Catalytically Inactive Lipoprotein Lipase Overexpression Increases Insulin Sensitivity in Mice

Shibasaki, Manabu; Bujo, Hideaki; Takahashi, Kei; Murakami, Kaori; Unoki, Hiroyuki; Saitō, Yasushi

doi:10.1055/s-2006-949530

Cited by 10 publications

(9 citation statements)

References 19 publications

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“…It has been established that the G188E mutation inactivates the enzyme [20]. The mutant was His-tagged to allow detection by western blot and transduced into N41 cells using a retroviral vector.…”

Section: Resultsmentioning

confidence: 99%

Lipoprotein lipase is an important modulator of lipid uptake and storage in hypothalamic neurons

Libby

Wang

Mittal

et al. 2015

Biochemical and Biophysical Research Communications

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LPL is the rate-limiting enzyme for uptake of TG-derived FFA in peripheral tissues, and the enzyme is expressed in the brain and CNS. We previously created a mouse which lacks neuronal LPL. This animal becomes obese on a standard chow, and we observed reduced lipid uptake in the hypothalamus at 3 months preceding obesity. In our present study, we replicated the animal phenotype in an immortalized mouse hypothalamic cell line (N41) to examine how LPL affects expression of AgRP as well as entry and storage of lipids into neurons. We show that LPL is able to modulate levels of the orexigenic peptide AgRP. LPL also exerts effects on lipid uptake into culture neurons, and that uptake of neutral lipid can be enhanced even by mutant LPL lacking catalytic activity. N41 cells also accumulate neutral lipid in droplets, and this is at least in part regulated by LPL. These data in addition to those published in mice with neuron-specific deletion of LPL suggest that neuronal LPL is an important regulator of lipid homeostasis in neurons and that alterations in LPL levels may have important effects on systemic metabolism and neuronal lipid biology.

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Section: Resultsmentioning

confidence: 99%

Lipoprotein lipase is an important modulator of lipid uptake and storage in hypothalamic neurons

Libby

Wang

Mittal

et al. 2015

Biochemical and Biophysical Research Communications

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“…14 The cells were incubated in DMEM without serum for 2 h at 37 1C, and then either treated or not treated with 100 nM insulin for 15 min at 37 1C, as described previously. 18 After stimulation, 10 mM 2-[ 3 H]deoxyglucose was added and incubated for 5 min. Glucose uptake was stopped by the addition of ice-cold Krebs-Ringer HEPES buffer with 5 mM cytochalasin B and Macrophage MMP-3 for the function of adipocytes H Unoki et al 25 mM glucose.…”

Section: -Deoxyglucose Uptake Assaymentioning

confidence: 99%

Macrophages regulate tumor necrosis factor-α expression in adipocytes through the secretion of matrix metalloproteinase-3

et al. 2008

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Objective: Adipocytes accumulated in the visceral area change their function to induce tumor necrosis factor-a (TNF-a) secretion with concomitant matrix metalloproteinase (MMP)-3 induction in mice. This study was performed to clarify the role of macrophages (Mf)-secreted MMP on the functional changes in adipocytes using a culture system. Design: Cultures of 3T3-L1 adipocytes with THP-1 Mf or the Mf-conditioned medium were used to investigate the role of Mf-MMP on the TNF-a gene in 3T3-L1 adipocytes by the addition of MMP inhibitors. For animal experiments, male C57BL/6J mice were rendered insulin resistant by feeding a high-fat diet, and the expression of an Mf marker F4/80, and MMP-3 genes in mesenteric and subcutaneous fat tissue specimens were examined. Results: Mf-conditioned media (Mf-CM) increased the levels of TNF-a mRNA expression in 3T3-L1 adipocytes, and these adipocyte responses were abolished by treatment with GM6001, a broad-spectrum MMP inhibitor, or NNGH (N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid), an MMP-3 inhibitor. The activated form of MMP-3 enhanced glycerol release as well as TNF-a protein secretion from 3T3-L1 adipocytes. The incubation of adipocytes with MMP-3 inhibited insulin-induced glucose uptake in adipocytes. Furthermore, a high-fat intake increased the expression of MMP-3, decreased the insulin-induced glucose uptake of adipocytes and induced expression of F4/80 in mesenteric fat tissue of C57BL/6 mice. Conclusion: Mf may cause a pathological link with surrounding adipocytes through the secretion of MMP-3 followed by TNF-a expression in adipocytes in visceral fat tissue.

