Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metformin is an anti-diabetic drug with anorexigenic properties. The precise cellular mechanisms of its action are not entirely understood. Adipose tissue has recently been recognized as an important endocrine organ that is pivotal for the regulation of insulin resistance and energy homeostasis. Due to its thermogenic capacity brown adipose tissue contributes to the regulation of energy metabolism and is an attractive target tissue for pharmacological approaches to treating insulin resistance and obesity. Leptin is the prototypic adipocyte-derived hormone inducing a negative energy balance. We investigated effects of metformin on adipocyte metabolism, signalling, and leptin secretion in a brown adipocyte model. Metformin acutely stimulated p44/p42 mitogen-activated protein (MAP) kinase in a dose- (3.2-fold at 1 mmol/l, P< 0.05) as well as time-dependent (3.8-fold at 5 min, P< 0.05) manner. This stimulation was highly selective since phosphorylation of intermediates in the stress kinase, janus kinase (JAK)-signal transducer and activator of transcription (STAT), and phosphatidylinositol (PI) 3-kinase signalling pathways such as p38 MAP kinase, STAT3, and Akt was unaltered. Furthermore, chronic metformin treatment for 12 days dose-dependently inhibited leptin secretion by 35% and 75% at 500 mumol/l and 1 mmol/l metformin respectively (P< 0.01). This reduction was not caused by alterations in adipocyte differentiation. Moreover, the impairment in leptin secretion by metformin was reversible within 48 h after removal of the drug. Pharmacological inhibition of p44/p42 MAP kinase prevented the metformin-induced negative effect on leptin secretion. Taken together, our data demonstrate direct acute effects of metformin on adipocyte signalling and endocrine function with robust inhibition of leptin secretion. They suggest a selective molecular mechanism that may contribute to the anorexigenic effect of this antidiabetic compound.
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PMID:Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes. 1553 18

Increased expression of plasminogen activator inhibitor -1 (PAI-1) in adipose tissues is thought to contribute to both the cardiovascular and metabolic complications associated with obesity. Tumor necrosis factor alpha (TNF-alpha) is chronically elevated in adipose tissues of obese rodents and humans and has been directly implicated to induce PAI-1 in adipocytes. In this study, we used 3T3-L1 adipocytes to examine the mechanism by which TNF-alpha up-regulates PAI-1 in the adipocyte. Acute (3 h) and chronic (24 h) exposure of 3T3-L1 adipocytes to TNF-alpha induces PAI-1 mRNA by increasing the rate of transcription of the PAI-1 gene, and de novo protein synthesis is not required for this process. Although the p44/42 and PKC signaling pathways appear to be significant in the induction of PAI-1 mRNA in response to acute treatment with TNF-alpha, the more dramatic induction of PAI-1 mRNA observed in response to chronic exposure of adipocytes to TNF-alpha was mediated by these and additional signaling molecules, including p38, PI3-kinase, tyrosine kinases, and the transcription factor NF-kappaB. Moreover, the dramatic increase in PAI-1 observed after chronic exposure of adipocytes to TNF-alpha was accompanied by increased metabolic insulin resistance. Finally, we demonstrate that the PKC pathway is also central for PAI-1 induction in response to insulin and transforming growth factor-beta (TGF-beta), two additional molecules which are elevated in obesity and shown to directly induce PAI-1 in the adipocyte. The understanding of the mechanism of regulating PAI-1 expression in the adipocytes at the molecular level provides new insight to help identify novel targets in fighting the pathological complications of obesity.
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PMID:Molecular mechanisms of tumor necrosis factor-alpha-mediated plasminogen activator inhibitor-1 expression in adipocytes. 1592 93

