Skeletal Muscle Lipoprotein Lipase Activity Research Articles

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.

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.

Differential effects of angiopoietin-like 4 in brain and muscle on regulation of lipoprotein lipase activity.

ObjectiveLipoprotein lipase (LPL) is a key regulator of circulating triglyceride rich lipoprotein hydrolysis. In brain LPL regulates appetite and energy expenditure. Angiopoietin-like 4 (Angptl4) is a secreted protein that inhibits LPL activity and, thereby, triglyceride metabolism, but the impact of Angptl4 on central lipid metabolism is unknown.MethodsWe induced type 1 diabetes by streptozotocin (STZ) in whole-body Angptl4 knockout mice (Angptl4-/-) and their wildtype littermates to study the role of Angptl4 in central lipid metabolism.ResultsIn type 1 (streptozotocin, STZ) and type 2 (ob/ob) diabetic mice, there is a ~2-fold increase of Angptl4 in the hypothalamus and skeletal muscle. Intracerebroventricular insulin injection into STZ mice at levels which have no effect on plasma glucose restores Angptl4 expression in hypothalamus. Isolation of cells from the brain reveals that Angptl4 is produced in glia, whereas LPL is present in both glia and neurons. Consistent with the in vivo experiment, in vitro insulin treatment of glial cells causes a 50% reduction of Angptl4 and significantly increases LPL activity with no change in LPL expression. In Angptl4-/- mice, LPL activity in skeletal muscle is increased 3-fold, and this is further increased by STZ-induced diabetes. By contrast, Angptl4-/- mice show no significant difference in LPL activity in hypothalamus or brain independent of diabetic and nutritional status.ConclusionThus, Angptl4 in brain is produced in glia and regulated by insulin. However, in contrast to the periphery, central Angptl4 does not regulate LPL activity, but appears to participate in the metabolic crosstalk between glia and neurons.

Abstract 621: Mice Lacking Prostaglandin E Receptor Subtype 4 Resist Diet-Induced Obesity Despite Hypertriglyceridemia

Objectives: Activation of prostaglandin E receptor subtype 4 (EP4) may suppress inflammation by regulating nuclear factor kappa B (NFκB). Indeed, chronic inflammation usually is accompanied by dyslipidemia. Thus, the present study tested the hypothesis that deletion of EP4 can accelerate the occurrence of metabolic syndrome Methods: EP4 wild-type and knockout mice were put on a high-fat diet (HFD) for thirty weeks. Body weight and food consumption were monitored. In addition, energy expenditure and fat composition were determined by indirect calorimetry and Minispec body composition analyzer, respectively. The impact of EP4 deletion on the ability to synthesize hepatic very low density lipoprotein (VLDL)-triglyceride (TG) and intestinal chylomicron (CM)-TG, as well as the ability to clear TG during HFD was examined. Circulating lipoprotein lipase (LPL) activity and tissue LPL activity were determined using a fluorometric assay kit and mRNA expression of lipid metabolism-related genes in adipose tissue was measured by quantitative polymerase chain reaction (Q-PCR). Results: After consuming a high-fat diet for thirty weeks, EP4 knockout mice exhibited reduced body weight gain and body fat mass, not attributable to changes in food intake, fat malabsorption and energy expenditure. However, EP4 knockout mice had a higher plasma TG level than wild-type mice. The deletion of EP4 did not influence hepatic VLDL-TG production or intestinal CM-TG synthesis but impaired TG clearance rate. EP4 knockout mice had a decreased circulating LPL activity, reduced LPL activity in epididymal fat and skeletal muscle, suggesting impaired hydrolysis and uptake of triglycerides in these tissues. Moreover, EP4 knockout mice had a reduced expression of CD36 in brown adipose tissue, which may indicate that the uptake of fatty acids is impaired. Conclusions: High-fat feeding of EP4 knockout mice resulted in a lean body phenotype, but caused hypertriglyceridemia resulting from impaired TG clearance, attributed to reduced LPL activity and expression of CD36. The results indicate that EP4 plays a critical role in systemic lipid homeostasis.

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.

