regulation of lipid handling and necessary for optimal PPARδ-mediated regulation of skeletal muscle lipid metabolism.

Association between skeletal muscle mass and serum concentrations of lipoprotein lipase, GPIHBP1, and hepatic triglyceride lipase in young Japanese men

BackgroundTwo important regulators for circulating lipid metabolisms are lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). In relation to this, glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1) has been shown to have a vital role in LPL lipolytic processing. However, the relationships between skeletal muscle mass and lipid metabolism, including LPL, GPIHBP1, and HTGL, remain to be elucidated. Demonstration of these relationships may lead to clarification of the metabolic dysfunctions caused by sarcopenia. In this study, these relationships were investigated in young Japanese men who had no age-related factors; participants included wrestling athletes with abundant skeletal muscle.MethodsA total of 111 young Japanese men who were not taking medications were enrolled; 70 wrestling athletes and 41 control students were included. The participants’ body compositions, serum concentrations of lipoprotein, LPL, GPIHBP1 and HTGL and thyroid function test results were determined under conditions of no extreme dietary restrictions and exercises.ResultsCompared with the control participants, wrestling athletes had significantly higher skeletal muscle index (SMI) (p < 0.001), higher serum concentrations of LPL (p < 0.001) and GPIHBP1 (p < 0.001), and lower fat mass index (p = 0.024). Kruskal–Wallis tests with Bonferroni multiple comparison tests showed that serum LPL and GPIHBP1 concentrations were significantly higher in the participants with higher SMI. Spearman’s correlation analyses showed that SMI was positively correlated with LPL (ρ = 0.341, p < 0.001) and GPIHBP1 (ρ = 0.309, p = 0.001) concentration. The serum concentrations of LPL and GPIHBP1 were also inversely correlated with serum concentrations of triglyceride (LPL, ρ = − 0.198, p = 0.037; GPIHBP1, ρ = − 0.249, p = 0.008). Serum HTGL concentration was positively correlated with serum concentrations of total cholesterol (ρ = 0.308, p = 0.001), low-density lipoprotein-cholesterol (ρ = 0.336, p < 0.001), and free 3,5,3′-triiodothyronine (ρ = 0.260, p = 0.006), but not with SMI.ConclusionsThe results suggest that increased skeletal muscle mass leads to improvements in energy metabolism by promoting triglyceride-rich lipoprotein hydrolysis through the increase in circulating LPL and GPIHBP1.

Influence of Genistein and Exercise on Lipid Metabolism in High Fat‐High Sugar Fed Mice

Intake of diets high in saturated fat with sugar have been associated with chronic diseases including type 2 diabetes and Alzheimer's disease (AD). This study varied diet and exercise and assessed the changes in adipose metabolism by measuring serum markers, hepatosteatosis, and skeletal muscle lipid metabolism. Male and female 5–6 week old C57BL/6J mice were randomly assigned one of the following groups for 12 weeks (n=8–10/group): lean control (Ln), high fat diet, HFD (60% of calories from fat), and high sucrose/fructose (42 g combined/L drinking water) (HFHS), HFHS with genistein (Gen), HFHS with exercise (Ex), or HFHS with genistein and exercise (Gen‐Ex). Exercise consisted of 150 min/week forced treadmill running. Genistein dose was 600 mg genistein/kg HFD. We hypothesize that Ex and Gen will improve deficits in lipid metabolism associated with diabetes and obesity. Males and females had significant weight increase in HFHS groups compared to Ln groups (40.8% and 27.5% respectively, P&lt;0.05). In males, body weight was significantly lower in Ex (8.9%), Gen (19.2%) and Gen‐Ex mice (32.6%, P&lt;0.05) compared to HFHS controls. In females, body weight was significantly lower in the Gen‐Ex (20.7%, P&lt;0.05) compared to HFHS controls. Weight loss was not attributed to reduced food intake, nor correlated to comparable changes in serum triglyceride. Male liver weight/body weight was increased in HFHS (31.8%, P&lt;0.05) versus Ln, and subsequently reduced by Ex (23.5%), Gen (39%) and Gen‐Ex (52%, P&lt;0.05) compared to HFHS controls. Female liver/body weight was comparable between groups. Glucose tolerance tests (GTT) in subgroups of mice (n=3–5/group) showed rescue of serum glucose in Gen‐Ex males (not females), which reflected concomitant changes in serum insulin. Protein expression of the skeletal muscle lipid metabolism marker, carnitine palmitoyltransferase 1b (CPT1b) was greater (80.5%, n=5/group, P&lt;0.05) in males fed HFHS compared to Ln controls, with no differences in treatment interventions. We aim to provide mechanistic evidence for sex‐dependent effects and to demonstrate an association between genistein‐ and exercise‐mediated improvements in diet induced diabetic‐obesity. Current studies continue to evaluate other metabolic markers. Data currently suggests significant weight changes are not correlated with concomitant changes in skeletal muscle lipid metabolism markers.Support or Funding InformationLayla Al‐Nakkash, and Tom Broderick were supported by Midwestern‐Arizona Alzheimer's Consortium and Midwestern Intramural funds. Amy Fisher and Chaheyla St Aubin were supported by the Department of Biomedical Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vascular endothelial growth factor B inhibits lipid accumulation in C2C12 myotubes incubated with fatty acids

