UMLS:C0028754 - FACTA Search

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

Disruption of the leptin signaling pathway within the heart causes left ventricular hypertrophy (LVH). Because human obesity is a syndrome of leptin resistance, which is not amenable to leptin treatment, the identification of parallel signal transduction pathways is of potential therapeutic value. Ciliary neurotrophic factor (CNTF), which acts parallel to leptin in the hypothalamus, is not previously recognized to have cardiac activity. We hypothesized that CNTF receptors are present on cardiomyocytes and their activation reverses LVH in both leptin-deficient ob/ob and leptin-resistant db/db mice. The localization of CNTF receptors (CNTFRalpha) to the sarcolemma in C57BL/6, ob/ob and db/db was confirmed in situ with immunohistochemistry, and immunoblotting (60 and 40 kDa) on isolated myocytes. ob/ob mice were randomly assigned to receive s.c. recombinant CNTF (CNTF(Ax15); 0.1 mg x kg(-1) per day; n = 11) calorie-restriction (n = 9), or feeding ad libitum (n = 11). db/db mice were allocated to three similar groups (n = 8, 7, and 8, respectively) plus a leptin group (1 mg x kg(-1) per day; n = 7). Echocardiography showed that CNTF(Ax15) reduced cardiac hypertrophy [posterior wall thickness decreased by 29 +/- 8% (P < 0.01) in ob/ob and by 21 +/- 3% in db/db mice (P < 0.01)], which was consistent with the reduction of myocyte width. Western blotting showed that leptin and CNTF(Ax15) activated Stat3 and ERK1/2 pathway in cultured adult mice cardiomyocytes and cardiac tissue from in ob/ob and db/db mice. Together, these findings support the role of a previously undescribed signaling pathway in obesity-associated cardiac hypertrophy and have therapeutic implications for patients with obesity-related cardiovascular disease and other causes of LVH.
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PMID:Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity. 1653 12

Hypertriglyceridemia is an important risk factor for atherosclerosis, especially in obesity. Macrophages are one of the primary cell types involved in atherogenesis and are thought to contribute to lesion formation through both lipid accumulation and proinflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride (TG)-rich VLDL-induced lipid accumulation on macrophage proinflammatory processes. Incubation of mouse peritoneal macrophages with 100 microg/ml VLDL for 6 h led to 2.8- and 3.7-fold increases in intracellular TGs and FFAs, respectively (P < 0.05). The inflammatory proteins tumor necrosis factor-alpha, interleukin-1beta, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein-1alpha (MIP-1alpha) were all upregulated by at least 2-fold (P < 0.05) in a dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory gene expression coincided with the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway members extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38 MAPK and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1alpha gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFAs and TGs, plays a substantive role in mediating the proinflammatory effects of VLDL. These data have important implications for the direct proatherogenic effects of VLDL on macrophage-driven atherosclerosis.
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PMID:The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages. 1663 77

Obesity has been recognized as a risk factor for breast cancer. Adipocyte-derived leptin may play as a paracrine regulator on the growth of breast cancer cells. Expression of both leptin and its OB-Rb receptor was detected in human breast cancer ZR-75-1 cells and further induced by leptin, suggesting that both expression and message mediation of leptin were autoregulated by itself. With cell counting and MTT assay, we had observed leptin stimulated ZR-75-1 growth in dose- and time-dependent manners. To study what steps of cell cycle progression leptin may involve in, we analyzed cell-cycle profile with flow cytometric analysis, mRNA and protein expressions of four cell-cycle regulators with RT-PCR and Western blotting analysis. Under the treatment of leptin, the G1 arrest of cells was reduced accompanied with up-regulation of G1 phase-specific cyclin D1 and proto-oncogene c-Myc, but down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and tumor suppressor p53. Furthermore, JAK2 inhibitor AG490, PI3K/Akt inhibitor Wortmannin, and MEK/ERK1/2 inhibitor PD98059 were efficiently prevented leptin-promoted cell growth. Effect of cooperation between leptin and estrogen on ZR-75-1 growth had been observed. Collectively, the results showed that the proliferative effect of leptin on ZR-75-1 was associated with the up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21(WAF1/CIP1) plausibly through a hypothesized JAK2-PI3K/Akt-MEK/ERK pathway. The leptin- and OB-Rb-expressing capability of ZR-75-1 created a possible autocrine control of leptin, in which signal could be effectively amplified by itself, on cell growth.
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PMID:Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1. 1675 79