Lipoprotein lipase and obesity

Obesity is one of the fast-growing major diseases in developed and developing countries. As has been persuasively argued, long-term imbalance between intake and expenditure of fat is a central factor in the etiology of obesity. Obesity aggravates insulin resistance and promotes cardiovascular diseases and atherosclerosis. We hypothesized that elevating lipoprOtein lipase (LPL) activity in skeletal muscle would cause an improvement of obesity. To test this hypothesis, we studied the effects of the LPL activator NO-1886 inobese animals. NO-1886 elevated LPL activity in skeletal muscle, and improved obesity as well as insulin resistance in obese rats. Furthermore, NO-1886 mitigated body weight gain induced by pioglitazone without suppressive effect on the adiponectin-increasing action of pioglitazone. LPL activators hold a lot of promise of curing several diseases shown above in clinical scene.

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

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

Leptin increases skeletal muscle lipoprotein lipase and postprandial lipid metabolism in mice

The ability of leptin to preserve lean tissue during weight loss may be in part due to differences in nutrient partitioning. Because lipoprotein lipase (LPL) plays a key role in partitioning lipid nutrients, this study was conducted to test the hypothesis that leptin would modify the tissue-specific regulation of LPL and result in increased lipid oxidation and decreased storage. The effects of daily intraperitoneal leptin injections (2 mg/kg body weight) over 2 weeks on LPL activity and postprandial lipid metabolism were tested in both wild-type (WT), leptin-deficient ob/ob obese mice and mice pair fed to the leptin-treated mice. On the experimental day, mice were given food by gavage, blood was drawn periodically, and adipose tissue and skeletal muscle were harvested for measurements of LPL activity at 240 minutes. After 2 weeks of leptin administration, skeletal muscle LPL (SMLPL) activity was increased in leptin-treated compared with pair-fed ( P = .012) and WT ( P = .002) mice. There was no effect of leptin or pair feeding on postprandial adipose tissue LPL activity. In ob/ob mice, leptin treatment normalized the decrease in postprandial free fatty acid concentration ( P = .066). Leptin had no effect on either the area under the triglyceride (TG) excursion or the integrated area under the TG excursion in WT mice. In ob/ob mice, however, the TG excursion was lower in the leptin-treated than the pair-fed mice by area under the TG excursion ( P = .012) and was lower than in the WT mice by integrated area under the TG excursion ( P = .027). As expected, 2 weeks of leptin treatment decreased body weight in both the WT and ob/ob mice (−2.6% and −10.4%, respectively). Leptin treatment increased SMLPL, an effect that may have contributed to the leptin-induced weight loss. The leptin-induced decreased postprandial TG excursion in ob/ob mice suggests that leptin acts to augment clearance of postprandial TG-rich lipoprotein lipid and that this increase may in part be secondary to the increased activity of SMLPL. The trend for decreased postprandial free fatty acid may indicate that leptin decreases adipose tissue lipid stores without increasing lipolysis.

Independent and Combined Effects of Aerobic Exercise and Pharmacological Strategies on Serum Triglyceride Concentrations: A Qualitative Review

Elevated fasting and postprandial serum triglyceride concentrations are associated with cardiovascular disease morbidity and mortality. Aerobic exercise reduces serum triglyceride concentrations in the presence or absence of weight loss. Although pharmacological interventions are often used in combination with aerobic exercise to achieve target triglyceride concentrations, information on the combined effects of aerobic exercise and lipid-modifying agents on serum triglycerides is limited. This review examines the independent and combined effects of both interventions on serum fasting and postprandial triglyceride concentrations from the available literature. Reductions in serum triglycerides after aerobic exercise are associated with an increase in skeletal muscle lipoprotein lipase activity and a decrease in hepatic triglyceride and very-low-density lipoprotein (VLDL) synthesis and secretion. Lipid-modifying agents such as niacin, omega-3 fatty acids, and statins also decrease fasting and postprandial triglycerides by increasing lipoprotein lipase (LPL) activity and/or decreasing VLDL synthesis. When combined, lipid-modifying agents may reduce fasting and postprandial triglyceride secretion to an extent in which aerobic exercise cannot provide any additional benefit. These observations indicate that aerobic exercise and pharmacological strategies reduce serum triglycerides by similar mechanisms, which may attenuate the triglyceride-lowering capacity of the concordant treatment.

