Skeletal Muscle Lipoprotein Lipase Research Articles

Angiopoietin-like proteins and postprandial partitioning of fatty acids.

Over the last two decades, evolving discoveries around angiopoietin-like (ANGPTL) proteins, particularly ANGPTL3, ANGPTL4, and ANGPTL8, have generated significant interest in understanding their roles in fatty acid (FA) metabolism. Until recently, exactly how this protein family regulates lipoprotein lipase (LPL) in a tissue-specific manner to control FA partitioning has remained elusive. This review summarizes the latest insights into mechanisms by which ANGPTL3/4/8 proteins regulate postprandial FA partitioning. Accumulating evidence suggests that ANGPTL8 is an insulin-responsive protein that regulates ANGPTL3 and ANGPTL4 by forming complexes with them to increase or decrease markedly their respective LPL-inhibitory activities. After feeding, when insulin levels are high, ANGPTL3/8 secreted by hepatocytes acts in an endocrine manner to inhibit LPL in skeletal muscle, whereas ANGPTL4/8 secreted by adipocytes acts locally to preserve adipose tissue LPL activity, thus shifting FA toward the fat for storage. Insulin also decreases hepatic secretion of the endogenous ANGPTL3/8 inhibitor, apolipoprotein A5 (ApoA5), to accentuate ANGPTL3/8-mediated LPL inhibition in skeletal muscle. The ANGPTL3/4/8 protein family and ApoA5 play critical roles in directing FA toward adipose tissue postprandially. Selective targeting of these proteins holds significant promise for the treatment of dyslipidemias, metabolic syndrome, and their related comorbidities.

Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.

Insulin suppression of fatty acid skeletal muscle enzyme activity in postmenopausal women, and improvements in metabolic flexibility and lipoprotein lipase with aerobic exercise and weight loss.

Obesity and insulin resistance are characterized by metabolic inflexibility, a condition described as an inability to switch from fat oxidation during fasting to carbohydrate oxidation during hyperinsulinemia. The purpose of this study was to examine predictors of metabolic flexibility in 103 obese (37-59% fat), sedentary (VO2max: 19.4 ± 0.5 ml/kg/min), postmenopausal (45-76 years) women, and changes in metabolic flexibility with exercise and weight loss interventions. Insulin sensitivity (M) and metabolic flexibility via an 80 mU/m2/min hyperinsulinemic-euglycemic clamp, VO2max, and body composition were measured. Metabolic flexibility was measured after 6-months aerobic training + weight loss (AEX + WL: n = 43) or weight loss (WL: n = 31). Basal and insulin-stimulated vastus lateralis skeletal muscle samples were available from a subset of these women (n = 45). Metabolic flexibility correlated inversely with glucose120 min of OGTT, fasting insulin, and the percent change (insulin-basal) in lipoprotein lipase (LPL) activity and positively with M, but not with VO2max, total body fat, visceral fat, or subcutaneous abdominal fat. Skeletal muscle acyl-CoA synthase and citrate synthase activities decreased during hyperinsulinemia. Metabolic flexibility increased after AEX + WL but not WL, and the percent change in metabolic flexibility was inversely related to the percent change in insulin's effect on LPL activity. Metabolic flexibility is related to insulin sensitivity and insulin's action on LPL. Furthermore, metabolic flexibility and insulin suppression of skeletal muscle LPL activity increase with AEX + WL in overweight and obese, sedentary older women.

Chronic fructose intake does not induce liver steatosis and inflammation in female Sprague-Dawley rats, but causes hypertriglyceridemia related to decreased VLDL receptor expression.