To investigate (1) the effect of vascular endothelial growth factor B (VEGFB) on lipid accumulation and the alteration of fatty acids and fatty acid-related enzymes in C2C12 myotubes incubated with fatty acids and (2) the regulatory effect of VEGFB on skeletal muscle lipid metabolism. Mouse C2C12 myotubes were incubated with oleic acid (OA) and palmitic acid (PA), and differentiated mature C2C12 myotubes were treated with VEGFB. Oil-red O staining, BODIPY staining and cell triglycerides (TG) content were examined. Total RNA was isolated, and real-time PCR analysis was performed. Treatment with 100 μM OA and 50 μM PA induced lipid droplet accumulation and increased TG content (p < .01), and 100 ng/mL VEGFB reduced lipid droplet accumulation and decreased TG content (p < .01). Treatment with 100 ng/mL VEGFB significantly induced the mRNA expression of fatty acid transport protein 1 (FATP1) (p < .01) and FATP4 (p < .01). Treatment with 100 ng/mL VEGFB significantly induced the mRNA expression of adipose TG lipase and hormone-sensitive lipase (p < .01) as well as carnitine palmitoyltransferase I (p < .01), peroxisome proliferator-activated receptor-γ coactivator-1α (p < .01), acyl-coa dehydrogenase very long chain (p < .05), acyl-coa synthetase long-chain family member 1 (p < .01), peroxisomal acyl-coenzyme A oxidase 1 (p < .05), and mitochondrial uncoupling protein 3 (p < .01). VEGFB enhanced FATP1and FATP4 expression, promoted C2C12 myotube fatty acid oxidation and TG decomposition, and inhibited C2C12 myotube fatty acid re-esterification, thus inhibiting lipid accumulation in C2C12 myotubes incubated with fatty acids.

Sex-based differences in hepatic and skeletal muscle triglyceride storage and metabolism 1.

Women and men store lipid differently within the body with men storing more fat in the android region and women storing more fat in the gynoid region. Fat is predominately stored in adipose tissue as triacylglycerides (TG); however, TG are also stored in other tissues including the liver and skeletal muscle. Excess hepatic TG storage, defined as a TG concentration >5% of liver weight and known as nonalcoholic fatty liver disease (NAFLD), is related to the metabolic syndrome. Similarly, elevated skeletal muscle TG, termed intramyocellular lipids (IMCL), are related to insulin resistance in obesity and type II diabetes. Men store more hepatic TG than women and, unsurprisingly, NAFLD is more prevalent in men than women. Women store more IMCL than men, yet type II diabetes risk is not greater, which is likely due to the manner in which women store TG within muscle. Sex-based differences in TG storage between men and women are underpinned by differences in messenger RNA expression, protein content, and enzyme activities of skeletal muscle and hepatic lipid metabolic pathways. Furthermore, women have a greater reliance on lipid during exercise because of upregulation of lipid oxidative pathways. The purpose of this review is to discuss the role of sex in mediating lipid storage and metabolism within skeletal muscle and the liver at rest and during exercise and its relationship with metabolic disease.

Short-term low-calorie diet remodels skeletal muscle lipid profile and metabolic gene expression in obese adults.

Diet intervention in obese adults is the first strategy to induce weight loss and improve insulin sensitivity. We hypothesized that improvements in insulin sensitivity after weight loss from a short-term dietary intervention tracks with alterations in expression of metabolic genes and abundance of specific lipid species. Eight obese, insulin-resistant, nondiabetic adults were recruited to participate in a 3-wk low-calorie diet intervention cohort study (1,000 kcal/day). Fasting blood samples and vastus lateralis skeletal muscle biopsies were obtained before and after the dietary intervention. Clinical chemistry and measures of insulin sensitivity were determined. Unbiased microarray gene expression and targeted lipidomic analysis of skeletal muscle was performed. Body weight was reduced, insulin sensitivity [measured by homeostatic model assessment of insulin resistance, (HOMA-IR)] was enhanced, and serum insulin concentration and blood lipid (triglyceride, cholesterol, LDL, and HDL) levels were improved after dietary intervention. Gene set enrichment analysis of skeletal muscle revealed that biosynthesis of unsaturated fatty acid was among the most enriched pathways identified after dietary intervention. mRNA expression of PDK4 and MLYCD increased, while SCD1 decreased in skeletal muscle after dietary intervention. Dietary intervention altered the intramuscular lipid profile of skeletal muscle, with changes in content of phosphatidylcholine and triglyceride species among the pronounced. Short-term diet intervention and weight loss in obese adults alters metabolic gene expression and reduces specific phosphatidylcholine and triglyceride species in skeletal muscle, concomitant with improvements in clinical outcomes and enhanced insulin sensitivity.