Leptin Augments the Acute Suppressive Effects of Insulin on Hepatic Very Low-Density Lipoprotein Production in Rats

It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Leptin and insulin also have potent effects on lipid metabolism. However, the effects of leptin on the regulation of liver lipid metabolism by insulin have not been investigated. The current study addressed the effects of leptin on insulin-regulated hepatic very low-density lipoprotein (VLDL) metabolism in vivo in rats. A 90-min hyperinsulinemic/euglycemic clamp (4 mU/kg x min(-1)) reduced plasma VLDL triglyceride (TG) by about 50% (P < 0.001 vs. saline control). Importantly, a leptin infusion (0.2 microg/kg x min(-1)) in combination with insulin reduced plasma VLDL-TG by about 80% (P < 0.001 vs. insulin alone). These effects did not require altered skeletal muscle lipoprotein lipase activity but did include differential effects of insulin and leptin on liver apolipoprotein (apo) B and TG metabolism. Thus, insulin decreased liver and plasma apoB100/B48 levels (approximately 50%, P < 0.01), increased liver TGs (approximately 20%, P < 0.05), and had no effect on fatty acid oxidation. Conversely, leptin decreased liver TGs (approximately 50%, P < 0.01) and increased fatty acid oxidation (approximately 50%, P < 0.01) but had no effects on liver or plasma apoB levels. Importantly, the TG-depleting and prooxidative effects of leptin were maintained in the presence of insulin. We conclude that leptin additively increases the suppressive effects of insulin on hepatic and systemic VLDL metabolism by stimulating depletion of liver TGs and increasing oxidative metabolism. The net effect of the combined actions of insulin and leptin is to decrease the production and TG content of VLDL particles.

Basal adipose tissue and hepatic lipid kinetics are not affected by a single exercise bout of moderate duration and intensity in sedentary women.

Hypertriacylglycerolaemia is an important risk factor for cardiovascular disease. In men, we have shown that the effects of evening exercise on basal VLDL (very-low-density lipoprotein) metabolism are dose-dependent: a single prolonged bout of aerobic exercise [2 h at 60% of VO(2 peak) (peak oxygen consumption)] reduces fasting plasma TAG [triacylglycerol (triglyceride)] concentrations, via enhanced clearance of VLDL-TAG from the circulation, whereas the same exercise performed for 1 h has no effect on VLDL-TAG metabolism and concentration. We hypothesized that women are more sensitive to the TAG-lowering effect of exercise because they reportedly use more intramuscular TAG as an energy source during exercise, and depletion of muscle TAG stores has been linked to reciprocal changes in skeletal muscle LPL (lipoprotein lipase) activity. To test our hypothesis, we measured basal VLDL-TAG and VLDL-apoB-100 (apolipoprotein B-100), and plasma NEFA [non-esterified fatty acid ('free fatty acid')] kinetics, by using stable isotope-labelled tracer techniques, on the morning after a single session of evening exercise of moderate duration and intensity (1 h at 60% of VO(2 peak)) in eight sedentary pre-menopausal women (age, 28+/-3 years; body mass index, 27+/-2 kg/m(2); body fat, 34+/-3%; values are means+/-S.E.M.). Compared with an equivalent period of evening rest, exercise had no effect on post-absorptive NEFA concentrations and the rate of appearance in plasma, VLDL-TAG and VLDL-apoB-100 concentrations, hepatic VLDL-TAG and VLDL-apoB-100 secretion and plasma clearance rates (all P>0.05). We conclude that, in women, as in men, a single session of exercise of moderate intensity and duration is not sufficient to bring about the alterations in VLDL metabolism that have been linked to post-exercise hypotriacylglycerolaemia.

Waging war on modern chronic diseases: primary prevention through exercise biology

