Lipoprotein lipase: from gene to obesity

2009 ◽  
Vol 297 (2) ◽  
pp. E271-E288 ◽  
Author(s):  
Hong Wang ◽  
Robert H. Eckel
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Lipoprotein Lipase ◽  
Insulin Action ◽  
Specific Activity ◽  
Neutral Lipids ◽  
Specific Substrate ◽  
Tissue Specific

Lipoprotein lipase (LPL) is a multifunctional enzyme produced by many tissues, including adipose tissue, cardiac and skeletal muscle, islets, and macrophages. LPL is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins, chylomicrons, and very low-density lipoproteins (VLDL). LPL-catalyzed reaction products, fatty acids, and monoacylglycerol are in part taken up by the tissues locally and processed differentially; e.g., they are stored as neutral lipids in adipose tissue, oxidized, or stored in skeletal and cardiac muscle or as cholesteryl ester and TG in macrophages. LPL is regulated at transcriptional, posttranscriptional, and posttranslational levels in a tissue-specific manner. Nutrient states and hormonal levels all have divergent effects on the regulation of LPL, and a variety of proteins that interact with LPL to regulate its tissue-specific activity have also been identified. To examine this divergent regulation further, transgenic and knockout murine models of tissue-specific LPL expression have been developed. Mice with overexpression of LPL in skeletal muscle accumulate TG in muscle, develop insulin resistance, are protected from excessive weight gain, and increase their metabolic rate in the cold. Mice with LPL deletion in skeletal muscle have reduced TG accumulation and increased insulin action on glucose transport in muscle. Ultimately, this leads to increased lipid partitioning to other tissues, insulin resistance, and obesity. Mice with LPL deletion in the heart develop hypertriglyceridemia and cardiac dysfunction. The fact that the heart depends increasingly on glucose implies that free fatty acids are not a sufficient fuel for optimal cardiac function. Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and the many aspects of obesity and other metabolic disorders that relate to energy balance, insulin action, and body weight regulation.

2008 Robert Levy Memorial Lecture—Tissue-Specific Regulation of Lipoprotein Lipase and Energy Balance: The Story Gets Even More Interesting

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Robert Eckel
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Body Weight ◽  
Adipose Tissue ◽  
Weight Regulation ◽  
Body Weight Regulation ◽  
Tissue Specific ◽  
Specific Manner ◽  
The Brain

Lipoprotein lipase (LPL) is a multifunctional enzyme produced by and studied in many tissues, including adipose tissue, cardiac and skeletal muscle, islets, and macrophages. After synthesis by parenchymal cells, the lipase is transported to the capillary endothelium, where it is rate-limiting for the hydrolysis of the triglyceride (TG) core of the circulating TG-rich lipoproteins, chylomicrons, and very low density lipoproteins (VLDL). The reaction products, fatty acids and monoacylglycerol, are in part taken up by the tissues locally, where they are processed in a tissue-specific manner, e.g., stored as neutral lipids (TG > cholesteryl esters[CE]) in adipose tissue, oxidized or stored in muscle, or as CE/TG in foam cells in macrophages. LPL is regulated in a tissue-specific manner. In adipose tissue, LPL is increased by insulin and meals but decreased by fasting, whereas muscle LPL is decreased by insulin and increased by fasting. In obesity, adipose tissue LPL is increased; however, the insulin dose-response curve is shifted to the right. After weight reduction and stabilization of the reduced obese state, adipose tissue LPL is increased, as is the response of the enzyme to insulin and meals. In skeletal muscle, insulin does not stimulate LPL nor is the enzyme activity changed in obesity; however, after weight reduction, LPL in skeletal muscle is decreased by 70%. These tissue-specific changes in LPL set the stage for lipid partitioning to help explain the recidivism of obesity. To examine this divergent regulation further, transgenic and knockout murine models of tissue-specific LPL expression have been developed. Mice with overexpression of LPL in skeletal muscle develop TG accumulation in muscle, develop insulin resistance, are protected from excessive weight gain, and increase their metabolic rate in the cold. When placed onto the LPL knockout and leptin deficient background, overexpression of LPL using an MCK promoter reduces obesity. Alternatively, a deletion of LPL in skeletal muscle reduces TG accumulation and increases insulin-mediated glucose transport into muscle but leads to lipid partitioning to other tissues, insulin resistance, and obesity. In the heart, loss of LPL is associated with hypertriglyceridemia and a greater utilization of glucose, implying that free fatty acids are not a sufficient fuel for optimal cardiac function. LPL is also produced in the brain, and that’s where the “story gets even more interesting.” We have just created mice with a neuron-specific deletion of LPL (NEXLPL−/−) using cre recombinase driven by the helix-loop-helix nuclear transcription factor NEX promoter. By 6 months of age, NEXLPL−/− mice weigh 50% more than their litter mates. This phenotype provides convincing evidence that lipoprotein sensing occurs in the brain and is important to energy balance and body weight regulation. Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and to the many aspects of metabolism that relate to cardiovascular disease, including energy metabolism, insulin action, body weight regulation, and atherosclerosis.