Sugar-sweetened beverage intake is a risk factor for insulin resistance, dyslipidemia, fatty liver, and steatohepatitis (NASH). Sub-chronic supplementation of liquid fructose, but not glucose, in female rats increases liver and plasma triglycerides without inflammation. We hypothesized that chronic supplementation of fructose would cause NASH and liver insulin resistance. We supplemented female Sprague-Dawley rats with water or either fructose or glucose 10% w/v solutions under isocaloric conditions for 7months. At the end, plasma analytes, insulin, and adiponectin were determined, as well as liver triglyceride content and the expression of key genes controlling inflammation, fatty acid synthesis and oxidation, endoplasmic reticulum stress, and plasma VLDL clearance, by biochemical and histological methods. Although sugar-supplemented rats increased their energy intake by 50-60%, we found no manifestation of liver steatosis, fibrosis or necrosis, unchanged plasma or tissue markers of inflammation or fibrosis, and reduced liver expression of gluconeogenic enzymes, despite both sugars increased fatty acid synthesis, mTORC1, and IRE1 activity, while decreasing fatty acid oxidation and PPARα activity. Only fructose-supplemented rats were hypertriglyceridemic, showing a reduced expression of VLDL receptor and lipoprotein lipase in skeletal muscle and vWAT. Glucose-supplemented rats showed increased adiponectinemia, which would explain the different metabolic outcomes of the two sugars. Chronic liquid simple sugar supplementation, as the sole risk factor, is not enough for female rats to develop NASH and increased liver gluconeogenesis. Nevertheless, under isocaloric conditions, only fructose induced hypertriglyceridemia, thus confirming that also the type of nutrient matters in the development of metabolic diseases.

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OBJECTIVES/SPECIFIC AIMS: Obesity is a rapidly growing epidemic and long-term interventions aimed to reduce body weight are largely unsuccessful due to an increased drive to eat and a reduced metabolic rate established during weight loss. Previously, our lab demonstrated that exercise has beneficial effects on weight loss maintenance by increasing total energy expenditure above and beyond the cost of an exercise bout and reducing the drive to eat when allowed to eat ad libitum (relapse). We hypothesized that exercise’s ability to counter these obesogenic-impetuses are mediated via improvements in skeletal muscle oxidative capacity, and tested this using a mouse model with augmented oxidative capacity in skeletal muscle. METHODS/STUDY POPULATION: We recapitulated the exercise-induced improvements in oxidative capacity using FVB mice that overexpress lipoprotein lipase in skeletal muscle (mLPL). mLPL and wild type (WT) mice were put through a weight-loss-weight-regain paradigm consisting of a high fat diet challenge for 13 weeks, with a subsequent 1-week calorie-restricted medium fat diet to induce a ~15% weight loss. This newly established weight was maintained for 2 weeks and followed with a 24-hour relapse. Metabolic phenotype was characterized by indirect calorimetry during each phase. At the conclusion of the relapse day, mice were sacrificed and tissues were harvested for molecular analysis. RESULTS/ANTICIPATED RESULTS: During weight loss maintenance, mLPL mice had a higher metabolic rate (p=0.0256) that was predominantly evident in the dark cycle (p=0.0015). Furthermore, this increased metabolic rate was not due to differences in activity (p=0.2877) or resting metabolic rate (p=0.4881). During relapse, mLPL mice ingested less calories and were protected from rapid weight regain (p=0.0235), despite WT mice exhibiting higher metabolic rates during the light cycle (p=0.0421). DISCUSSION/SIGNIFICANCE OF IMPACT: These results highlight the importance of muscular oxidative capacity in preventing a depression in total energy expenditure during weight loss maintenance, and in curbing overfeeding and weight regain during a relapse. Moreover, our data suggest that the thermic effect of food is responsible for the differences in metabolic rate, because no differences were found in activity or resting metabolic rate. Additional studies are warranted to determine the molecular mechanisms driving the ability of oxidative capacity to assist with weight loss maintenance.

Exercise with weight loss improves adipose tissue and skeletal muscle markers of fatty acid metabolism in postmenopausal women.

ObjectiveThe effects of six-months weight loss (WL) versus aerobic exercise training (AEX)+WL on fat and skeletal muscle markers of fatty acid metabolism were determined in normal (NGT) and impaired (IGT) glucose tolerant African-American and Caucasian postmenopausal women with overweight/obesity.MethodsFat (gluteal and abdominal) lipoprotein lipase (LPL), and skeletal muscle LPL, acyl-CoA synthase (ACS), β-hydroxacyl-CoA dehydrogenase, carnitine palmitoyltransferase (CPT-1), and citrate synthase (CS) activities were measured at baseline (n=104) and before and after WL (n=34) and AEX+WL (n=37).ResultsAfter controlling for age and race, muscle LPL and CPT-1 were lower in IGT, and the ratios of fat/muscle LPL activity were higher in IGT compared to NGT. Muscle LPL was related to insulin sensitivity (M), and inversely related to G120, fasting insulin, and HOMA-IR. AEX+WL decreased abdominal fat LPL and increased muscle LPL, ACS, and CS. The ratios of fat/muscle LPL decreased after AEX+WL. The change in VO2max was related to the changes in LPL, ACS, and CS and inversely related to the changes in fat/muscle LPL activity ratios.ConclusionsSix-month AEX+WL, and not WL alone, is capable of enhancing skeletal muscle fatty acid metabolism in postmenopausal African-American and Caucasian women with NGT, IGT, and overweight/obesity.