In this review, we develop a blueprint for exercise biology research in new millennium. The first part of our plan provides statistics to support contention that there has been an epidemic emergence of modern chronic diseases in latter part of 20th century. The health care costs of these conditions were almost two-thirds of a trillion dollars and affected 90 million Americans in 1990. We estimate that these costs are now approaching $1 trillion and stand to further dramatically increase as baby boom generation ages. We discuss reaction of biomedical establishment to this epidemic, which has primarily been to apply modern technologies to stabilize overt clinical problems (e.g., secondary and tertiary prevention). Because this approach has been largely unsuccessful in reversing epidemic, we argue that more emphasis must be placed on novel approaches such as primary prevention, which requires attacking environmental roots of these conditions. In this respect, a strong association exists between increase in physical inactivity and emergence of modern chronic diseases in 20th century industrialized societies. Approximately 250,000 deaths per year in United States are premature due to physical inactivity. Epidemiological data have established that physical inactivity increases incidence of at least 17 unhealthy conditions, almost all of which are chronic diseases or considered risk factors for chronic diseases. Therefore, as part of this review, we present concept that human genome evolved within an environment of high physical activity. Accordingly, we propose that exercise biologists do not study the effect of physical activity but in reality study effect of reintroducing exercise into an unhealthy sedentary population that is genetically programmed to expect physical activity. On basis of healthy gene function, exercise research should thus be viewed from a nontraditional perspective in that control group should actually be taken from a physically active population and not from a sedentary population with its predisposition to modern chronic diseases. We provide exciting examples of exercise biology research that is elucidating underlying mechanisms by which physical inactivity may predispose individuals to chronic disease conditions, such as mechanisms contributing to insulin resistance and decreased skeletal muscle lipoprotein lipase activity. Some findings have been surprising and remarkable in that novel signaling mechanisms have been discovered that vary with type and level of physical activity/inactivity at multiple levels of gene expression. Because this area of research is underfunded despite its high impact, final part of our blueprint for next millennium calls for National Institutes of Health (NIH) to establish a major initiative devoted to study of biology of primary prevention of modern chronic diseases. We justify this in several ways, including following estimate: if percentage of all US morbidity and mortality statistics attributed to combination of physical inactivity and inappropriate diet were applied as a percentage of NIH's total operating budget, resulting funds would equal budgets of two full institutes at NIH! Furthermore, fiscal support of studies elucidating scientific foundation(s) targeted by primary prevention strategies in other public health efforts has resulted in an increased efficacy of overall prevention effort. We estimate that physical inactivity impacts 80-90% of 24 integrated review group (IRG) topics proposed by NIH's Panel on Scientific Boundaries for Review, which is currently directing a major restructuring of NIH's scientific funding system. Unfortunately, primary prevention of chronic disease and investigation of physical activity/inactivity and/or exercise are not mentioned in almost 200 total subtopics comprising t

Adiponectin Reduces Plasma Triglyceride by Increasing VLDL Triglyceride Catabolism

OBJECTIVE—Adiponectin is an adipocyte-derived hormone that plays an important role in glucose and lipid metabolism. The main aims of this study are to investigate the effects of adiponectin on VLDL triglyceride (VLDL-TG) metabolism and the underlying mechanism.RESEARCH DESIGN AND METHODS—Adenoviruses were used to generate a mouse model with elevated circulating adiponectin. HepG2 and C2C12 cells were treated with recombinant human adiponectin.RESULTS—Three days after Ad-mACRP30 adenovirus injection, plasma adiponectin protein levels were increased 12-fold. All three main multimeric adiponectin molecules were proportionally elevated. Fasting plasma TG levels were significantly decreased (∼40%) in the mice with elevated adiponectin in circulation, as were the plasma levels of large and medium VLDL subclasses. Although apolipoprotein B mRNA levels were robustly suppressed in the livers of adiponectin-overexpressing mice and in cultured HepG2 cells treated with recombinant human adiponectin, hepatic VLDL-TG secretion rates were not altered by elevated plasma adiponectin. However, Ad-mACRP30–treated mice exhibited a significant increase of postheparin plasma lipoprotein lipase (LPL) activity compared with mice that received control viral vector. Skeletal muscle LPL activity and mRNA levels of LPL and VLDL receptor (VLDLr) were also increased in Ad-mACRP30–treated mice. Recombinant human adiponectin treatment increased LPL and VLDLr mRNA levels in differentiated C1C12 myotubes.CONCLUSIONS—These results suggest that adiponectin decreases plasma TG levels by increasing skeletal muscle LPL and VLDLr expression and consequently VLDL-TG catabolism.