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“…LPL has also been implicated in INSR signaling, although the mechanism of this interaction is unclear (31,53).…”

Section: Common Genes 19mentioning

confidence: 99%

“…FOXO1A can in turn upregulate expression of LPL (27), an integral protein for chylomicron processing (24) and a proposed regulator of insulin signaling (31,53), thus providing a possible direct regulatory connection between transmembrane receptor activation/ signal transduction and the processes of chylomicron processing and insulin receptor signaling.…”

Section: Common Genes 19mentioning

confidence: 99%

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Prioritization of candidate disease genes for metabolic syndrome by computational analysis of its defining phenotypes

Tiffin

Okpechi

Perez‐Iratxeta

et al. 2008

Physiological Genomics

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Tiffin N, Okpechi I, Perez-Iratxeta C, Andrade-Navarro MA, Ramesar R. Prioritization of candidate disease genes for metabolic syndrome by computational analysis of its defining phenotypes. Physiol Genomics 35: 55-64, 2008. First published July 8, 2008 doi:10.1152/physiolgenomics.90247.2008.-There is a rapid increase in the world-wide burden of disease attributed to metabolic syndrome, as defined by co-occurrence of an array of phenotypes including abdominal obesity, dysglycemia, hypertriglyceridemia, low levels of high density lipoprotein cholesterol, and hypertension. Familial studies clearly indicate a genetic component to the disease and many linkage studies have identified a large number of linked loci. No disease-causing genes, however, have been conclusively identified, most likely because this is a multigenic disease for which effects of many causative genes may be small and combined with environmental effects. To assist empirical identification of metabolic syndrome associated genes, we present here a novel computational approach to prioritize candidate genes. We have used linkage studies and the clinical and population-specific presentation of the disease to select a final candidate gene list of 19 most likely disease-causing genes. These are predominantly involved in chylomicron processing, transmembrane receptor activity, and signal transduction pathways. We propose here that information about the clinical presentation of a complex trait can be used to effectively inform computational prioritization of disease-causing genes for that trait. candidate genes; complex disease METABOLIC SYNDROME IS AN INCREASINGLY common complex disease that is defined by co-occurrence of an array of metabolic phenotypes. These phenotypes have been classified in multiple ways (Ref. 2 and reviewed in Ref. 49) to provide a list of simple clinical markers that can diagnose individuals with the syndrome. The guidelines of the 2001 National Cholesterol Education Program-Adult Treatment Panel III are in common use and characterize metabolic syndrome as the co-occurrence of any three of the five following phenotypes: abdominal obesity, dysglycemia including insulin resistance/hyperinsulinemia, increased triglycerides, decreased high-density lipoprotein (HDL) cholesterol, hypertension (2,17,22,44). Currently, ϳ25% of North Americans are thought to be affected by metabolic syndrome (15). Obesity is the prevalent phenotype and is rising as a global epidemic (1) that is likely to result in a concurrent increase in metabolic syndrome incidence (42, 54) and related morbidity and mortality.Familial studies clearly indicate a heritable component to metabolic syndrome (reviewed in Ref. 49); however, multiple linkage studies have generated a large number of metabolic syndrome-associated loci (Supplementary Data File S1) 1 without subsequent identification of etiological genes. To date, existing approaches have in general failed to identify genes underlying complex diseases or traits such as metabolic syndrome, as they often present with ...

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Catalytically Inactive Lipoprotein Lipase Overexpression Increases Insulin Sensitivity in Mice

Cited by 10 publications

References 19 publications

Lipoprotein lipase is an important modulator of lipid uptake and storage in hypothalamic neurons

Lipoprotein lipase is an important modulator of lipid uptake and storage in hypothalamic neurons

Macrophages regulate tumor necrosis factor-α expression in adipocytes through the secretion of matrix metalloproteinase-3

Prioritization of candidate disease genes for metabolic syndrome by computational analysis of its defining phenotypes

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