Leptin is a 16 kDa product of the obesity gene secreted primarily by adipocytes. We recently identified cardiomyocytes as a target for the direct hypertrophic effects of leptin and suggested that leptin may be a biological link between obesity and cardiovascular pathologies. Activation of the renin-angiotensin and endothelin systems is associated with development of cardiovascular diseases and plasma renin levels are elevated in obese individuals. We therefore determined possible interaction between these factors in mediating hypertrophy in cultured neonatal rat ventricular myocytes. Treatment for 24 h with leptin (3.1 nM), angiotensin II (100 nM) or endothelin-1 (ET-1, 10 nM) significantly increased cell area by 37%, 36% and 35%, respectively and significantly increased gene expression of myosin light chain-2 and alpha-skeletal actin as well as leucine incorporation. The hypertrophic effects of all three agents were prevented by leptin and a leptin triple mutant receptor antagonist whereas the AT(1) receptor blocker (Sar1-lle(8))-Ang II or the ET(A) receptor blocker BQ123 was ineffective against leptin-induced hypertrophy. Both angiotensin II and ET-1 significantly increased leptin levels in the culture medium by fivefold. Moreover, both angiotensin II and ET-1 increased the gene expression of the short form (OBRa) by 180% and long form (OBRb) of leptin receptors by 200%, and this increase was abolished by both leptin receptor and leptin antibodies and leptin triple mutant. Although both angiotensin II and ET-1 increased phosphorylation of MAPK (p38, ERK1/2 and JNK) and NF-kappaB, the ability of leptin blockade to attenuate the hypertrophic responses was generally dissociated from these effects suggesting an alternate, yet to be identified cellular pathway mediating this role of leptin. Our studies therefore suggest a novel autocrine function for leptin in mediating the hypertrophic effects of both angiotensin II and ET-1 in cardiac myocytes.
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PMID:An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1. 1680 60

Adiponectin, the most abundantly synthesized protein in adipose tissue, has plieotropic effects on liver, muscle, endothelium, placenta, and other tissues. We examined direct effects of recombinant porcine adiponectin on porcine ovarian granulosa cells in vitro. We demonstrate that adiponectin, at physiologically relevant levels (10-25 microg/ml), provokes expression of genes associated with periovulatory remodeling of the ovarian follicle over a time frame of 6-24 h. These include cyclooxygenase-2, prostaglandin E synthase, and vascular endothelial growth factor. Adiponectin modulates steroid synthetic protein gene expression, increasing steroidogenic acute regulatory protein transcript abundance and reducing cytochrome P450aromatase. Adiponectin has antidiabetic properties and sensitizes tissues to insulin. We show that it interacts with both LH and insulin in inducing expression of cyclooxygenase-2 transcripts in granulosa cells. We determined that the MAPK pathway, via phosphorylation of ERK1/2, is involved in mediation of the adiponectin signal in ovarian granulosa cells, rather than protein kinase A or the classic adiponectin transducer, AMP-activated protein kinase. Adiponectin synthesis is reduced in obesity, and our findings suggest that this reduction plays a role in obesity-related ovarian dysfunction.
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PMID:Adiponectin induces periovulatory changes in ovarian follicular cells. 1691 53

The melanocortin-4 (MC4) receptor plays a pivotal role in regulating food intake and energy expenditure, and obesity results from mutations that interfere with the MC4 receptor pathway. We investigated the effect of glucocorticoids on endogenous MC4 receptors expressed in GT1-1 cells, an immortalized hypothalamic neuronal cell line. Dexamethasone (Dex) caused a 5- to 10-fold increase in the cAMP response to the MC4 receptor agonist, NDP-alphaMSH. The stimulatory effect of Dex reached a maximum within 24 h and was blocked by the glucocorticoid antagonist RU486. This glucocorticoid effect was specific for the MC4 receptor and not a result of up-regulation of another component of the cAMP cascade, because the response to endogenous beta-adrenergic receptor stimulation was not altered by Dex. Dex also potentiated NDP-alphaMSH-mediated ERK1/2 activation. After 12 h, Dex caused a 3- to 5-fold increase in [125I]NDP-alphaMSH binding, which was maintained for at least 48 h and prevented by RU486. Dex withdrawal caused a rapid return of MC4 receptor concentration to the basal level. Dex-mediated increases in MC4 receptor concentration resulted from a rapid but transient increase in MC4 receptor mRNA. This regulation apparently requires genomic regulatory sequences because Dex did not increase MC4 receptor expression or signaling in CHO cells expressing the MC4 receptor under the control of a cytomegalovirus promoter. We conclude that in GT1-1 hypothalamic neurons, glucocorticoids increase the amplitude of MC4 receptor signaling. This regulation may serve as a control to limit the effects of glucocorticoids on food intake.
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PMID:Regulation of endogenous melanocortin-4 receptor expression and signaling by glucocorticoids. 1697 23