Higher Post‐absorptive Skeletal Muscle LPL Activity in African American vs. Non‐Hispanic White Pre‐menopausal Women

Higher post-absorptive post-heparin plasma lipoprotein lipase (LPL) activity has been reported in African Americans as compared to non-Hispanic whites but differences in tissue-specific LPL activity are unclear. Post-absorptive skeletal muscle (SM)-LPL (vastus lateralis ) and subcutaneous abdominal adipose tissue (AT)-LPL activity was measured in overweight, sedentary African American females (n = 11) as well as in their non-Hispanic white counterparts (n = 6) during a period of controlled low fat (30%) diet (for 10 days) combined with physical activity (for days 8-10). Post-absorptive substrate utilization was measured on day 10; fasting blood levels and SM and AT biopsies were obtained on day 11. African Americans had significantly greater post-absorptive SM-LPL activity (P = 0.04) when compared to non-Hispanic whites. There were no significant differences in post-absorptive AT-LPL activity, free fatty acids, and systemic fat oxidation or respiratory quotient between African American and white non-Hispanic women in this study (P > 0.2 for all). During a controlled low fat (30%) diet post-absorptive vastus lateralis SM-LPL activity is higher in sedentary pre-menopausal African American as compared to non-Hispanic white women.

NO-1886 (ibrolipim), a lipoprotein lipase activator, increases the expression of uncoupling protein 3 in skeletal muscle and suppresses fat accumulation in high-fat diet–induced obesity in rats

Although the lipoprotein lipase (LPL) activator NO-1886 shows antiobesity effects in high-fat–induced obese animals, the mechanism remains unclear. To clarify the mechanism, we studied the effects of NO-1886 on the expression of uncoupling protein (UCP) 1, UCP2, and UCP3 in rats. NO-1886 was mixed with a high-fat chow to supply a dose of 100 mg/kg to 8-month-old male Sprague-Dawley rats. The animals were fed the high-fat chow for 8 weeks. At the end of the administration period, brown adipose tissue (BAT), mesenteric fat, and soleus muscle were collected and levels of UCP1, UCP2, and UCP3 messenger RNA (mRNA) were determined. NO-1886 suppressed the body weight increase seen in the high-fat control group after the 8-week administration (585 ± 39 vs 657 ± 66 g, P < .05). NO-1886 also suppressed fat accumulation in visceral (46.9 ± 10.4 vs 73.7 ± 14.5 g, P < .01) and subcutaneous (43.1 ± 18.1 vs 68.9 ± 18.8 g, P < .05) tissues and increased the levels of plasma total cholesterol and high-density lipoprotein cholesterol in comparison to the high-fat control group. In contrast, NO-1886 decreased the levels of plasma triglycerides, nonesterified free fatty acid, glucose, and insulin. NO-1886 increased LPL activity in soleus muscle (0.082 ± 0.013 vs 0.061 ± 0.016 μmol of free fatty acid per minute per gram of tissue, P < .05). NO-1886 increased the expression of UCP3 mRNA in soleus muscle 3.14-fold ( P < .01) compared with the high-fat control group without affecting the levels of UCP3 in mesenteric adipose tissue and BAT. In addition, NO-1886 did not affect the expression of UCP1 and UCP2 in BAT, mesenteric adipose tissue, and soleus muscle. In conclusion, NO-1886 increased the expression of UCP3 mRNA and LPL activity only in skeletal muscle. Therefore, a possible mechanism for NO-1886's antiobesity effects in rats may be the enhancement of LPL activity in skeletal muscle and the accompanying increase in UCP3 expression.

Physical inactivity amplifies the sensitivity of skeletal muscle to the lipid-induced downregulation of lipoprotein lipase activity

Physical inactivity is a risk factor for lipoprotein disorders and the metabolic syndrome. Physical inactivity has a powerful effect on suppressing lipoprotein lipase (LPL) activity in skeletal muscle, the rate-limiting enzyme for hydrolysis of triglyceride (TG)-rich lipoproteins. We tested the ability of several compounds to prevent the decrease in LPL. The present study minimized standing and ordinary light nonexercise movements in rats to compare the effects of inactivity and nonexercise activity thermogenesis (NEAT) on LPL activity. The key new insight was that the typically quick decrease in LPL activity of oxidative muscle caused by physical inactivity was prevented by nicotinic acid (NA), whereas inhibitors of TNF-alpha, inducible nitric oxide synthase, and NF-kappaB had no such effect. NA was administered at a dose known to acutely impede the appearance of plasma TG from the liver and free fatty acids from adipose tissue, and it was effective at intentionally lowering plasma lipid concentrations to the same level in active and inactive groups. As measured from heparin-releasable LPL activity, LPL in the microvasculature of the most oxidative muscles was approximately 90% lower in the inactive group compared with controls, and this suppression was completely blocked by NA. In contrast to inactivity, NA did not raise muscle LPL in ambulatory controls, whereas a large exogenous fat delivery did decrease LPL activity. In vitro control studies revealed that NA did not have a direct effect on skeletal muscle LPL activity. In conclusion, physical inactivity amplifies the ability of plasma lipids to suppress muscle LPL activity. The light ambulatory contractions responsible for NEAT are sufficient for mitigating these deleterious effects.

