Muscle Lipoprotein Lipase Activity Research Articles

Progress of research on dyslipidemia accompanied by nephrotic syndrome

Nephrotic syndrome is a relatively common clinical disease. Associated dyslipidemia is a risk factor for the occurrence and development of cardiovascular and renal diseases that might gradually develop into atherosclerosis, glomerulosclerosis or tubulointerstitial injury. It also confers an elevated risk of complications such as thromboembolism. If not properly controlled over the long term, dyslipidemia will become a key factor in a poor prognosis. Furthermore, dyslipidemia correlates with an increase in hepatic compensatory synthetic lipoprotein levels and a decrease in lipoprotein clearance, which can be sourced to the downregulation of hepatic and lipoprotein lipase activities in endothelial cells, muscle, and adipose tissue, and clinically characterized as hypertriglyceridemia or hypercholesterolemia. However, further investigations into the mechanism(s) of dyslipidemia are needed, with the resultant detailed perspectives and analyses substantially aiding the further development of treatment guidelines. Currently, statins represent the most popular type of pharmaceutical intervention because they lower hepatic cholesterol production and promote the absorption of low-density lipoprotein-cholesterol from the bloodstream, followed by second-line and other potential therapies to regulate the expression of specific receptors.

Induction of Free Fatty Acid‐mediated Angiopoietin‐Like Protein‐4 Gene Expression is Independent of PPARδ Activity in Skeletal Muscle Cells In Vitro

Angiopoietin‐like protein‐4 (ANGPTL4) inhibits lipoprotein lipase activity in skeletal muscle. Free fatty acids (FFAs) activate ANGPTL4 expression, yet the method by which FFAs induce ANGPTL4 in skeletal muscle is not well‐known. The purpose of this study was to examine the effect of FFAs on peroxisome proliferator‐activated receptor δ (PPARδ)‐mediated ANGPTL4 expression in C2C12 cells. Chronic exposure of mono‐ (MUFA) and poly‐unsaturated fatty acids (PUFA), but not saturated fatty acids (SFA), significantly induced ANGPTL4 mRNA expression in C2C12 cells (MUFA: 4.5±1.1, p=0.02; PUFA: 5.6±1.6, p=0.02; SFA: 0.4±0.1, p=0.4 respectively). To analyze the mechanism of FFA‐induced PPARδ activation of ANGPTL4, mRNA expression of PPARδ, which is believed to induce ANGPTL4 activity, was measured. However, there was no significant difference in PPARδ expression after FFA treatments. Next, we used the PPARδ agonist (GW0742) and antagonist (GSK0660) to modulate PPARδ activity independent of FFA treatment and examined ANGPTL4 expression. GW0742 significantly increased ANGPTL4 in undifferentiated and differentiated C2C12 cells (12.6±3.9, p=0.01 and 2.8±0.2, p<0.001 respectively), while GSK0660 significantly suppressed basal ANGPTL4 expression (0.2±0.1, p=0.05 and 0.2±0.03, p<0.001 respectively). Yet, in the presence of FFA and GSK0660, ANGPTL4 gene expression significantly increased despite the absence of PPARδ activity in both undifferentiated and differentiated C2C12 cells (7.1±2.5, p=0.03 and 3.8±0.4, p<0.001). Taken together, these results indicate that FFAs may activate ANGPTL4 in a PPARδ independent manner, and a revised mechanism of FFA‐induced skeletal muscle ANGPTL4 expression may be warranted.

Enhancing lipid metabolism and inducing antioxidant and immune responses to adapt to acute hypoxic stress in Schizothorax prenanti