SEDding Ourselves Up for Problems

SEDding Ourselves Up for Problems

Angiopoietin-Like Protein 4 and Postprandial Skeletal Muscle Lipid Metabolism in Overweight and Obese Prediabetics.

Angiopoietin-like protein 4 (ANGPTL4) decreases plasma triacylglycerol (TAG) clearance by inhibiting lipoprotein lipase (LPL) and may contribute to impairments in lipid metabolism under compromised metabolic conditions. To investigate the effects of a high-saturated fatty acid (SFA) mixed meal on plasma ANGPTL4 concentrations in relation to in vivo muscle LPL activity, to study the effects of dietary fat quality, and to examine skeletal muscle ANGPTL4 release. Design, Participants, Setting, and Interventions: We used a dual stable-isotope tracer technique in combination with measurements of arteriovenous concentration differences across forearm muscle to investigate muscle ANGPTL4 secretion and fatty acid handling under fasting conditions and after a high-SFA mixed meal in 73 overweight and obese humans at the Metabolic Research Unit of Maastricht University. The effect of dietary fat quality manipulation on plasma ANGPTL4 was investigated in 10 obese insulin-resistant participants. The high-SFA meal decreased circulating ANGPTL4 concentrations (fasting, 5.2 ng/mL; vs 4 hours postprandial, 4.0 ng/mL; P < .001). Furthermore, skeletal muscle ANGPTL4 secretion into the circulation was observed (AUC0-4 h, P = .048). However, no association was observed between plasma ANGPTL4 and skeletal muscle very low-density lipoprotein or dietary (chylomicron) TAG extraction (AUC0-4 h, P = .372 and P = .139, respectively). In contrast to a high-SFA or high-monounsaturated fat meal, plasma ANGPTL4 remained unchanged after a high-polyunsaturated fat meal. ANGPTL4 is secreted by human forearm muscle in postprandial conditions after a high-SFA meal. Plasma ANGPTL4 concentrations were not associated with in vivo skeletal muscle LPL activity after a high-SFA meal. Dietary fat quality affects plasma ANGPTL4, but it remains to be elucidated whether this influences short-term skeletal muscle lipid handling.

Alipogene tiparvovec: a review of its use in adults with familial lipoprotein lipase deficiency.

Alipogene tiparvovec (Glybera®; AMT-011, AAV1-LPL(S447X)) is an adeno-associated virus serotype 1-based gene therapy for adult patients with familial lipoprotein lipase (LPL) deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. It is administered as a one-time series of intramuscular injections in the legs. LPLD, a rare autosomal recessive disorder, results in hyperchylomicronaemia and severe hypertriglyceridaemia, which in turn, are associated with an increased risk of clinical complications, the most debilitating of which is recurrent severe and potentially life-threatening pancreatitis. In clinical studies (n = 27 patients), one-time administration of alipogene tiparvovec was associated with significant reductions in plasma triglyceride levels during the 12 or 14 week study period post administration. Although triglyceride levels returned to pre-treatment levels within 16-26 weeks after administration, patients had sustained improvements in postprandial chylomicron metabolism, with sustained expression of functional copies of the LPL (S477X) gene and of biologically active LPL in skeletal muscle. Moreover, after up to 6 years' follow-up post administration, there were clinically relevant reductions in the incidence of documented pancreatitis and acute abdominal pain events consistent with pancreatitis. Alipogene tiparvovec was generally well tolerated, with most adverse events being localized, transient, mild to moderate injection-site reactions. This article reviews the pharmacology of alipogene tiparvovec and its efficacy and safety in adults with LPLD.