Relationship Between Skeletal Muscle LPL Activity and the Ability of Endothelial Cells to Bind LPL

Lipoprotein lipase (LPL) in skeletal muscle has been a focus of many exercise studies. The interesting feature of this protein is that while it is synthesized in muscle fibers, it is functional when bound to the vascular endothelium lumen. However because of prior technical limitations, almost nothing is known about the endothelial regulation of LPL protein in skeletal muscle. Thus, we have developed methodologies to quantify the binding of radiolabeled LPL to rat tissues in vivo and to isolated perfused muscle. PURPOSE To determine if the endothelial binding of exogenous 125I-LPL is associated with the amount of endogenous LPL activity residing in the muscle tissue. We tested the hypothesis that the ability of muscles to bind 125I-LPL would be correlated with the amount of endogenous LPL activity on the endothelium. METHODS Tyrosine residues of the LPL protein were iodinated. Dimeric LPL was purified by heparin-sepharose chromatography. The 125I-LPL was either injected intravenously into the jugular vein or perfused into the femoral artery of an isolated rat hindlimb. Tissues were obtained after thoroughly flushing the limb with perfusate to remove any tracer from the blood. In some of the experiments, heparin was perfused prior to taking tissue samples in order to determine how much of the 125I-LPL was binding to the heparin-sensitive sites that anchor LPL. RESULTS The dimeric 125I-LPL rapidly bound to the skeletal muscle vasculature (>95% complete in 10 minutes). A subset of experiments indicated that the tracer was very likely binding to vascular sites also anchoring the functional pool of endogenous LPL because heparin perfusion released 98–100% of the 125I-LPL from skeletal muscles into the venous outflow. There was a 34% coefficient of variation (CV) for LPL binding when comparing different rats. When comparing contra-lateral muscles within each rat, the CV for LPL binding was only 8%. Predominantly oxidative muscles bound 200–300% more 125I-LPL than glycolytic muscles (e.g. the endothelium of the red gastrocnemius bound 220±15% more LPL than observed in the white gastrocnemius; P = 0.0001). Most interestingly, there was a striking relationship between endogenous heparin-releasable LPL activity in skeletal muscle and the ability of 125I-LPL to bind to the endothelium (R2=0.833, P=0.0006). CONCLUSION These studies indicate that the binding of exogenous LPL to the vascular endothelium accounts for 83% of the variance in rat skeletal muscle LPL activity. Thus the results are consistent with the hypothesis that the endothelium may be a primary determinant of the amount of skeletal muscle LPL activity. Supported in part by NIH Grant HL07482

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Topiramate (TPM) is a novel neurotherapeutic agent currently indicated for the treatment of epilepsy and undergoing development for other central nervous system indications including neuropathic pain, bipolar disorder, and migraine prophylaxis. TPM is synthesized from d-fructose and contains a sulfamate moiety that is essential for its pharmacologic activity. TPM has been observed to significantly reduce body weight in patients treated for seizure, which has prompted the realization of preclinical studies to characterize the effects of TPM in the regulation of energy balance. Studies carried out in various strains of rats have provided good evidence for the ability of TPM to blunt energy deposition. Body composition analyses from rat trials have demonstrated that TPM inhibits fat deposition while reducing the activity of lipoprotein lipase (LPL) in various white adipose tissue depots. High doses of TPM (likely above the therapeutic dose range) have also been observed to reduce protein gain without catabolic effects. Although TPM cannot be described as a potent anorectic agent, it seems to have the ability to reduce food intake; significant reductions in food intake have been observed in female obese (fa/fa) Zucker rats and in female Wistar rats. TPM can also reduce energy deposition in the absence of alterations in food intake. This effect has been clearly emphasized in female lean (Fa/?) Zucker rats. In female Sprague–Dawley rats, TPM also increased energy expenditure and it has been observed to increase LPL activity in brown adipose tissue, which could indicate that TPM has the ability to enhance regulatory thermogenesis. In addition, TPM stimulates LPL activity in skeletal muscles, further emphasizing its potential to promote substrate oxidation. The mechanisms whereby TPM affects the regulation of energy balance have yet to be understood. TPM represents an antiepileptic drug (AED) with complex biochemical/pharmacologic actions. Its negative effects on energy deposition cannot be readily predicted from these actions, as AEDs are generally expected to stimulate body weight gain. Recent data, obtained from investigations aimed at assessing the effects of TPM on neuropeptidergic systems involved in the regulation of energy balance, have failed to demonstrate any significant effects of TPM on the neuropeptide Y and proopiomelanocortin systems. In conclusion, it is clear that TPM can reduce fat deposition by either reducing food intake or stimulating energy expenditure. The mechanisms whereby an AED such as TPM controls food intake and energy expenditure remains to be delineated.©1999 ASCRS and ESCRS

