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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetic nephropathy characterized by proteinuria and sclerosis is the leading cause of renal failure, but its mechanisms are not well understood. Zucker Obese (ZO) rat model of obesity, insulin resistance, and hypertension has been used to study nephropathy. We hypothesize that chronically elevated intrarenal angiotensin II (ANG II) down-regulates nephrin, a key slit-pore protein and up-regulates fibrogenic molecule transforming growth factor (TGFbeta1) and thus result in progression of nephropathy in type 2 diabetes. Untreated or angiotensin converting enzyme (ACE) inhibitor, captopril, treated ZO and control Lean (ZL) rats were used to measure intrarenal levels of ANG II, glomerular nephrin, TGFbeta1, collagen and fibronectin with age using radioimmunoassay, RT-PCR and immunoblot techniques. Progression of nephropathy was established by measuring proteinuria and sclerosis. ZO rats developed obesity, hyperglycemia, hyperinsulinimia, increase in intrarenal ANG II and proteinuria. Expression of glomerular nephrin decreased while expression of TGFbeta1 and matrix components increased in ZO rats. Captopril treatment prevented increase in intrarenal ANG II, and reversed expression of nephrin, TGFbeta1, collagen and fibronectin. We conclude that in this model of type 2 diabetic nephropathy, chronically elevated intrarenal ANG II causes proteinuria via decrease in nephrin and glomerulosclerosis via TGFbeta1 mediated increase in matrix component.
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PMID:Chronically increased intrarenal angiotensin II causes nephropathy in an animal model of type 2 diabetes. 1614 87

The diabetic heart shows increased fibrosis, which impairs cardiac function. Endothelin (ET)-1 and nuclear factor-kappaB (NF-kappaB) interactively regulate fibroblast growth. We have recently demonstrated that Punica granatum flower (PGF), a Unani anti-diabetic medicine, is a dual activator of peroxisome proliferator-activated receptor (PPAR)-alpha and -gamma, and improves hyperglycemia, hyperlipidemia, and fatty heart in Zucker diabetic fatty (ZDF) rat, a genetic animal model of type 2 diabetes and obesity. Here, we demonstrated that six-week treatment with PGF extract (500 mg/kg, p.o.) in Zucker diabetic fatty rats reduced the ratios of van Gieson-stained interstitial collagen deposit area to total left ventricular area and perivascular collagen deposit areas to coronary artery media area in the heart. This was accompanied by suppression of overexpressed cardiac fibronectin and collagen I and III mRNAs. Punica granatum flower extract reduced the up-regulated cardiac mRNA expression of ET-1, ETA, inhibitor-kappaBbeta and c-jun, and normalized the down-regulated mRNA expression of inhibitor-kappaBalpha in Zucker diabetic fatty rats. In vitro, Punica granatum flower extract and its components oleanolic acid, ursolic acid, and gallic acid inhibited lipopolysaccharide-induced NF-kappaB activation in macrophages. Our findings indicate that Punica granatum flower extract diminishes cardiac fibrosis in Zucker diabetic fatty rats, at least in part, by modulating cardiac ET-1 and NF-kappaB signaling.
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PMID:Pomegranate flower extract diminishes cardiac fibrosis in Zucker diabetic fatty rats: modulation of cardiac endothelin-1 and nuclear factor-kappaB pathways. 1630 13