Recently, adipose triglyceride lipase (ATGL, also called desnutrin and calcium-independent phospholipase A2 [iPLA(2)] zeta) was isolated as a novel adipose-expressed triglyceride lipase which is downregulated in obesity and may contribute to obesity-associated metabolic disorders such as hyperlipidemia and insulin resistance. To clarify expression and regulation of this fat-derived lipase, ATGL mRNA was measured in 3T3-L1 adipocytes by quantitative real-time reverse transcription-polymerase chain reaction after treatment with isoproterenol, tumor necrosis factor (TNF) alpha, insulin, and growth hormone (GH) which have been shown to influence lipolysis and insulin sensitivity profoundly. Interestingly, treatment of adipocytes with 100 nM isoproterenol, 30 ng/ml TNF alpha, and 100 nM insulin for 16 h significantly decreased ATGL mRNA to 74%, 17%, and 49% of control levels, respectively. GH did not influence ATGL synthesis. The effect of isoproterenol, TNFalpha, and insulin on ATGL expression was time- and dose-dependent. Similarly, HSL mRNA was downregulated by the three hormones. Furthermore, signaling studies suggested that activation of Gs-protein-coupled pathways by forskolin and cholera toxin is sufficient to significantly downregulate ATGL mRNA. Moreover, p44/42 mitogen-activated protein kinase appears to partly mediate the negative effect of insulin but not TNFalpha on ATGL. Taken together, downregulation of ATGL by isoproterenol, TNFalpha, and insulin might contribute to dysregulated expression and function of this lipase in obesity, hyperlipidemia, and insulin resistance.
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PMID:Isoproterenol, TNFalpha, and insulin downregulate adipose triglyceride lipase in 3T3-L1 adipocytes. 1600 85

It is well established that obesity is a risk factor for breast cancer and that blood levels of adiponectin, a hormone mainly secreted by white adipocytes, are inversely correlated with the body fat mass. As adiponectin elicits anti-proliferative effects in some cell types, we tested the hypothesis that adiponectin could influence human breast cancer MCF-7 cell growth. Here we show that MCF-7 cells express adiponectin receptors and respond to human recombinant adiponectin by reducing their growth, AMPkinase activation, and p42/p44 MAPkinase inactivation. Further, we demonstrate that the anti-proliferative effect of adiponectin involves activation of cell apoptosis and inhibition of cell cycle. These findings suggest that adiponectin could act in vivo as a paracrine/endocrine growth inhibitor towards mammary epithelial cells. Moreover, adipose adiponectin production being strongly reduced in obesity, this study may help to explain why obesity is a risk factor of developing breast cancers.
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PMID:Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. 1667 25

Various adipocytokines have been described which influence insulin sensitivity and vascular function profoundly and might, therefore, potentially link obesity, insulin resistance, and atherosclerosis. Among those, plasminogen activator inhibitor (PAI)-1 is an adipose-secreted factor upregulated in obesity and insulin resistance that inhibits fibrinolysis. Furthermore, recent studies in knockout mice suggest that PAI-1 directly impairs insulin sensitivity. In the current study, the impact of growth hormone (GH) and interleukin (IL)-6 on PAI-1 mRNA synthesis and secretion was determined in 3T3-L1 adipocytes. Interestingly, 500 ng/ml GH and 30 ng/ml IL-6 increased PAI-1 secretion five-fold and 3.6-fold, respectively. Furthermore, GH and IL-6 induced PAI-1 mRNA by up to 7.3-fold, and 3.6-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 5 ng/ml GH and 10 ng/ml IL-6. Other insulin resistance-inducing hormones which stimulated PAI-1 synthesis included insulin, TNFalpha, and dexamethasone. Studies using pharmacological inhibitors suggested that basal and GH-induced PAI-1 synthesis were at least in part mediated by p44/42 mitogen-activated protein kinase but not janus kinase 2 and phosphatidylinositol 3-kinase. Taken together, our results show a differential regulation of PAI-1 mRNA by insulin resistance-inducing hormones including GH and IL-6.
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PMID:Plasminogen activator inhibitor-1 expression and secretion are stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes. 1671 70