Tissue‐specific regulation of lipoprotein lipase in humans: effects of fasting

We have previously reported that the activity of lipoprotein lipase (LPL) measured in postheparin plasma from humans fasted for 30 h is increased relative to the fed state. This is in contrast to laboratory animals, where the strong down-regulation of LPL in their adipose tissue on fasting is reflected in decreased levels of LPL activity in postheparin plasma. To search for the tissue source of the increase in LPL activity on fasting of humans, young, healthy subjects were fasted for 10, 20 or 30 h, and LPL was measured in plasma (pre- and postheparin) and in biopsies from subcutaneous adipose tissue (abdominal) and from a skeletal muscle (tibialis anterior). Both LPL activity and LPL protein mass were measured in the tissue homogenates. Values after fasting were compared with values from postprandial samples obtained 2 h after a meal. Fasting for up to 30 h did not alter LPL activity in basal plasma (preheparin). LPL activity in postheparin plasma remained unchanged after 10 and 20 h of fasting, but was increased by 50% after 30 h (P < 0.05). Ten hours of fasting caused a 25% (P < 0.05) decrease in LPL activity in subcutaneous adipose tissue, while LPL activity in skeletal muscle remained unchanged. After 30 h of fasting, both LPL activity and mass had decreased by approximately 50% (P < 0.05) in adipose tissue, but had increased by approximately 100% (P < 0.05) in muscle. The increase in postheparin plasma LPL activity after 30 h of total food deprivation of healthy human subjects seemed to reflect an increased activity and mass of LPL in skeletal muscle.

Differential regulation of fatty acid trapping in mouse adipose tissue and muscle by ASP.

Acylation-stimulating protein (ASP) is a lipogenic hormone secreted by white adipose tissue (WAT). Male C3 knockout (KO; C3(-/-)) ASP-deficient mice have delayed postprandial triglyceride (TG) clearance and reduced WAT mass. The objective of this study was to examine the mechanism(s) by which ASP deficiency induces differences in postprandial TG clearance and body composition in male KO mice. Except for increased (3)H-labeled nonesterified fatty acid (NEFA) trapping in brown adipose tissue (BAT) of KO mice (P = 0.02), there were no intrinsic tissue differences between wild-type (WT) and KO mice in (3)H-NEFA or [(14)C]glucose oxidation, TG synthesis or lipolysis in WAT, muscle, or liver. There were no differences in WAT or skeletal muscle hydrolysis, uptake, and storage of [(3)H]triolein substrate [in situ lipoprotein lipase (LPL) activity]. ASP, however, increased in situ LPL activity in WAT (+64.8%, P = 0.02) but decreased it in muscle (-35.0%, P = 0.0002). In addition, after prelabeling WAT with [(3)H]oleate and [(14)C]glucose, ASP increased (3)H-lipid retention, [(3)H]TG synthesis, and [(3)H]TG-to-[(14)C]TG ratio, whereas it decreased (3)H-NEFA release, indicating increased NEFA trapping in WAT. Conversely, in muscle, ASP induced effects opposite to those in WAT and increased lipolysis, indicating reduced NEFA trapping within muscle by ASP (P < 0.05 for all parameters). In conclusion, novel data in this study suggest that 1) there is little intrinsic difference between KO and WT tissue in the parameters examined and 2) ASP differentially regulates in situ LPL activity and NEFA trapping in WAT and skeletal muscle, which may promote optimal insulin sensitivity in vivo.