PO-193 Exercise training decreased lipid accumulation in murine skeletal muscle through Sestrin2-mediated SHIP2-JNK signaling pathway

Objective Obesity is becoming increasingly prevalent and is an important contributor to the worldwide burden of diseases. It is widely accepted that exercise training is beneficial for the prevention and treatment of obesity. However, the underlying mechanism by which exercise training improving skeletal muscle lipid metabolism is still not fully described.&#x0D; Sestrins (Sestrin1-3) are highly conserved stress-inducible protein. Concomitant ablation of Sestrin2 and Sestrin3 has been reported to provoke hepatic mTORC1/S6K1 activation and insulin resistance even without nutritional overload and obesity, implicating that Sestrin2 and Sestrin3 have an important homeostatic function in the control of mammalian glucose and lipid metabolism. Our previous results demonstrated that physical exercise increased Sestrin2 expression in murine skeletal muscle, while the role of Sestrin2 in regulating lipid metabolism remains unknown. &#x0D; SH2 domain containing inositol 5-phosphatase (SHIP2) acts as a negative regulator of the insulin signaling both in vitro and in vivo. An increased expression of SHIP2 inhibits the insulin-induced Akt activation, glucose uptake, and glycogen synthesis in 3T3-L1 adipocytes, L6 myotubes and tissues of animal models. Alterations of SHIP2 expression and/or enzymatic function appear to have a profound impact on the development of insulin resistance. However, the regulatory function of SHIP2 in lipid metabolism after exercise remains unclear. It has been reported that SHIP2 modulated lipid metabolism through regulating the activity of c-Jun N-terminal kinase (JNK) and Sterol regulatory element-binding protein-1 (SREBP-1).&#x0D; JNK is a subclass of mitogen-activated protein kinase (MAPK) signaling pathway in mammalian cells and plays a crucial role in metabolic changes and inflammation associated with a high-fat diet. Inhibition of JNK reduces lipid deposition and proteins level of fatty acid de novo synthesis in liver cells. It has been reported that Sestrin2 regulated the phosphorylation of JNK, however the underlying mechanism remains unclear. SREBP-1 is important in regulating cholesterol biosynthesis and uptake and fatty acid biosynthesis, and SREBP-1 expression produces two different isoforms, SREBP-1a and SREBP-1c. SREBP-1c is responsible for regulating the genes required for de novo lipogenesis and its expression is regulated by insulin. SREBP-1a regulates genes related to lipid and cholesterol production and its activity is regulated by sterol levels in the cell.&#x0D; Altogether, the purpose of this study was to explore the effect and underlying mechanism of Sestrin2 on lipid accumulation after exercise training.&#x0D; Methods Male wild type and SESN2−/− mice were divided into normal chow (NC) and high-fat diet (HFD) groups to create insulin resistance mice model. After 8 weeks the IR model group was then divided into HFD sedentary control and HFD exercise groups (HE). Mice in HE group underwent 6-week treadmill exercise to reveal the effect of exercise training on lipid metabolism in insulin resistance model induced by HFD. We explored the mechanism through which Sestrin2 regulated lipid metabolism in vitro by supplying palmitate, overexpressing or inhibiting SESNs, SHIP2 and JNK in myotubes.&#x0D; Results We found that 6-week exercise training decreased body weight, BMI and fat mass in wild type and SESN2-/- mice after high-fat diet (HFD) feeding. And exercise training decreased the level of plasma glucose, serum insulin, triglycerides and free fatty acids in wild type but not in Sestrin2-/- mice. Lipid droplet in skeletal muscle was also decreased in wild type but did not in Sestrin2-/- mice. Moreover, exercise training increased the proteins expression involved in fatty acid oxidation and decreased the proteins which related to fatty acid de novo synthesis. The results of oil red staining and the change of proteins related to fatty acid de novo synthesis and beta oxidation in myotubes treated with palmitate, Ad-SESN2 and siRNA-Sestrin2 were consisted with the results in vivo, which suggested that Sestrin2 was a key regulator in lipid metabolism. Exercise training increased Sestrin2 expression and reversed up-regulation of SHIP2 and pJNK induced by HFD in wild type mice but not in Sestrin2-/- mice. In parallel, overexpression of Sestrin2 decreased the level of SHIP2 and pJNK induced by palmitate while Sestrin2 knock down by siRNA-Sestrin2 treatment did not change the expression of SHIP2 and pJNK, which suggested that Sestrin2 modulated SHIP2 and JNK in the state of abnormal lipid metabolism. Inhibition of SHIP2 reduced the activity of JNK, increased lipid accumulation and the proteins of fatty acid synthesis after palmitate treatment and over expression of Sestrin2, which suggest that Sestrin2 modulated lipid metabolism through SHIP2/JNK pathway.&#x0D; Conclusions Sestrin2 plays an important role in improving lipid metabolism after exercise training, and Sestrin2 regulates lipid metabolism by SHIP2-JNK pathway in skeletal muscle.