Several hormones that regulate nutritional status also impact on bone metabolism. Preptin is a recently isolated 34-amino acid peptide hormone that is cosecreted with insulin and amylin from the pancreatic beta-cells. Preptin corresponds to Asp(69)-Leu(102) of pro-IGF-II. Increased circulating levels of a pro-IGF-II peptide complexed with IGF-binding protein-2 have been implicated in the high bone mass phenotype observed in patients with chronic hepatitis C infection. We have assessed preptin's activities on bone. Preptin dose-dependently stimulated the proliferation (cell number and DNA synthesis) of primary fetal rat osteoblasts and osteoblast-like cell lines at periphysiological concentrations (>10(-11) M). In addition, thymidine incorporation was stimulated in murine neonatal calvarial organ culture, likely reflecting the proliferation of cells from the osteoblast lineage. Preptin did not affect bone resorption in this model. Preptin induced phosphorylation of p42/p44 MAP kinases in osteoblastic cells in a dose-dependent manner (10(-8)-10(-10) M), and its proliferative effects on primary osteoblasts were blocked by MAP kinase kinase inhibitors. Preptin also reduced osteoblast apoptosis induced by serum deprivation, reducing the number of apoptotic cells by >20%. In vivo administration of preptin increased bone area and mineralizing surface in adult mice. These data demonstrate that preptin, which is cosecreted from the pancreatic beta-cell with amylin and insulin, is anabolic to bone and may contribute to the preservation of bone mass observed in hyperinsulinemic states such as obesity.
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PMID:Preptin, another peptide product of the pancreatic beta-cell, is osteogenic in vitro and in vivo. 1691 56

In addition to its well known stimulation of cAMP production, the human melanocortin type 4 (hMC4) receptor recently has been shown to mediate p44/42 MAPK activation. This finding opens new questions about the structural and signaling mechanisms that connect the receptor to this alternate cell signaling pathway. Point mutants in the hMC4 receptor that have been associated with obesity were constructed and transfected into HEK 293 cells. Functional analyses then were done to determine if these mutations would similarly impact cAMP formation and p44/42 MAPK signaling. Whereas a D90N mutation in the second transmembrane domain and a D298A mutation in the seventh transmembrane domain impaired both cAMP formation and p44/42 MAPK activation, a more conservative D298N mutation retained cAMP formation but abolished p44/42 MAPK activation. The D298N mutation identified, for the first time, differential structural requirements of the hMC4 receptor for activation of the cAMP and p44/42 MAPK pathways. Furthermore, functional characterizations of a series of chimeric receptors combining the hMC4 receptor and the hMC3 subtype, a receptor that does not couple to p44/42 MAPK activation despite stimulating adenylyl cyclase, indicate that the hMC4 cytoplasmic tail is a necessary structural element for p44/42 MAPK signaling. Subsequent investigation of the signaling requirements for p44/42 MAPK activation demonstrated that the adenylyl cyclase inhibitor 2', 5'-dideoxyadenosine blocked agonist-induced p44/42 MAPK activation, but the PKA inhibitor Rp cAMPS did not. Taken together, these data indicate that cAMP is required, but not sufficient for p44/42 MAPK activation and suggest structural elements required for hMC4 receptor signaling.
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PMID:Structural and signaling requirements of the human melanocortin 4 receptor for MAP kinase activation. 1737 47

Leptin is elevated in obesity and has been suggested to increase the risk of colorectal cancer (CRC), although the evidence is conflicting. The objective of this study was to compare the susceptibility to colon carcinogenesis of db/db mice that have highly elevated circulating leptin and leptin-deficient ob/ob mice, both of which are obese. Seven-week-old male ob/ob, db/db, and WT mice received 4 weekly i.p. injections of 5 mg/kg azoxymethane (AOM) and were killed 14 wk later for the analysis of putative preneoplastic aberrant crypt foci (ACF). There were no differences in ACF number or multiplicity between ob/ob and db/db mice. Leptin has been shown to induce CYP2E1, the main enzyme that activates AOM, but we observed no differences in hepatic CYP2E1 activity or colonic CYP2E1 protein levels between ob/ob and db/db mice. We also induced ACF with 2 oral doses 3 d apart of 30 mg/kg methylnitrosourea (MNU), a direct-acting carcinogen. There were no differences in ACF number or multiplicity between the two groups of obese animals 5 wk following the last dose of MNU. The colonic mucosa of db/db mice expressed significantly lower mRNA levels of ObRa, the predominant short form of the leptin receptor, compared to ob/ob mice, and following i.p. injection with 1 mg/kg recombinant mouse leptin, exhibited significantly reduced p44/42 pMAPK compared to saline-treated controls. These results show that ObRa is functionally active in the colons of db/db mice. We conclude that leptin does not play a significant role in ACF development.
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PMID:Development of aberrant crypt foci in the colons of ob/ob and db/db mice: evidence that leptin is not a promoter. 1824 Feb 95