Tissue-specific regulation of lipoprotein lipase by isoproterenol in normal-weight humans

1996 ◽  
Vol 271 (5) ◽  
pp. R1280-R1286 ◽  
Author(s):  
R. H. Eckel ◽  
D. R. Jensen ◽  
I. R. Schlaepfer ◽  
T. J. Yost
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Lipoprotein Lipase ◽  
Plasma Norepinephrine ◽  
Vastus Lateralis Muscle ◽  
Specific Response ◽  
Tissue Specific ◽  
Percent Change ◽  
Specific Regulation

Lipoprotein lipase (LPL) is a hydrolytic enzyme, involved in lipoprotein metabolism and nutrient partitioning, that is subject to tissue-specific regulation. Evidence for divergent regulation of the lipase by insulin has been demonstrated, but alterations in the tissue-specific response of LPL to catecholamines has not been studied in humans. The regulation of LPL in gluteal adipose tissue and vastus lateralis muscle by isoproterenol (epinephrine isopropyl homologue) in humans was examined over 2 h in subjects infused with 0 (saline) or 8 or 24 ng.kg-1.min-1 isoproterenol. The infusion of normal saline into control subjects failed to alter adipose tissue or skeletal muscle LPL activity. However, in the saline-infused subjects there was a positive correlation between the percent change in plasma norepinephrine concentrations and the percent change in muscle LPL activity (r = 0.826, P < 0.05). Isoproterenol infusion did not change LPL in either adipose tissue or muscle compared with saline-infused controls, but plasma insulin levels in addition to plasma glucose, free fatty acids, and glycerol were increased. To prevent the isoproterenol-induced hyperinsulinemia, a pancreatic clamp technique was utilized. An increase in muscle LPL was demonstrated (P = 0.037) with no change in adipose tissue LPL. The change in muscle LPL activity after the 2-h infusion correlated with the change in muscle mRNA (P = 0.021). Overall, these studies indicate that in humans the response of LPL to catecholamines is tissue specific with no effect in adipose tissue but a stimulation in skeletal muscle. Endogenous regulation of LPL in muscle by catecholamines could be important in muscle fuel metabolism and could relate to effects of adenosine 3',5'-cyclic monophosphate and/or fatty acids at the level of the LPL gene.

scholarly journals Interorgan Metabolic Crosstalk in Human Insulin Resistance

2018 ◽  
Vol 98 (3) ◽  
pp. 1371-1415 ◽  
Author(s):  
Sofiya Gancheva ◽  
Tomas Jelenik ◽  
Elisa Álvarez-Hernández ◽  
Michael Roden
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Short Chain Fatty Acids ◽  
Fatty Acid Esters

Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived from dietary intake or secreted from adipose tissue, gut, and liver contribute to energy homeostasis. Recent metabolomic studies identified novel metabolites and enlarged our knowledge on classic metabolites. This review summarizes the evidence of their roles as mediators of interorgan crosstalk and regulators of insulin sensitivity and energy metabolism. Circulating lipids such as free fatty acids, acetate, and palmitoleate from adipose tissue and short-chain fatty acids from the gut effectively act on liver and skeletal muscle. Intracellular lipids such as diacylglycerols and sphingolipids can serve as lipotoxins by directly inhibiting insulin action in muscle and liver. In contrast, fatty acid esters of hydroxy fatty acids have been recently shown to exert a series of beneficial effects. Also, ketoacids are gaining interest as potent modulators of insulin action and mitochondrial function. Finally, branched-chain amino acids not only predict metabolic diseases, but also inhibit insulin signaling. Here, we focus on the metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue.

The 1990 Borden Award Lecture Dietary regulation of fatty acid and triglyceride metabolism

1991 ◽  
Vol 69 (11) ◽  
pp. 1637-1647 ◽  
Author(s):  
Gene R. Herzberg
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Lipoprotein Lipase ◽  
Fatty Acid Synthesis ◽  
Dietary Fat ◽  
Acid Synthesis ◽  
Fish Oils ◽  
Dietary Fish

The level of circulating triacylglycerols is determined by the balance between their delivery into the plasma and their removal from it. Plasma triacylglycerols are derived either from dietary fat as chylomicrons or from endogenous hepatic synthesis as very low density lipoproteins. Their removal occurs through the action of lipoprotein lipase after which the fatty acids are either stored in adipose tissue or oxidized, primarily in skeletal muscle and heart. The composition of the diet has been shown to influence many of these processes. Hepatic fatty acid synthesis and triacylglycerol secretion are affected by the quantity and composition of dietary fat, carbohydrate, and protein. Polyunsaturated but not saturated fats reduce hepatic fatty acid synthesis by decreasing the amount of the lipogenic enzymes needed for de novo fatty acid synthesis. Dietary fish oils are particularly effective at reducing both fatty acid synthesis and triacylglycerol secretion and as a result are hypotriacylglycerolemic, particularly in hypertriacylglycerolemic individuals. In addition, dietary fish oils can increase the oxidation of fatty acids and lead to increased activity of lipoprotein lipase in skeletal muscle and heart. It appears that the hypotriacylglycerolemic effect of dietary fish oils is mediated by effects on both synthesis and removal of circulating triacylglycerols.Key words: lipid, fish oil, fructose, liver, adipose tissue, oxidation.

scholarly journals Muscle-specific overexpression of lipoprotein lipase in transgenic mice results in increased α-tocopherol levels in skeletal muscle

1996 ◽  
Vol 318 (1) ◽  
pp. 15-19 ◽  
Author(s):  
Wolfgang SATTLER ◽  
Sanja LEVAK-FRANK ◽  
Herbert RADNER ◽  
Gerhard M. KOSTNER ◽  
Rudolf ZECHNER
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Transgenic Mice ◽  
Cardiac Muscle ◽  
Lipoprotein Lipase ◽  
Excellent Correlation ◽  
Peripheral Tissues ◽  
Tissue Specific

Lipoprotein lipase (LPL) has been implicated in the delivery of chylomicron-located α-tocopherol (α-TocH) to peripheral tissues. To investigate the role of LPL in the cellular uptake of α-TocH in peripheral tissue in vivo, three lines of transgenic mice [mouse creatine kinase- (MCK) L, MCK-M and MCK-H] expressing various amounts of human LPL were compared with regard to α-TocH levels in plasma, skeletal muscle, cardiac muscle, adipose tissue and brain. Depending on the copy number of the transgene, LPL activity was increased 3- to 27-fold in skeletal muscle and 1.3- to 3.7-fold in cardiac muscle. The intracellular levels of α-TocH in skeletal muscle were significantly increased in MCK-M and MCK-H animals and correlated highly with the tissue-specific LPL activity (r = 0.998). The highest levels were observed in MCK-H (21.4 nmol/g) followed by MCK-M (13.3 nmol/g) and MCK-L (8.2 nmol/g) animals when compared with control mice (7.3 nmol/g). Excellent correlation was also observed between intracellular α-TocH and non-esterified fatty acid (NEFA) levels (r = 0.998). Although LPL activities in cardiac muscle were also increased in the transgenic mouse lines, α-TocH concentrations in the heart remained unchanged. Similarly, α-TocH levels in plasma, adipose tissue and brain were unaffected by the tissue specific overexpression of LPL in muscle. The transgenic model presented in this report provides evidence that the uptake of α-TocH in muscle is directly dependent on the level of LPL expression in vivo. Increased intracellular α-TocH concentrations with increased triglyceride lipolysis and NEFA uptake might protect the myocyte from oxidative damage during increased β-oxidation.