Glucagon-like peptide-1 (GLP-1) is a potent insulin secretagogue released from L-cells in the intestine. Meat hydrolysate (MH) is a powerful activator of GLP-1 secretion in the human enteroendocrine NCI-H716 cell line, but the mechanisms involved in nutrient-stimulated GLP-1 secretion are poorly understood. The objective of this study was to characterize the intracellular signalling pathways regulating MH- and amino acid-induced GLP-1 secretion. Individually, the pharmacological inhibitors, SB203580 (inhibitor of p38 mitogen-activated protein kinase (MAPK)), wortmannin (inhibitor of phosphatidyl inositol 3-kinase) and U0126 (inhibitor of mitogen activated or extracellular signal-regulated protein kinase (MEK1/2) upstream of extracellular signal-regulated kinase (ERK)1/2) all inhibited MH-induced GLP-1 secretion. Further examination of the MAPK pathway showed that MH increased the phosphorylation of ERK1/2, but not p38 or c-Jun N-terminal kinase over 2-15 min. Incubation with SB203580 resulted in a decrease in phosphorylated p38 MAPK and a concomitant increase in the phosphorylation of ERK1/2. Phosphorylation of ERK1/2 was augmented by co-incubation of MH with SB203580. Inhibitors of protein kinase A and protein kinase C did not inhibit MH-induced GLP-1 secretion. In contrast to non-essential amino acids, essential amino acids (EAAs) increased GLP-1 secretion and similar to MH, activated ERK1/2. However, they also activated p38-suggesting type of protein may affect GLP-1 secretion. In conclusion, there appears to be a crosstalk between p38 and ERK1/2 MAPK in the human enteroendocrine cell with the activation of ERK1/2 common to both MH and EAA. Understanding the cellular pathways involved in nutrient-stimulated GLP-1 secretion has important implications for the design of new treatments aimed at increasing endogenous GLP-1 release in type-2 diabetes and obesity.
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PMID:Meat hydrolysate and essential amino acid-induced glucagon-like peptide-1 secretion, in the human NCI-H716 enteroendocrine cell line, is regulated by extracellular signal-regulated kinase1/2 and p38 mitogen-activated protein kinases. 1706 99

Obesity is often associated with diabetes and insulin resistance. This review summarizes evidence obtained in our lab on the role of the serine phosphorylation of the insulin receptor substrate 1 in the down regulation of insulin signalling. The role of the ERK1 isoform in the development of adipose tissue and insulin sensitivity is also presented.
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PMID:[Obesity, diabetes and insulin resistance. Alterations of insulin signalling]. 1714 67

Obesity has been implicated in several diseases, including cancer; however, the relationship of obesity and susceptibility to ultraviolet (UV) radiation-caused skin diseases has not been investigated. As UV-induced oxidative stress has been implicated in several skin diseases, we assessed the role of obesity on UVB-induced oxidative stress in genetically obese Lep(ob)/Lep(ob) (leptin-deficient) mice. Here, we report that chronic exposure to UVB (120 mJ/cm(2)) resulted in greater oxidative stress in the skin of obese mice in terms of higher levels of H(2)O(2) and NO production, photo-oxidative damage of lipids and proteins, and greater depletion of antioxidant defense enzymes, like glutathione, glutathione peroxidase, and catalase. As UV-induced oxidative stress mediates activation of MAPK and NF-kappaB signaling pathways, we determined the effects of UVB on these pathways in obese mice. Exposure of obese mice to UVB resulted in phosphorylation of ERK1/2, JNK, and p38 proteins of the MAPK family. Compared to wild-type mice, the obese mice exhibited higher levels of phosphorylation of these proteins, greater activation of NF-kappaB/p65, and higher levels of circulating proinflammatory cytokines, including TNF-alpha, IL-1beta and IL-6, on UVB irradiation. Taking these results together, our study suggests for the first time that obesity in mice is associated with greater susceptibility to UVB-induced oxidative stress and therefore may be a risk factor for skin diseases associated with UVB-induced oxidative stress.
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PMID:Obesity increases the risk of UV radiation-induced oxidative stress and activation of MAPK and NF-kappaB signaling. 1718 35

Obesity is a well-defined risk factor for the development of insulin resistance in target tissues, such as skeletal muscle, and thus type 2 diabetes. This may occur due to endocrine effects mediated by adipokines including leptin, the product of the obese (ob) gene, whose circulating levels positively correlate with body mass index. Induction of suppressor of cytokine-3 (SOCS-3) protein expression has been implicated as a possible mechanism of leptin-induced insulin resistance. Here, we show that treatment of rat skeletal muscle cells with leptin activated the SOCS-3 gene promoter and caused a time-dependent increase in both SOCS-3 mRNA and protein content. Confocal microscopy demonstrated increased co-localization of SOCS-3 with insulin receptor in leptin-treated cells and we confirmed a direct interaction between these two proteins by showing increased coimmunoprecipitation of SOCS-3 and insulin receptor after exposure of cells to leptin. However, the expected functional consequences were not observed, as we saw no change in basal or insulin-stimulated glucose uptake and phosphorylation of GSK3beta, Akt (T308 and S473) or ERK1/2. In summary, leptin induced SOCS-3 expression and its association with the insulin receptor in rat skeletal muscle cells but functional significance of this increase was not apparent upon measuring glucose uptake.
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PMID:Regulation of SOCS-3 expression by leptin and its co-localization with insulin receptor in rat skeletal muscle cells. 1722 56

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