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 CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction

2013 ◽  
Vol 305 (5) ◽  
pp. R522-R533 ◽  
Author(s):  
Jonathan M. Peterson ◽  
Zhikui Wei ◽  
Marcus M. Seldin ◽  
Mardi S. Byerly ◽  
Susan Aja ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Fat Oxidation ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
High Fat ◽  
Diet Induced Obesity

CTRP9 is a secreted multimeric protein of the C1q family and the closest paralog of the insulin-sensitizing adipokine, adiponectin. The metabolic function of this adipose tissue-derived plasma protein remains largely unknown. Here, we show that the circulating levels of CTRP9 are downregulated in diet-induced obese mice and upregulated upon refeeding. Overexpressing CTRP9 resulted in lean mice that dramatically resisted weight gain induced by a high-fat diet, largely through decreased food intake and increased basal metabolism. Enhanced fat oxidation in CTRP9 transgenic mice resulted from increases in skeletal muscle mitochondrial content, expression of enzymes involved in fatty acid oxidation (LCAD and MCAD), and chronic AMPK activation. Hepatic and skeletal muscle triglyceride levels were substantially decreased in transgenic mice. Consequently, CTRP9 transgenic mice had a greatly improved metabolic profile with markedly reduced fasting insulin and glucose levels. The high-fat diet-induced obesity, insulin resistance, and hepatic steatosis observed in wild-type mice were prevented in transgenic mice. Consistent with the in vivo data, recombinant protein significantly enhanced fat oxidation in L6 myotubes via AMPK activation and reduced lipid accumulation in H4IIE hepatocytes. Collectively, these data establish CTRP9 as a novel metabolic regulator and a new component of the metabolic network that links adipose tissue to lipid metabolism in skeletal muscle and liver.

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 Urtica dioica Whole Vegetable as a Functional Food Targeting Fat Accumulation and Insulin Resistance-a Preliminary Study in a Mouse Pre-Diabetic Model

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1059
Author(s):  
Si Fan ◽  
Samnhita Raychaudhuri ◽  
Olivia Kraus ◽  
Md Shahinozzaman ◽  
Leila Lofti ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Metabolism ◽  
High Fat Diet ◽  
Urtica Dioica ◽  
Whole Body ◽  
High Fat ◽  
Fat Accumulation ◽  
Diet Induced Obesity

The shoot of Urtica dioica is used in several cultures as a vegetable or herb. However, not much has been studied about the potential of this plant when consumed as a whole food/vegetable rather than an extract for dietary supplements. In a 12-week dietary intervention study, we tested the effect of U. dioica vegetable on high fat diet induced obesity and insulin resistance in C57BL/6J mice. Mice were fed ad libitum with isocaloric diets containing 10% fat or 45% fat with or without U. dioica. The diet supplemented with U. dioica attenuated high fat diet induced weight gain (p < 0.005; n = 9), fat accumulation in adipose tissue (p < 0.005; n = 9), and whole-body insulin resistance (HOMA-IR index) (p < 0.001; n = 9). Analysis of gene expression in skeletal muscle showed no effect on the constituents of the insulin signaling pathway (AKT, IRS proteins, PI3K, GLUT4, and insulin receptor). Notable genes that impact lipid or glucose metabolism and whose expression was changed by U. dioica include fasting induced adipocyte factor (FIAF) in adipose and skeletal muscle, peroxisome proliferator-activated receptor-α (Ppar-α) and forkhead box protein (FOXO1) in muscle and liver, and Carnitine palmitoyltransferase I (Cpt1) in liver (p < 0.01). We conclude that U. dioica vegetable protects against diet induced obesity through mechanisms involving lipid accumulation and glucose metabolism in skeletal muscle, liver, and adipose tissue.

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.

Chronic High-Fat Feeding and Middle-Aging Reduce in an Additive Fashion Glut4 Expression in Skeletal Muscle and Adipose Tissue

1997 ◽  
Vol 235 (1) ◽  
pp. 89-93 ◽  
Author(s):  
Lidia Sevilla ◽  
Anna Gumà ◽  
Gemma Enrique-Tarancón ◽  
Silvia Mora ◽  
Purificación Muñoz ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
High Fat ◽  
Glut4 Expression ◽  
Fat Feeding

Short-term resistance to diet-induced obesity in A/J mice is not associated with regulation of hypothalamic neuropeptides

2004 ◽  
Vol 287 (4) ◽  
pp. E662-E670 ◽  
Author(s):  
John W. Bullen ◽  
Mary Ziotopoulou ◽  
Linda Ungsunan ◽  
Jatin Misra ◽  
Ilias Alevizos ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Microarray Analysis ◽  
Energy Homeostasis ◽  
Uncoupling Protein ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Hypothalamic Neuropeptides ◽  
Fat Feeding

To investigate the mechanisms underlying long-term resistance of the A/J mouse strain to diet-induced obesity, we studied, over a period of 4 wk, the expression of uncoupling proteins in brown adipose tissue and the expression of hypothalamic neuropeptides known to regulate energy homeostasis and then used microarray analysis to identify other potentially important hypothalamic peptides. Despite increased caloric intake after 2 days of high-fat feeding, body weights of A/J mice remained stable. On and after 1 wk of high-fat feeding, A/J mice adjusted their food intake to consume the same amount of calories as mice fed a low-fat diet; thus their body weight and insulin, corticosterone, free fatty acid, and glucose levels remained unchanged for 4 wk. We found no changes in hypothalamic expression of several orexigenic and/or anorexigenic neuropeptides known to play an important role in energy homeostasis for the duration of the study. Uncoupling protein-2 mRNA expression in brown adipose tissue, however, was significantly upregulated after 2 days of high-fat feeding and tended to remain elevated for the duration of the 4-wk study. Gene array analysis revealed that several genes are up- or downregulated in response to 2 days and 1 wk of high-fat feeding. Real-time PCR analysis confirmed that expression of the hypothalamic IL-1 pathway (IL-1β, IL-1 type 1 and 2 receptors, and PPM1b/PP2C-β, a molecule that has been implicated in the inhibition of transforming growth factor-β-activated kinase-1-mediated IL-1 action) is altered after 2 days, but not 1 wk, of high-fat feeding. The role of additional molecules discovered by microarray analysis needs to be further explored in the future.

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.

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