scholarly journals Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action

2009 ◽  
Vol 296 (6) ◽  
pp. E1300-E1310 ◽  
Author(s):  
Vijayalakshmi Varma ◽  
Aiwei Yao-Borengasser ◽  
Neda Rasouli ◽  
Greg T. Nolen ◽  
Bounleut Phanavanh ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Palmitic Acid ◽  
Vastus Lateralis ◽  
Nonesterified Fatty Acids ◽  
Muscle Inflammation ◽  
Human Myotubes ◽  
Phosphorylated Akt

Obesity is characterized by adipose tissue expansion as well as macrophage infiltration of adipose tissue. This results in an increase in circulating inflammatory cytokines and nonesterified fatty acids, factors that cause skeletal muscle insulin resistance. Whether obesity also results in skeletal muscle inflammation is not known. In this study, we quantified macrophages immunohistochemically in vastus lateralis biopsies from eight obese and eight lean subjects. Our study demonstrates that macrophages infiltrate skeletal muscle in obesity, and we developed an in vitro system to study this mechanistically. Myoblasts were isolated from vastus lateralis biopsies and differentiated in culture. Coculture of differentiated human myotubes with macrophages in the presence of palmitic acid, to mimic an obese environment, revealed that macrophages in the presence of palmitic acid synergistically augment cytokine and chemokine expression in myotubes, decrease IκB-α protein expression, increase phosphorylated JNK, decrease phosphorylated Akt, and increase markers of muscle atrophy. These results suggest that macrophages alter the inflammatory state of muscle cells in an obese milieu, inhibiting insulin signaling. Thus in obesity both adipose tissue and skeletal muscle inflammation may contribute to insulin resistance.

scholarly journals Insulin-stimulated glucose uptake in skeletal muscle, adipose tissue and liver: a positron emission tomography study

2018 ◽  
Vol 178 (5) ◽  
pp. 523-531 ◽  
Author(s):  
Miikka-Juhani Honka ◽  
Aino Latva-Rasku ◽  
Marco Bucci ◽  
Kirsi A Virtanen ◽  
Jarna C Hannukainen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Positron Emission Tomography ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Principal Component ◽  
Emission Tomography ◽  
Study Cohort ◽  
Tissue Specific ◽  
Positron Emission

Objective Insulin resistance is reflected by the rates of reduced glucose uptake (GU) into the key insulin-sensitive tissues, skeletal muscle, liver and adipose tissue. It is unclear whether insulin resistance occurs simultaneously in all these tissues or whether insulin resistance is tissue specific. Design and methods We measured GU in skeletal muscle, adipose tissue and liver and endogenous glucose production (EGP), in a single session using 18F-fluorodeoxyglucose with positron emission tomography (PET) and euglycemic–hyperinsulinemic clamp. The study population consisted of 326 subjects without diabetes from the CMgene study cohort. Results Skeletal muscle GU less than 33 µmol/kg tissue/min and subcutaneous adipose tissue GU less than 11.5 µmol/kg tissue/min characterized insulin-resistant individuals. Men had considerably worse insulin suppression of EGP compared to women. By using principal component analysis (PCA), BMI inversely and skeletal muscle, adipose tissue and liver GU positively loaded on same principal component explaining one-third of the variation in these measures. The results were largely similar when liver GU was replaced by EGP in PCA. Liver GU and EGP were positively associated with aging. Conclusions We have provided threshold values, which can be used to identify tissue-specific insulin resistance. In addition, we found that insulin resistance measured by GU was only partially similar across all insulin-sensitive tissues studied, skeletal muscle, adipose tissue and liver and was affected by obesity, aging and gender.