Hypoxia is an adverse environmental condition for fish that can have multiple effects. Compared to the natural environment, high-density farming of Schizothorax prenanti is more likely to experience hypoxic conditions. To evaluate the effects of hypoxia, activities of enzymes and expressions of genes that are related to hypoxia responses were measured to understand lipid metabolism, antioxidant capacity, and immnue response changed during hypoxic conditions (dissolved oxygen: 3.0 ± 0.2 mg/L [MHG] and 1.2 ± 0.2 mg/L [SHG]). During hypoxia, the red blood cell content increased. Furthermore, the lactic acid levels in the brain, liver, and muscle increased. Surprisingly, brain Na+/K+-ATPase activity was decreased. Brain and muscle triglyceride (TG) increased at frst, and then decreased, while the nonesterified fatty acids (NEFA) opposite in the brain had the opposite response, Liver TG and NEFA increased during hypoxia. Brain lipoprotein lipase (LPL) activity decreased, but liver and muscle LPL activities and LPL mRNA levels increased during exposure at 0 h and 12 h. Fatty acid binding protein, fatty acid synthase, peroxisome proliferators activated receptor γ coactivator-1α, peroxisome proliferator activated receptors α and γ genes were up-regulated at different time points, especially in SHG. Also, in SHG, malondiadehyde (MDA) levels in the brain and Intestine increased to some extent. Total antioxidative capability (T-AOC) in the brain and muscle tissue decreased, while it increased in gill, Intestine and liver tissue. Catalase (CAT) activity in the brain, gill, Intestine and muscle increased, while it decreased in the liver. Glutathione peroxidase (GSH-Px) activity was decreased in all tissues except brain. The mRNA levels of superoxide dismutase, GSH-Px, CAT, and hypoxia-inducible factor 1 alpha in the brain, gill and liver increased during hypoxia. Tumor necrosis factor, interleukin 1 beta and tropinone reductase-like 22 levels were up-regulated in all tissues, especially in SHG. Also, brain, gill, liver and muscle HSP70 and HSP90 levels increased. In short, hypoxia enhanced lipid metabolism and antioxidant response, and induced up-regulation of antioxidant and immune genes to adapt to environmental hypoxic stress.

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.

Inulin Improves Postprandial Hypertriglyceridemia by Modulating Gene Expression in the Small Intestine.

Postprandial hyperlipidemia is an important risk factor for cardiovascular diseases in the context of obesity. Inulin is a non-digestible carbohydrate, known for its beneficial properties in metabolic disorders. We investigated the impact of inulin on postprandial hypertriglyceridemia and on lipid metabolism in a mouse model of diet-induced obesity. Mice received a control or a western diet for 4 weeks and were further supplemented or not with inulin for 2 weeks (0.2 g/day per mouse). We performed a lipid tolerance test, measured mRNA expression of genes involved in postprandial lipid metabolism, assessed post-heparin plasma and muscle lipoprotein lipase activity and measured lipid accumulation in the enterocytes and fecal lipid excretion. Inulin supplementation in western diet-fed mice decreases postprandial serum triglycerides concentration, decreases the mRNA expression levels of Cd36 (fatty acid receptor involved in lipid uptake and sensing) and apolipoprotein C3 (Apoc3, inhibitor of lipoprotein lipase) in the jejunum and increases fecal lipid excretion. In conclusion, inulin improves postprandial hypertriglyceridemia by targeting intestinal lipid metabolism. This work confirms the interest of using inulin supplementation in the management of dyslipidemia linked to obesity and cardiometabolic risk.

Effects of Clostridium butyricum on breast muscle lipid metabolism of broilers

To investigate the effects of Clostridium butyricum (C. butyricum) on breast muscle lipid metabolism of broilers, 192 one-day-old male Arbor Acres broilers were randomly allocated into 2 treatments with 6 replicates in a completely randomised design. The broilers were fed corn-soybean meal-based diets and supplemented with 0 or 1 × 109 cfu of C. butyricum/kg of diet for 42 days. The birds in the C. butyricum-supplemented group showed higher (p < .05) average daily gain during the grower phase and throughout the entire period of the experiment and a lower (p = .047) feed conversion rate during the grower phase. Supplementation with C. butyricum increased (p < .05) the intramuscular fat content, lipoprotein lipase activity and mRNA levels in the breast muscle at 42 days of age, increased (p = .032) the serum insulin level at 21 days of age, and enhanced (p = .020) the caecal Firmicutes relative abundance at 42 days of age. Additionally, supplementation with C. butyricum reduced (p < .05) the serum growth hormone levels at both 21 and 42 days of age, decreased (p < .05) the ileum angiopoietin-like protein 4 (ANGPTL4) mRNA levels and serum ANGPTL4 concentrations at 42 days of age, and decreased (p < .05) the hormone-sensitive lipase activity, carnitine palmitoyltransferase 1, carnitine palmitoyltransferase 2, and long-chain acyl-CoA dehydrogenase mRNA levels in the breast muscle at 42 days of age. In conclusion, dietary supplementation with C. butyricum could potentially target caecal microbiota and reduced the breast muscle fatty acid oxidation of broilers.

Striated muscle gene therapy for the treatment of lipoprotein lipase deficiency.