Role of AMPK and PPARγ1 in exercise-induced lipoprotein lipase in skeletal muscle

Exercise can effectively ameliorate type 2 diabetes and insulin resistance. Here we show that the mRNA levels of one of peroxisome proliferator-activated receptor (PPAR) family members, PPARγ1, and genes related to energy metabolism, including PPARγ coactivator-1 protein-1α (PGC-1α) and lipoprotein lipase (LPL), increased in the gastrocnemius muscle of habitual exercise-trained mice. When mice were intraperitoneally administered an AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), the mRNA levels of the aforementioned three genes increased in gastrocnemius muscle. AICAR treatment to C2C12 differentiated myotubes also increased PPARγ1 mRNA levels, but not PPARα and -δ mRNA levels, concomitant with increased PGC-1α mRNA levels. An AMPK inhibitor, compound C, blocked these AICAR effects. AICAR treatment increased the half-life of PPARγ1 mRNA nearly threefold (4-12 h) by activating AMPK. When C2C12 myoblast cells infected with a PPARγ1 expression lentivirus were differentiated into myotubes, PPARγ1 overexpression dramatically increased LPL mRNA levels more than 40-fold. In contrast, when PPARγ1 expression was suppressed in C2C12 myotubes, LPL mRNA levels were significantly reduced, and the effect of AICAR on increased LPL gene expression was almost completely blocked. These results indicated that PPARγ1 was intimately involved in LPL gene expression in skeletal muscle and the AMPK-PPARγ1 pathway may play a role in exercise-induced LPL expression. Thus, we identified a novel critical role for PPARγ1 in response to AMPK activation for controlling the expression of a subset of genes associated with metabolic regulation in skeletal muscle.

Tissue‐Specific Responses of Lipoprotein Lipase to Dietary Macronutrient Composition as a Predictor of Weight Gain Over 4 Years

This study evaluated if the effect of dietary macronutrient composition on adipose tissue lipoprotein lipase (ATLPL) and skeletal muscle lipoprotein lipase (SMLPL) predicted the long-term (over 4 years) changes in body weight and composition in free-living adults. Using a crossover design, 39 healthy subjects (n = 24 normal weight, n = 7 overweight, n = 8 obese) each followed a 2-week isocaloric high-carbohydrate (HC; 55% CHO:25% fat) and high-fat (HF; 30% CHO:50% fat) diet. On day 15 of each diet, biopsies were performed in the fasted state and 6 h after a meal. Body weight and composition were measured annually over 4 years. The outcomes for body weight, fat mass and % body fat were assessed using a linear two-stage mixed model. The mean (±SEM) increase in body weight and fat mass over 4 years was 0.29 ± 0.15 kg/year (P = 0.063) and 0.31 ± 0.15 kg/year (P = 0.051), respectively. The most consistent predictors of future body weight and fat changes were the ΔATLPL and ΔSMLPL responses (0-6 h) to a HC diet/meal. For the HC diet/meal, the subjects who had an increase in ATLPL activity/cell gained more % body fat over 4 years (P = 0.006) whereas subjects who had a decrease in SMLPL activity/g also had an increase in fat mass (P = 0.021). No significant relationships were observed between fasting ATLPL and SMLPL or enzyme responses to meals and any of the outcomes following the HF diet. In free-living adults the variability in tissue-specific lipoprotein lipase (LPL) responsiveness to a HC diet/meal predicts longitudinal changes in body composition.

Atorvastatin and pitavastatin enhance lipoprotein lipase production in L6 skeletal muscle cells through activation of adenosine monophosphate-activated protein kinase