Prevention of diet-induced obesity in transgenic mice overexpressing skeletal muscle lipoprotein lipase

1997 ◽  
Vol 273 (2) ◽  
pp. R683-R689 ◽  
Author(s):  
D. R. Jensen ◽  
I. R. Schlaepfer ◽  
C. L. Morin ◽  
D. S. Pennington ◽  
T. Marcell ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Lipoprotein Lipase ◽  
Lipid Content ◽  
High Fat ◽  
Muscle Creatine Kinase ◽  
Plasma Triglycerides ◽  
Diet Induced Obesity ◽  
Fat Feeding

Transgenic (Tg) FVB/N mice were produced that overexpress human lipoprotein lipase (LPL) in skeletal muscle using the muscle creatine kinase promoter and enhancers. It was hypothesized that, by overexpressing LPL in muscle, high fat feeding-induced obesity would be prevented by diverting lipoprotein-derived triglyceride fatty acids away from storage in adipose tissue to oxidation in muscle. Mice were examined both at 6 wk of age before high fat (HF) feeding and at 19 wk of age after 13 wk of HF (46.1% fat) or high carbohydrate (HC) feeding (11.5% fat). At 6 wk in heterozygous Tg mice, LPL was increased 11-fold in white muscle and 2.5-fold in red muscle, but not in cardiac muscle or spleen, brain, lung, kidney, or adipose tissue. Plasma triglycerides (mg/dl) were lower in Tg mice (87 +/- 7 vs. 117 +/- 7, P < 0.0001), and glucose increased (201 +/- 9 vs. 167 +/- 8 mg/dl, P = 0.029). There were no differences in body weight between Tg and nontransgenic (nTg) mice; however, carcass lipid content (% body wt) was significantly decreased in male Tg mice at 6 wk (7.5 +/- 1.0 vs. 9.0 +/- 1.0%, P = 0.035). Body composition was not different in female Tg mice at 6 wk. Overall, when Tg mice were fed either a HC or HF diet for 13 wk, plasma triglycerides (P < 0.001) and free fatty acids (P < 0.001) were decreased, whereas plasma glucose (P = 0.01) and insulin (P = 0.05) were increased compared with nTg mice. HF feeding increased carcass lipid content twofold in both male (10.3 +/- 1.1 vs. 21.4 +/- 2.6%, HC vs. HF, P < 0.001) and female nTg mice (6.7 +/- 0.9 vs. 12.9 +/- 1.8%, P = 0.01). However, the targeted overexpression of LPL in skeletal muscle prevented HF diet-induced lipid accumulation in both Tg male (10.2 +/- 0.7 vs. 13.5 +/- 2.2%, HC vs. HF, P = NS) and female Tg mice (6.8 +/- 0.6 vs. 10.1 +/- 1.4%, P = NS). The potential to increase LPL activity in muscle by gene or drug delivery may prove to be an effective tool in preventing and/or treating obesity in humans.

scholarly journals Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity

2016 ◽  
Vol 310 (3) ◽  
pp. E190-E199 ◽  
Author(s):  
Young-Min Park ◽  
R. Scott Rector ◽  
John P. Thyfault ◽  
Terese M. Zidon ◽  
Jaume Padilla ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
High Capacity ◽  
Tissue Specific ◽  
Subcutaneous White Adipose Tissue ◽  
Brown Adipose ◽  
Glucose Clearance

High-capacity running (HCR) rats are protected against the early (i.e., ∼11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats ( n = 40; aged ∼22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3-3H]glucose was used to determine glucose clearance, whereas 2-[14C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR ( P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ∼40% greater gastrocnemius glucose uptake compared with LCR ( P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR ( P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance.

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