Excessive circulating triglycerides due to reduction or loss of lipoprotein lipase activity contribute to hypertriglyceridemia and increased risk for pancreatitis. The only gene therapy treatment for lipoprotein lipase deficiency decreases pancreatitis but minimally reduces hypertriglyceridemia. Synthesized in multiple tissues including striated muscle and adipose tissue, lipoprotein lipase is trafficked to blood vessel endothelial cells where it is anchored at the plasma membrane and hydrolyzes triglycerides into free fatty acids. We conditionally knocked out lipoprotein lipase in differentiated striated muscle tissue lowering striated muscle lipoprotein lipase activity causing hypertriglyceridemia. We then crossed lipoprotein lipase striated muscle knockout mice with mice possessing a conditional avian retroviral receptor gene and injected mice with either a human lipoprotein lipase retrovirus or an mCherry control retrovirus. Post-heparin plasma lipoprotein lipase activity increased for three weeks following human lipoprotein lipase retroviral infection compared to mCherry infected mice. Human lipoprotein lipase infected mice had significantly lower blood triglycerides compared to mCherry controls and were comparable to wild-type blood triglyceride levels. Thus, targeted delivery of human lipoprotein lipase into striated muscle tissue identifies a potential therapeutic target for lipoprotein lipase deficiency.

Abstract 21251: Lipase Maturation Factor 1 Plays a Lipase-Independent Role in Energy Metabolism and Adiposity

Vascular lipases including lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL) are important determinants of plasma lipid homeostasis and coronary artery disease risk. The ER-resident lipase-chaperone Lipase Maturation Factor 1 (LMF1) plays a key role in the biogenesis of active vascular lipases and plasma lipid metabolism. While mice and humans harboring loss-of-function mutations in LMF1 exhibit deficiencies in all three vascular lipases and hypertriglyceridemia, detailed metabolic characterization of LMF1 deficiency has been hampered by the neonatal lethality of LMF1-/- mice. The goal of the present study was to investigate the metabolic consequences of combined lipase deficiency in the adult mouse. To overcome the lethality associated with whole-body LMF1 deficiency, we pursued a transgene rescue strategy involving cross-breeding of Mck-LMF1 transgenic and LMF1-/- mice. Mice expressing LMF1 exclusively in muscle tissue (Mck-LMF1-/-) exhibited normal survival and plasma lipid levels indicating that restoration of LPL activity in muscle only is sufficient to normalize plasma lipid metabolism in LMF1-/- mice. However, Mck-LMF1-/- mice also demonstrated decreased body weight (BW) and adiposity, reduced hepatic steatosis and improved insulin sensitivity; phenotypes that have not been observed in single-lipase deficient mouse models. Mechanistic studies revealed that decreased energy expenditure was responsible for diminished BW in Mck-LMF1-/- mice. To investigate the role of adipose tissue in this phenotype, we generated adipose-specific LMF1 knock-out (Ad-LMF1-KO) mice. While Ad-LMF1-KO mice exhibited hypertriglyceridemia, BW and adiposity remained unaffected indicating that adipose tissue was not the driver of lean phenotype in LMF1 deficiency. Furthermore, normolipemic heterozygous LMF1+/- mice exhibited lower BW and adiposity relative to wild-type littermates. Finally, we observed direct correlation between hepatic LMF1 expression and adiposity across ~100 inbred mouse strains in the Hybrid Mouse Diversity Panel. In conclusion, our results implicate hepatic LMF1 expression in energy metabolism and suggest that LMF1 plays a novel, lipase-independent role in metabolic regulation.

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.

Lipoprotein lipase activity does not predict very low-density lipoprotein-triglyceride fatty acid oxidation during exercise.

Exercise lowers plasma triglyceride levels, but the physiological mechanisms remain not fully elucidated. Lipoprotein lipase (LPL) is a key enzyme in facilitating fatty acid uptake from lipoproteins. As exercise increases the efficiency of very low-density lipoprotein-triglyceride (VLDL-TG) oxidation, we hypothesized that muscle LPL activity would be a rate-limiting step and predict VLDL-TG Fatty acids oxidation during exercise. Sixteen healthy, lean subjects (eight men and eight women) were examined before and during an acute exercise bout (90minutes at 50% of VO2-max). Heparin-releasable LPL activity was measured in muscle and adipose tissue biopsies. Breath 14 CO2 was measured after a primed-constant infusion of ex vivo labeled [14 C]-triolein VLDL-TG. Fractional VLDL-TG storage was measured in adipose tissue biopsies. Exercise did not affect muscle LPL activity (P=.30). No association was observed between muscle LPL activity and VLDL-TG oxidation, neither in the basal state (P=.17) nor during exercise (P=.83). Exercise did not affect upper body or lower body adipose tissue LPL activity (both P=.92). The basal adipose tissue fractional VLDL-TG storage (abdominal.13%±9%; femoral 17%±10% (P=.18)) was not associated with upper body (P=.56) or lower body (P=.44) subcutaneous adipose tissue LPL activity. Muscle LPL activity does not predict VLDL-TG oxidation during rest or exercise. In addition, adipose tissue LPL activity was not associated with VLDL-TG storage during rest. This suggests that LPL activity is present in excess of what is required to facilitate lipid uptake for oxidation during both rest and exercise.