Pravastatin and atorvastatin increase the serum level of lipoprotein lipase (LPL) mass in vivo but do not increase LPL activity in 3T3-L1 preadipocytes in vitro. LPL is mainly produced by adipose tissue and skeletal muscle cells. Metformin enhances LPL in skeletal muscle through adenosine monophosphate-activated protein kinase (AMPK) activation but not in adipocytes. This study aimed to examine the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on LPL production and to investigate the mechanism by which statins enhance skeletal muscle cell LPL production. L6 skeletal muscle cells were incubated with pravastatin, simvastatin, atorvastatin or pitavastatin. LPL activity, protein levels and mRNA expression were measured. Atorvastatin and pitavastatin significantly increased LPL activity, protein levels and mRNA expression in L6 skeletal muscle cells at 1μmol/L, but neither statin had an effect at 10μmol/L. We measured AMPK to clarify the mechanism by which statins increase LPL production in skeletal muscle cells. At 1μmol/L, both atorvastatin and pitavastatin enhanced AMPK activity, but this enhancement was abolished when AMPK signaling was blocked by compound C. The increased expressions of LPL protein and mRNA by atorvastatin and pitavastatin were reduced by compound C. In addition, mevalonic acid abolished atorvastatin- and pitavastatin-induced AMPK activation and LPL expression. These results suggest that atorvastatin and pitavastatin increase LPL activity, protein levels and LPL mRNA expression by activating AMPK in skeletal muscle cells.

Regulation of Mitochondrial Biogenesis by Lipoprotein Lipase in Muscle of Insulin-Resistant Offspring of Parents With Type 2 Diabetes

Recent studies reveal a strong relationship between reduced mitochondrial content and insulin resistance in human skeletal muscle, although the underlying factors responsible for this association remain unknown. To address this question, we analyzed muscle biopsy samples from young, lean, insulin resistant (IR) offspring of parents with type 2 diabetes and control subjects by microarray analyses and found significant differences in expression of ∼512 probe pairs. We then screened these genes for their potential involvement in the regulation of mitochondrial biogenesis using RNA interference and found that mRNA and protein expression of lipoprotein lipase (LPL) in skeletal muscle was significantly decreased in the IR offspring and was associated with decreased mitochondrial density. Furthermore, we show that LPL knockdown in muscle cells decreased mitochondrial content by effectively decreasing fatty acid delivery and subsequent activation of peroxisome proliferator–activated receptor (PPAR)-δ. Taken together, these data suggest that decreased mitochondrial content in muscle of IR offspring may be due in part to reductions in LPL expression in skeletal muscle resulting in decreased PPAR-δ activation.

Lipoprotein particle distribution and skeletal muscle lipoprotein lipase activity after acute exercise.

BackgroundMany of the metabolic effects of exercise are due to the most recent exercise session. With recent advances in nuclear magnetic resonance spectroscopy (NMRS), it is possible to gain insight about which lipoprotein particles are responsible for mediating exercise effects.MethodsUsing a randomized cross-over design, very low density lipoprotein (VLDL) responses were evaluated in eight men on the morning after i) an inactive control trial (CON), ii) exercising vigorously on the prior evening for 100 min followed by fasting overnight to maintain an energy and carbohydrate deficit (EX-DEF), and iii) after the same exercise session followed by carbohydrate intake to restore muscle glycogen and carbohydrate balance (EX-BAL).ResultsThe intermediate, low and high density lipoprotein particle concentrations did not differ between trials. Fasting triglyceride (TG) determined biochemically, and mean VLDL size were lower in EX-DEF but not in EX-BAL compared to CON, primarily due to a reduction in VLDL-TG in the 70–120 nm (large) particle range. In contrast, VLDL-TG was lower in both EX-DEF and EX-BAL compared to CON in the 43–55 nm (medium) particle range. VLDL-TG in smaller particles (29–43 nm) was unaffected by exercise. Because the majority of VLDL particles were in this smallest size range and resistant to change, total VLDL particle concentration was not different between any of these conditions. Skeletal muscle lipoprotein lipase (LPL) activity was also not different across these 3 trials. However, in CON only, the inter-individual differences in LPL activity were inversely correlated with fasting TG, VLDL-TG, total, large and small VLDL particle concentration and VLDL size, indicating a regulatory role for LPL in the non-exercised state.ConclusionsThese findings reveal a high level of differential regulation between different sized triglyceride-rich lipoproteins following exercise and feeding, in the absence of changes in LPL activity.