We previously showed that the cysteine protease cathepsin S (CTSS), known to degrade several components of the extracellular matrix (ECM), is produced by human adipose cells and increased in obesity. Because ECM remodeling is a key process associated with adipogenesis, this prompted us to assess the potential role of CTSS to promote preadipocyte differentiation. Kinetic studies in primary human preadipocytes revealed a modest increase in CTSS gene expression and secretion at the end of differentiation. CTSS activity was maximal in preadipocyte culture medium but decreased thereafter, fitting with increased release of the CTSS endogenous inhibitor, cystatin C, during differentiation. Inhibition of CTSS activity by an exogenous-specific inhibitor added along the differentiation, resulted in a 2-fold reduction of lipid content and expression of adipocyte markers in differentiated cells. Conversely, the treatment of preadipocytes with human recombinant CTSS increased adipogenesis. Moreover, CTSS supplementation in preadipocyte media markedly reduced the fibronectin network, a key preadipocyte-ECM component, the decrease of which is required for adipogenesis. Using immunohistochemistry on serial sections of adipose tissue of obese subjects, we showed that adipose cells staining positive for CTSS are mainly located in the vicinity of fibrosis regions containing fibronectin. Herein we propose that CTSS may promote human adipogenesis, at least in part, by degrading fibronectin in the early steps of differentiation. Taken together, these results indicate that CTSS released locally by preadipocytes promotes adipogenesis, suggesting a possible contribution of this protease to fat mass expansion in obesity.
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PMID:Cathepsin s promotes human preadipocyte differentiation: possible involvement of fibronectin degradation. 1682 21

Obesity is considered a chronic low-grade inflammatory state. The white adipose tissue produces a variety of inflammation-related proteins whose expression is increased in obese subjects. The nonadipose cell fraction, which includes infiltrated macrophages, is a determinant source of inflammation-related molecules within the adipose tissue. Our working hypothesis is that macrophage infiltration affects fat expansion through a paracrine action on adipocyte differentiation. Human primary preadipocytes were then differentiated in the presence of conditioned media obtained from macrophages differentiated from blood monocytes. Preadipocytes treated by macrophage-conditioned medium displayed marked reduction of adipogenesis as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic and lipogenic markers. In addition to this effect, the activation of macrophages by lipopolysaccharides stimulated nuclear factor kappaB signaling, increased gene expression and release of proinflammatory cytokines and chemokines, and induced preadipocyte proliferation. This phenomenon was associated with increased cyclin D1 gene expression and maintenance of the fibronectin-rich matrix. Anti-TNFalpha neutralizing antibody inhibits the inflammatory state of preadipocytes positioning TNFalpha as an important mediator of inflammation in preadipocytes. Strikingly, conditioned media produced by macrophages isolated from human adipose tissue exerted comparable effects with activated macrophages, i.e. decreased adipogenesis and increased inflammatory state in the preadipocytes. These data show that macrophage-secreted factors inhibit the formation of mature adipocytes, suggesting possible role in limiting adipose tissue expansion in humans.
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PMID:Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes. 1708 59

Various epidemiologic studies have shown that obesity is associated with hepatocellular carcinoma. Leptin, the key player in the regulation of energy balance and body weight control, also acts as a growth factor on certain organs in both normal and disease states. It is plausible that leptin acts to promote hepatocellular carcinogenesis directly affecting malignant properties of liver cancer cells. However, a direct role for leptin in hepatocellular carcinoma has not been shown. In this study, we analyzed the role of leptin and the mechanism(s) underlying its action in hepatocellular carcinoma cells, which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of both HepG2 and Huh7 cells and involves activation of signal transducers and activators of transcription 3 (STAT3), AKT, and extracellular signal-regulated kinase (ERK) signaling pathways. Leptin-induced phosphorylation of ERK and AKT was dependent on Janus-activated kinase (JAK)/STAT activation. Intriguingly, we also found that leptin potently induces invasion of hepatocellular carcinoma cells in Matrigel invasion and electric cell-substrate impedance-sensing assays. Leptin-stimulated invasion was effectively blocked by pharmacologic inhibitors of JAK/STAT and, to a lesser extent, by ERK and phosphatidylinositol 3-kinase (PI3K) inhibition. Importantly, leptin also induced the migration of both HepG2 and Huh7 cells on fibronectin matrix. Inhibition of JAK/STAT, ERK, and PI3K activation using pharmacologic inhibitors effectively blocked leptin-induced migration of HepG2 and Huh7 cells. Taken together, these data indicate that leptin promotes hepatocellular carcinoma growth, invasiveness, and migration and implicate the JAK/STAT pathway as a critical mediator of leptin action. Our findings have potential clinical implications for hepatocellular carcinoma progression in obese patients.
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PMID:Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. 1736 67