Increased VLDL-TG Fatty Acid Storage in Skeletal Muscle in Men With Type 2 Diabetes.

Lipoprotein lipase (LPL) activity is considered the rate-limiting step of very-low-density-lipoprotein triglycerides (VLDL-TG) tissue storage, and has been suggested to relate to the development of obesity as well as insulin resistance and type 2 diabetes. The objective of the study was to assess the relationship between the quantitative storage of VLDL-TG fatty acids and LPL activity and other storage factors in muscle and adipose tissue. In addition, we examine whether such relations were influenced by type 2 diabetes. We recruited 23 men (12 with type 2 diabetes, 11 nondiabetic) matched for age and body mass index. Postabsorptive VLDL-TG muscle and subcutaneous adipose tissue (abdominal and leg) quantitative storage was measured using tissue biopsies in combination with a primed-constant infusion of ex vivo triolein labeled [1-14C]VLDL-TG and a bolus infusion of ex vivo triolein labeled [9,10-3H]VLDL-TG. Biopsies were analyzed for LPL activity and cellular storage factors. VLDL-TG storage rate was significantly greater in men with type 2 diabetes compared with nondiabetic men in muscle tissue (P = 0.02). We found no significant relationship between VLDL-TG storage rate and LPL activity or other storage factors in muscle or adipose tissue. However, LPL activity correlated with fractional VLDL-TG storage in abdominal fat (P = 0.04). Men with type 2 diabetes have increased VLDL-TG storage in muscle tissue, potentially contributing to increased intramyocellular triglyceride and ectopic lipid deposition. Neither muscle nor adipose tissue storage rates were related to LPL activity. This argues against LPL as a rate-limiting step in the postabsorptive quantitative storage of VLDL-TG.

SEDding Ourselves Up for Problems

SEDding Ourselves Up for Problems

Changes in activities and mRNA expression of lipoprotein lipase and fatty acid synthetase in large yellow croaker,Larimichthys crocea(Richardson), during fasting

Over-winter fasting and man-made food deprivation to increase meat quality are common in the process of large yellow croaker (Larimichthys crocea) aquaculture. This study aimed to determine the changes in lipoprotein lipase (LPL) and fatty acid synthetase (FAS) activities and mRNA expressions, and the relationships between these changes and fat content in large yellow croaker liver and muscle tissues during fasting. A total of 2933 bp LPL cDNA, including an open reading frame of 1533 bp encoding 510 amino acids, and a 1233 bp fragment of FAS cDNA coding 411 amino acids were cloned. Expressions of both genes were ubiquitous. During a 35-day fasting period, the hepatosomatic index and fat content in muscle and liver were significantly decreased (P < 0.05). mRNA levels of LPL increased significantly during the fasting period except the first 3 days, and FAS mRNA levels decreased significantly in both muscle and liver (P < 0.05) although there were some fluctuations. Muscle and liver LPL activities were significantly higher following fasting for 7 days, decreased to the initial value following fasting for 14 days, and elevating significantly afterwards (P < 0.05). FAS activities in muscle and liver maintained a significantly decreasing trend during the short-term fasting (P < 0.05) and kept obviously rising thereafter (P < 0.05). Activities and mRNA levels of both LPL and FAS were not always consistent, which implied that both pre-translational and post-translational regulations existed during fasting. Our results suggest that the reasonable fasting time is 21 days before harvesting when fat content decreased significantly.

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.

TRANS FATTY ACIDS MODIFY NUTRITIONAL PARAMETERS AND TRIACYLGLYCEROL METABOLISM IN RATS: DIFFERENTIAL EFFECTS AT RECOMMENDED AND HIGH-FAT LEVELS.