Seasonal and nutrients intake regulation of lipoprotein lipase (LPL) activity in grazing yak ( Bos grunniens) in the Alpine Regions around Qinghai Lake

Lipoprotein lipase (LPL) is considered as a key enzyme in the lipid deposition and metabolism in tissues. To better understand fat cycling in grazing yak to adapt to the harsh environment on the Qinghai-Tibetan Plateau, and we have therefore explored seasonal and nutritional regulation of LPL in adipose tissue, liver and skeletal muscle. Sixty 3 year old growing yaks (BW. 120.3 ± 15.28 kg) were subdivided into six groups, each used to determine effects on chemical body composition and LPL activity in different tissues. The alpine pastures had the highest Crude protein (CP, 11.06%) contents and the gross energy (GE, 11.49 MJ/kg) in summer. Growth rates and body fat content were responsive to CP and GE intake regimen. Late spring up-regulation of LPL activity in the subcutaneous adipose tissue was consistent with a pronounced increase of body weight (BW) and whole body fat content. The highest LPL activity in the skeletal muscle was found in September (774 ± 64.1 mU/g tissue), which may serve to cover the increased energy demands for compensatory growth and maintenance of adiposity in the coming cold season. Furthermore, the seasonal regulation of LPL involves some factors in addition to insulin and triglycerides (TG). These results suggest that yaks could rely, in part, on LPL activity to adapt to the harsh forage environment. During the growing season, an enhanced synthesis of LPL production in the adipose tissues along with mechanisms for the recycling of fat contributes toward the rapid recovery of body weight.

Lipoprotein lipase deficiency in chronic kidney disease is accompanied by down-regulation of endothelial GPIHBP1 expression

Chronic renal failure (CRF) is associated with hypertriglyceridemia and impaired clearance of very low density lipoprotein (VLDL) and chylomicrons which are largely due to lipoprotein lipase (LPL) deficiency/dysfunction. After its release from myocytes and adipocytes, LPL binds to the endothelium in the adjacent capillaries where it catalyzes hydrolysis of triglycerides in VLDL and chylomicrons. The novel endothelium-derived molecule, glycosylphosphatidylinositol-anchored binding protein 1 (GPIHBP1), plays a critical role in LPL metabolism and function by anchoring LPL to the endothelium and binding chylomicrons. GPIHBP1-deficient mice and humans exhibit severe hypertriglyceridemia and diminished heparin-releasable LPL, pointing to the critical role of GPIHBP1 in regulation of LPL activity. Given its central role in regulation of LPL activity and triglyceride metabolism, we explored the effect of chronic kidney disease (CKD) on GPIHBP1 expression. Expression of GPIHBP1 and LPL were determined by reverse transcriptase-polymerase chain reaction, Western blot and immunohistochemical analyses in the adipose tissue, skeletal muscle and myocardium of rats 12weeks after 5/6 nephrectomy (CRF) or sham-operation (control). Compared to the controls, the CRF group exhibited severe hypertriglyceridemia, significant reduction of the skeletal muscle, myocardium and adipose tissue LPL mRNA and protein abundance. This was accompanied by parallel reductions of GPIHBP1 mRNA abundance and immunostaining in the tested tissues. LPL deficiency in CKD is associated with and compounded by GPIHBP1 deficiency. Together these abnormalities contribute to impaired clearance of triglyceride-rich lipoproteins, diminished availability of lipid fuel for energy storage in adipocytes and energy production in myocytes and consequent hypertriglyceridemia, cachexia, muscle weakness and atherosclerosis.

Cyanidin-3-O-β-glucoside improves obesity and triglyceride metabolism in KK-Aymice by regulating lipoprotein lipase activity

Cyanidin-3-O-β-glucoside (Cy-3-g)-rich foods have been reported to inhibit the onset of obesity, but whether the pure anthocyanin supplementation affects obesity remains uncertain. Cy-3-g supplementation significantly reduced obesity, accumulation of fat in visceral adipose and liver tissues, and plasma triglyceride levels. Furthermore, adenosine monophosphate (AMP)-activated protein kinase phosphorylation (pAMPK) in the skeletal muscle and visceral adipose were significantly increased by Cy-3-g consumption. This was followed by the activation of lipoprotein lipase (LPL) in plasma and skeletal muscle but the suppression of this enzyme in visceral adipose. LPL activation in skeletal muscle cells and its suppression in adipocytes by Cy-3-g were blocked by inhibition of pAMPK. Our present data thus demonstrate that Cy-3-g improves obesity and triglyceride metabolism in KK-Ay mice. The underlying mechanism is found to be partly related to the activation of LPL in plasma and skeletal muscle, and inhibition of LPL in adipose tissue following the activation of pAMPK.

