heparitin-sulfate and Obesity

To determine if endothelial dysfunction in a mouse model of diet-induced obesity and in obese humans is mediated by the suppression of endothelial Kir (inwardly rectifying K. We conclude that obesity-induced impairment of flow-induced vasodilation is attributed to the loss of flow-sensitivity of endothelial Kir channels and propose that the latter is mediated by the biophysical alterations of the glycocalyx.

Topics: Adult; Animals; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Female; Glycocalyx; Heparitin Sulfate; Humans; Male; Mechanotransduction, Cellular; Membrane Potentials; Mesenteric Arteries; Mice; Middle Aged; Obesity; Potassium Channels, Inwardly Rectifying; Regional Blood Flow; Vasodilation

We investigated the renoprotective effects of imidapril hydrochloride ((-)-(4 S)-3-[(2 S)-2-[[(1 S)-1-ethoxycarbonyl-3-phenylpropyl] amino] propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril), an angiotensin-converting enzyme inhibitor, in a diabetic animal model. We used BKS.Cg-+Lepr(db)/+Lepr(db) (db/db) mice, a genetic animal model of obese type 2 diabetes. Diabetic db/db mice suffered from glomerular hyperfiltration, albuminuria and hypoalbuminemia. Oral administration of 5 mg/kg/day of imidapril for 3 weeks suppressed renal hyperfiltration, reduced albuminuria and normalized hypoalbuminemia. Imidapril did not influence body weights, blood pressure or blood glucose concentrations in db/db mice. Urinary excretion of heparan sulfate (HS) in non-treated 11-week-old db/db mice was significantly lower than that in age-matched non-diabetic db/+m mice. HS is a component of HS proteoglycans, which are present in glomerular basement membranes and glycocalyx of cell surfaces. Reduced urinary HS excretion indicated glomerular HS loss in db/db mice. Imidapril increased urinary excretion of HS to concentrations observed in db/+m mice, indicating that imidapril prevented the loss of renal HS. These results suggest that imidapril ameliorates renal hyperfiltration and loss of renal contents of HS. Improvement of filtration function and maintenance of HS, which is an important structural component of glomeruli, may contribute to renoprotective effects of imidapril.

Topics: Administration, Oral; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Heparitin Sulfate; Humans; Hypoalbuminemia; Imidazolidines; Kidney Glomerulus; Mice; Mice, Inbred NOD; Obesity

We evaluated the presence/absence of proteins encoded by 14 077 genes in adipocytes obtained from different tissue samples using immunohistochemistry. By combining this with previously published adipocyte-specific proteome data, we identified proteins associated with 7340 genes in human adipocytes. This information was used to reconstruct a comprehensive and functional genome-scale metabolic model of adipocyte metabolism. The resulting metabolic model, iAdipocytes1809, enables mechanistic insights into adipocyte metabolism on a genome-wide level, and can serve as a scaffold for integration of omics data to understand the genotype-phenotype relationship in obese subjects. By integrating human transcriptome and fluxome data, we found an increase in the metabolic activity around androsterone, ganglioside GM2 and degradation products of heparan sulfate and keratan sulfate, and a decrease in mitochondrial metabolic activities in obese subjects compared with lean subjects. Our study hereby shows a path to identify new therapeutic targets for treating obesity through combination of high throughput patient data and metabolic modeling.

Topics: Adipocytes; Androsterone; Body Mass Index; G(M2) Ganglioside; Genome, Human; Heparitin Sulfate; Humans; Immunohistochemistry; Keratan Sulfate; Mitochondria; Models, Biological; Obesity; Proteome; Reproducibility of Results; Transcriptome

FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.

Topics: Animals; Cell Line, Tumor; Diabetes Mellitus, Type 2; Endocrine System; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heparitin Sulfate; Humans; Mice; Mice, Mutant Strains; Models, Biological; Obesity; Paracrine Communication; Signal Transduction