White adipose tissue (WAT) in obese humans is characterized by macrophage accumulation the effects of which on WAT biology are not fully understood. We previously demonstrated that macrophage-secreted factors impair preadipocyte differentiation and induce inflammation, and we described the excessive fibrotic deposition in WAT from obese individuals. Microarray analysis revealed significant overexpression of extracellular matrix (ECM) genes in inflammatory preadipocytes. We show here an organized deposition of fibronectin, collagen I, and tenascin-C and clustering of the ECM receptor alpha5 integrin, characterizing inflammatory preadipocytes. Anti-alpha5 integrin-neutralizing antibody decreased proliferation of these cells, underlining the importance of the fibronectin/integrin partnership. Fibronectin-cultured preadipocytes exhibited increased proliferation and expression of both nuclear factor-kappaB and cyclin D1. Small interfering RNA deletion of nuclear factor-kappaB and cyclin D1 showed that these factors link preadipocyte proliferation with inflammation and ECM remodeling. Macrophage-secreted molecules increased preadipocyte migration through an increase in active/phosphorylated focal adhesion kinase. Gene expression and neutralizing antibody experiments suggest that inhibin beta A, a TGF-beta family member, is a major fibrotic factor. Interactions between preadipocytes and macrophages were favored in a three-dimensional collagen I matrix mimicking the fibrotic context of WAT. Cell-rich regions were immunostained for preadipocytes, proliferation, and macrophages in the vicinity of fibrotic WAT from obese individuals. In conclusion, an inflammatory environment leads to profound modifications of the human preadipocyte phenotype, producing fibrotic components with increased migration and proliferation. This phenomenon might play a role in facilitating the constitution of quiescent preadipocyte pools and eventually in the maintenance and aggravation of increased fat mass in obesity.
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PMID:Macrophage-secreted factors promote a profibrotic phenotype in human preadipocytes. 1894 11

Osteoarthritis (OA) is the most common form of arthritis worldwide. In this condition, damage to the extracellular matrix (ECM) of cartilage occurs, resulting in joint destruction. Factors mediating cartilage damage include mechanical injury, cytokine and superoxide release on a background of genetic susceptibility and obesity. Studies of arthritic cartilage show increased production of ECM molecules including type II collagen, cartilage oligomeric matrix protein, fibronectin (FN) and fibromodulin. Recent reports suggest that ECM proteins may become endogenous catabolic factors during joint damage. Activation of pro-inflammatory pathways by ECM proteins has led to their description as damage-associated molecular patterns (DAMPs). The ECM proteins involved include fibromodulin, which activates the complement pathway and may promote the persistence of joint inflammation. Fragmentation of type II collagen, FN and hyaluronan reveals cryptic epitopes that stimulate proteolytic enzymes including matrix metalloproteinases and aggrecanases (ADAMTSs - a disintegrin and metalloproteinase with thrombospondin type 1 motifs). Proteolytic fragments also stimulate the release of nitric oxide, chemokines and cytokines and activation of the MAP kinases. Reports are emerging that the receptors for the fragments described involve interaction with integrins and toll-like receptors. In this review the contribution of endogenous ECM molecules to joint destruction will be discussed. A deeper understanding of the pathways stimulated by endogenous ligands could offer potential avenues for novel therapies in the future.
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PMID:Analysing the role of endogenous matrix molecules in the development of osteoarthritis. 1976 1