there is still little evidence on the metabolic trans fatty acids (TFA) effects at recommended fat levels. to investigate the differential TFA effects on some nutritional parameters, TFA retention, and triacylglycerol (TAG) regulation in rats fed recommended and high-fat diets. male Wistar rats were fed (30 days) diets containing recommended (7%,w/w) or high-fat (20%,w/w) levels, supplemented or not with TFA (C7, C20, TFA7 and TFA20). TFA7 (vs.C7) rats showed an increased body weight associated with higher fat pads and liver and serum TAG. The hypertriacylglyceridaemia was related to a decreased muscle LPL activity, while the higher hepatic TAG content was associated with both an increased SREBP-1c gene expression and ACC activity, and a reduced CPT-Ia gene expression. The TFA20 diet did not potentiate the higher body weight, fat pads and TAG levels induced by the C20 diet. Although the hepatic TAG-secretion rate (TAG-SR) increased by TFA20 vs. C20, the same triacylglyceridaemia was associated with a compensatory increase of the adipose tissue LPL activity. The attenuated hepatic TAG accretion in TFA20 was related to an increase of TAG-SR and to a lower increase of SREBP-1c and SCD1 mRNA expressions, paralleled to a relative decrease of SCD1 index and ACC activity. TFA alters nutritional parameters and lipid metabolism in rats. However, different responses to the TFA on TAG levels and their regulation were observed between rats fed recommended and high-fat diets. These divergences might be related to different tissue TFA retentions and rumenic acid bioconversion.

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.

Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice.

Diabetic hypertriglyceridemia is thought to be primarily driven by increased hepatic de novo lipogenesis. However, experiments in animal models indicated that insulin deficiency should decrease hepatic de novo lipogenesis and reduce plasma triglyceride levels. To address the discrepancy between human data and genetically altered mouse models, we investigated whether insulin-deficient diabetic mice had triglyceride changes that resemble those in diabetic humans. Streptozotocin-induced insulin deficiency increased plasma triglyceride levels in mice. Contrary to the mouse models with impaired hepatic insulin receptor signaling, insulin deficiency did not reduce hepatic triglyceride secretion and de novo lipogenesis-related gene expression. Diabetic mice had a marked decrease in postprandial triglycerides clearance, which was associated with decreased lipoprotein lipase and peroxisome proliferator-activated receptor α mRNA levels in peripheral tissues and decreased lipoprotein lipase activity in skeletal muscle, heart, and brown adipose tissue. Diabetic heterozygous lipoprotein lipase knockout mice had markedly elevated fasting plasma triglyceride levels and prolonged postprandial triglycerides clearance. Insulin deficiency causes hypertriglyceridemia by decreasing peripheral lipolysis and not by an increase in hepatic triglycerides production and secretion.

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.

D-Psicose increases energy expenditure and decreases body fat accumulation in rats fed a high-sucrose diet

We investigated the anti-obesity effects of d-psicose by increasing energy expenditure in rats pair-fed the high-sucrose diet (HSD). Wistar rats were divided into two dietary groups: HSD containing 5% cellulose (C) and 5% d-psicose (P). The C dietary group was further subdivided into two groups: rats fed the C diet ad libitum (C-AD) and pair-fed the C diet along with those in the P group (C-PF). Resting energy expenditure during darkness and lipoprotein lipase activity in the soleus muscle were significantly higher in the P group than in the C-PF group. Serum levels of glucose, leptin and adiponectin; glucose-6-phosphate dehydrogenase activities in the liver and perirenal adipose tissue; and body fat accumulation were all significantly lower in the P group than in the C-PF group. The anti-obesity effects of D-psicose could be induced not only by suppressing lipogenic enzyme activity but also by increasing EE in rats.

Adipose-specific Lipoprotein Lipase Deficiency More Profoundly Affects Brown than White Fat Biology

Adipose fat storage is thought to require uptake of circulating triglyceride (TG)-derived fatty acids via lipoprotein lipase (LpL). To determine how LpL affects the biology of adipose tissue, we created adipose-specific LpL knock-out (ATLO) mice, and we compared them with whole body LpL knock-out mice rescued with muscle LpL expression (MCK/L0) and wild type (WT) mice. ATLO LpL mRNA and activity were reduced, respectively, 75 and 70% in gonadal adipose tissue (GAT), 90 and 80% in subcutaneous tissue, and 84 and 85% in brown adipose tissue (BAT). ATLO mice had increased plasma TG levels associated with reduced chylomicron TG uptake into BAT and lung. ATLO BAT, but not GAT, had altered TG composition. GAT from MCK/L0 was smaller and contained less polyunsaturated fatty acids in TG, although GAT from ATLO was normal unless LpL was overexpressed in muscle. High fat diet feeding led to less adipose in MCK/L0 mice but TG acyl composition in subcutaneous tissue and BAT reverted to that of WT. Therefore, adipocyte LpL in BAT modulates plasma lipoprotein clearance, and the greater metabolic activity of this depot makes its lipid composition more dependent on LpL-mediated uptake. Loss of adipose LpL reduces fat accumulation only if accompanied by greater LpL activity in muscle. These data support the role of LpL as the "gatekeeper" for tissue lipid distribution.