Treatment with a melanocortin agonist improves abnormal lipid metabolism in streptozotocin-induced diabetic mice

Impairments in leptin-melanocortin signaling are associated with insulin-deficient diabetes and leptin treatment has been shown to be effective in reversing hyperglycemia in animal models of type 1 diabetes. Therefore, we hypothesized that enhanced central melanocortin signaling reverses the metabolic impairments associated with type 1 diabetes. To address this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with daily intracerebroventricular injection of MTII, a melanocortin agonist, for 11days. STZ-induced hyperglycemia and glucose intolerance were not improved by MTII treatment. MTII treatment did not alter expression levels of genes encoding gluconeogenic enzymes including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), in the liver of diabetic mice. Skeletal muscle and white adipose tissue glucose transporter 4 (GLUT4) mRNA levels were not altered by MTII treatment in diabetic mice. In contrast, serum nonesterified fatty acid (NEFA) levels were significantly increased in STZ-induced diabetic mice compared to non-diabetic control mice and MTII treatment significantly reduced serum NEFA levels in diabetic mice. MTII treatment also significantly reduced expression levels of hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) mRNA in white adipose tissue of diabetic mice without a significant change in serum insulin levels. Expression levels of lipoprotein lipase (LPL) and fatty acid translocase (FAT/CD36) mRNA in white adipose tissue and skeletal muscle were not changed by MTII treatment. These data suggest that central melanocortin signaling regulates lipid metabolism and that enhancing central melanocortin signaling is effective in reversing abnormal lipid metabolism, but not carbohydrate metabolism, at least partly by reducing lipolysis in type 1 diabetes.

Effects of hyperinsulinemia on glucose and lipid transporter expression in insulin-sensitive horses

Plasma insulin concentrations are elevated (hyperinsulinemia) in horses with obesity-associated insulin resistance. In other species, insulin resistance is partly due to reduced levels of insulin receptor and the insulin-sensitive glucose transporter, and, in vitro, chronic hyperinsulinemic conditions reduce the expression of these proteins. Consumption of grain-based concentrate feeds results in postprandial hyperinsulinemia in horses, and adaptation to these diets is associated with insulin resistance. As such, it is possible that the repeated, chronic postprandial hyperinsulinemia associated with these diets could contribute to the development of insulin resistance. The purpose of the current study was to investigate the influence of a 6-h insulin infusion that increased plasma insulin concentrations to >1,000 mIU/L, on the expression of insulin receptor and glucose and lipid transporters in skeletal muscle and adipose tissue of lean, insulin-sensitive horses. Insulin infusion decreased transcript abundance of the glucose transporter 4 ( P < 0.05), glucose transporter 1 ( GLUT1; P < 0.09), and the insulin receptor ( P < 0.001) in adipose tissue, while increasing transcript abundance of GLUT1 ( P < 0.09) and decreasing protein abundance of the insulin receptor ( P < 0.09) in skeletal muscle. The acute, 6 hyperinsulinemic conditions achieved in this experiment resulted in alterations to mechanisms of glucose transport that could promote insulin resistance via reduced insulin-stimulated glucose disposal. Insulin infusion also reduced transcript abundance of the lipid transporters CD36 ( P < 0.001) and fatty acid transporter protein ( FATP; P < 0.05) in adipose tissue while increasing FATP ( P < 0.05) and lipoprotein lipase ( P < 0.01) in skeletal muscle. The reduction in adipose tissue lipid transporters could have been due to the decreased plasma lipid concentrations, whereas the increase in skeletal muscle may indicate that insulin stimulates lipid uptake into equine skeletal muscle. This report provides preliminary evidence that severe hyperinsulinemia alters glucose and lipid transporter expression that could promote an insulin-resistant state; these should be further investigated in horses consuming grain-based concentrates.

Evidence of Health Risks from Occupational Sitting: Where Do We Stand?

Evidence of Health Risks from Occupational Sitting: Where Do We Stand?