Maternal obesity (MO) is increasing at an alarming rate. The objective of this study was to evaluate the effect of MO on fibrogenesis in fetal skeletal muscle during maturation in late gestation. Nonpregnant ewes were assigned to a control diet (Con; fed 100% of NRC nutrient recommendations, n = 6) or obesogenic diet (OB; fed 150% of NRC recommendations, n = 6) from 60 days before conception, and fetal semitendenosus (St) muscle was sampled at 135 days of gestation (term 148 days). Total concentration and area of collagen in cross-sections of muscle increased by 27.0 +/- 6.0 (P < 0.05) and 105.1 +/- 5.9% (P = 0.05) in OB compared with Con fetuses. The expression of precursor TGF-beta was 177.3 +/- 47.6% higher, and concentration of phospho-p38 74.7 +/- 23.6% was higher (P < 0.05) in OB than in CON fetal muscle. Increases of 327.9 +/- 168.0 (P < 0.05) and 188.9 +/- 82.1% (P < 0.05), respectively, were observed for mRNA expression of Smad7 and fibronectin in OB compared with Con muscles. In addition, enzymes involved in collagen synthesis, including lysyl oxidase, lysyl hydroxylase 2b, and prolyl 4-hydroxylase-alpha1, were increased by 350.2 +/- 90.0 (P < 0.05), 236.5 +/- 25.2 (P < 0.05), and 82.0 +/- 36.2% (P = 0.05), respectively, in OB muscle. In conclusion, MO-enhanced fibrogenesis in fetal muscle in late gestation was associated with upregulation of the TGF-beta/p38 signaling pathway. Enhanced fibrogenesis at such an early stage of development is expected to negatively affect the properties of offspring muscle because muscle fibrosis is a hallmark of aging.
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PMID:Enhanced transforming growth factor-beta signaling and fibrogenesis in ovine fetal skeletal muscle of obese dams at late gestation. 2037 34

1. Obesity is a metabolic disease of pandemic proportions largely arising from positive energy balance, a consequence of sedentary lifestyle, conditioned by environmental and genetic factors. Several central and peripheral neurohumoral factors (the major ones being the anorectic adipokines leptin and adiponecin and the orexigenic gut hormone ghrelin) acting on the anorectic (pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript) and orexigenic (neuropeptide Y and agouti gene-related protein) neurons regulate energy balance. These neurons, mainly in the arcuate nucleus of the hypothalamus, project to parts of the brain modulating functions such as wakefulness, autonomic function and learning. A tilt in the anorectic-orexigenic balance, perhaps determined genetically, leads to obesity. 2. Excess fat deposition requires space, created by adipocyte (hypertrophy and hyperplasia) and extracellular matrix (ECM) remodelling. This process is regulated by several factors, including several adipocyte-derived Matrix metalloproteinases and the adipokine cathepsin, which degrades fibronectin, a key ECM protein. Excess fat, also deposited in visceral organs, generates chronic low-grade inflammation that eventually triggers insulin resistance and the associated comorbidities of metabolic syndrome (hypertension, atherosclerosis, dyslipidaemia and diabetes mellitus). 3. The perivascular adipose tissue (PVAT) has conventionally been considered non-physiological structural tissue, but has recently been shown to serve a paracrine function, including the release of adipose-derived relaxant and contractile factors, akin to the role of the vascular endothelium. Thus, PVAT regulates vascular function in vivo and in vitro, contributing to the cardiovascular pathophysiology of the metabolic syndrome. Defining the mechanism of PVAT regulation of vascular reactivity requires more and better controlled investigations than currently seen in the literature.
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PMID:Obesity, metabolic syndrome, adipocytes and vascular function: A holistic viewpoint. 2108 97

After long-term estradiol deficiency, female rats displayed body mass gain accompanied by an increase in the size of adipocytes, an increase in hyperglycemia, and a decrease in insulinemia. The effects were reversed by daily estradiol treatment. Adiposity was suggested by the increased vascular endothelial growth factor expression in castrated rats, whereas the proliferative effect of estradiol was suggested by the increased fibronectin expression in treated rats.
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PMID:Fat tissue morphology of long-term sex steroid deficiency and estrogen treatment in female rats. 2131 40


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