Protection against myocardial ischemia-reperfusion injury, including that induced by leptin, involves activation of the reperfusion injury salvage kinase pathway and inhibition of the mitochondrial permeability transition pore. In the current study, we explored the mechanisms underlying leptin-induced cardioprotection further with reference to the leptin receptor (OB-R) and obesity. We examined hearts from Wistar and Zucker lean rats that express functional OB-R and Zucker obese (fa/fa) rats with nonfunctional OB-R. In Langendorff experiments, leptin (10 nM) caused significant reductions in infarct size in hearts from Wistar (leptin treated, 32.4% +/- 3.9% vs. control, 53.2% +/- 3.2%, P < 0.01) and Zucker lean animals (leptin treated, 25.2% +/- 3.7% vs. control, 53.9% +/- 11.3%, P < 0.01). By contrast, hearts from (fa/fa) did not exhibit significant decreases in infarct size. Leptin increased p44 and p42 phosphorylation in Wistar rat hearts by 103.9% (P < 0.05) and 157.3% (P < 0.001), respectively, and by 97.0% (P < 0.05) and 158.1% (P < 0.05) in hearts from Zucker lean rats. Akt/serine-473 phosphorylation was increased in Wistar hearts by 96.7% (P < 0.05), whereas Akt/threonine-308 phosphorylation was elevated by 43.9% (P < 0.05) in Zucker lean rat hearts. Leptin did not influence Akt or p44/42 phosphorylation in (fa/fa) animals. On leptin treatment, mitochondrial permeability transition pore opening was delayed by 43% (P < 0.01) and 30.9% (P < 0.01), respectively, in cardiomyocytes from Wistar and Zucker lean rat hearts but not in cardiomyocytes from (fa/fa). This study provides the first evidence that myocardial sensitivity to the tissue preserving actions of leptin is influenced by adiposity and OB-R status.
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PMID:The cardioprotective actions of leptin are lost in the Zucker obese (fa/fa) rat. 1939 Mar 47

Visfatin is a proinflammatory and potentially insulin-mimetic adipokine contributing to whole body glucose and lipid metabolism, as well as atherosclerosis. Monocyte chemoattractant protein (MCP)-1 is an adipocyte-secreted protein which might play a crucial role in metabolic and vascular disease. MCP-1 expression and secretion after visfatin treatment were determined by quantitative real-time reverse transcription-PCR and enzyme-linked immunosorbent assay (ELISA) in fully differentiated human mesenchymal stem cell-derived adipocytes (hMSC-Ads) in vitro. In addition, circulating levels of MCP-1 and visfatin were quantified by ELISA in 60 patients (30 nondiabetic, 30 diabetic) and MCP-1 serum levels in mice were determined after visfatin treatment in vivo. Interestingly, protein secretion and mRNA production of MCP-1 were induced significantly in hMSC-Ads after visfatin stimulation. Visfatin-induced MCP-1 secretion 1.9-fold after 8 h and 2.5-fold after 24 h relative to untreated cells (P < 0.05). MCP-1 mRNA synthesis was significantly stimulated by visfatin with maximal upregulation detectable at 250 ng/ml visfatin and after 4 h of treatment. Signaling studies suggested that p44/42 mitogen-activated protein (MAP) kinase is involved in visfatin-induced MCP-1 mRNA expression in hMSC-Ads. Detectability of visfatin in serum predicted circulating MCP-1 independent of age and gender in humans in vivo. MCP-1 serum levels were significantly increased more than twofold after visfatin treatment in mice in vivo. Taken together, our results demonstrate that visfatin upregulates MCP-1 supporting a possible role of MCP-1 in mediating the proinflammatory effects of visfatin.
Obesity (Silver Spring) 2010 Aug
PMID:Visfatin is a positive regulator of MCP-1 in human adipocytes in vitro and in mice in vivo. 2003 81


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