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)

Tumor necrosis factor (TNF) alpha-induced adipose-related protein (TIARP) has recently been cloned as a TNFalpha-stimulated protein expressed in adipocytes. Its expression is differentiation-dependent and potentially involved in mediating TNFalpha-induced insulin resistance. To further characterize regulation of TIARP gene expression, 3T3-L1 adipocytes were treated with key hormones modulating insulin sensitivity and influencing adipocyte metabolism, and TIARP gene expression was determined by quantitative real-time RT-PCR. Interestingly, TIARP mRNA expression was stimulated almost 9-fold after 500 ng/ml GH were added for 16 h whereas addition of 10 microM isoproterenol, 100 nM insulin and 100 nM dexamethasone for 16 h significantly decreased TIARP gene expression to between 35 and 50% of control levels. In contrast, angiotensin 2 (10 microM) and triiodothyronine (1 microM) did not have any effect. The stimulatory effect of GH was time- and dose-dependent with stimulation occurring as early as 1 h after effector addition and at concentrations as low as 5 ng/ml GH. Moreover, pharmacological inhibition of Janus kinase 2 and p42/44 mitogen-activated protein kinase reversed the stimulatory effect of GH, suggesting that both signaling molecules are involved in activation of TIARP gene expression by GH. Furthermore, an increase of TIARP mRNA could be completely reversed to control levels by withdrawal of GH for 24 h. Taken together, these results show that TIARP is not only responsive to TNFalpha but also to important other hormones influencing glucose homeostasis and adipocyte metabolism. Thus, this factor may play an integrative role in the pathogenesis of insulin resistance and its link to obesity.
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PMID:GH is a positive regulator of tumor necrosis factor alpha-induced adipose related protein in 3T3-L1 adipocytes. 1296 43

The hypothalamus is a major site for integration of central and peripheral signals that regulate energy homeostasis. Within the hypothalamus, neurons residing in the ARC (arcuate nucleus)-PVN (paraventricular)-PF/LH (perifornical/lateral hypothalamus) axis communicate among each other and are subjected to the influence of several peripheral factors, including leptin and insulin. Proper signaling in the hypothalamus by leptin, a long-sought peripheral factor that relays the status of fat stores, is critical to normal regulation of food intake and body weight. Leptin action in the hypothalamus is mediated by a large number of orexigenic and anorectic peptide-producing neurons of the ARC-PVN-PF/LH axis. Not only the classical JAK2 (Janus kinase 2)-STAT3 (signal transducer and activator of transcription 3) pathway, but also the phosphatidylinositol-3 kinase-phosphodiesterase 3B-cAMP pathway mediates hypothalamic leptin receptor signaling. It appears that hypothalamic leptin resistance, possibly due to defective nutritional regulation of leptin receptor expression and/or reduced STAT3 signaling in the hypothalamus, contributes to the development of obesity associated with high-fat feeding and aging. Interestingly, hypothalamic neurons may develop leptin resistance despite an intact JAK2-STAT3 signaling path. The role of suppressor of cytokine signaling 3 and other negative regulators of leptin signaling in central leptin resistance needs to be established, an important area of future investigation. Further understanding of the neural circuitry and leptin signaling in the hypothalamus is critical not only for the advancement of our knowledge on the hypothalamic role in energy balance but also for future development of drugs for the attenuation or treatment of obesity and related disorders in humans.
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PMID:Minireview: A hypothalamic role in energy balance with special emphasis on leptin. 1504 60

Ciliary neurotrophic factor (CNTF), originally known for its involvement in the modulation of neuronal growth, has been discovered to exert anorexigenic effects and is currently being investigated in clinical studies for the treatment of obesity and insulin resistance. This neuropeptide acts on the central nervous system. However, we have recently demonstrated direct peripheral effects on adipocyte signalling and thermogenesis. Given the emerging endocrine role of adipose tissue in the regulation of energy homeostasis and insulin resistance, we investigated potential effects of CNTF on leptin expression and secretion. Our study demonstrates a direct inhibition of leptin expression and secretion by acute and chronic CNTF treatment. Furthermore, we demonstrate a differentiation- and Janus kinase 2 (JAK2)-independent, but phosphatidylinositol 3-kinase-dependent signalling pathway mediating this negative effect. These results provide novel evidence for a role of CNTF in the selective modulation of adipocyte endocrine function which may have important implications for the regulation of energy homeostasis.
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PMID:Ciliary neurotrophic factor influences endocrine adipocyte function: inhibition of leptin via PI 3-kinase. 1535 77

A chronic increase in systemic levels of acute-phase reactants contributes to the development of insulin resistance and associated disorders such as cardiovascular disease. Recently, serum amyloid A3 (SAA3) has been characterized as an adipocyte-secreted acute-phase reactant, expression of which is dramatically increased in insulin resistance and obesity. To further clarify expression and regulation of this adipocytokine in fat, SAA3 mRNA was measured by quantitative real-time reverse transcriptase PCR during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance and contribute to atherosclerosis. SAA3 mRNA was dramatically induced up to 77-fold during differentiation of 3T3-L1 preadipocytes. Furthermore, 100 nM dexamethasone and 30 ng/ml interleukin (IL)-6 induced SAA3 mRNA by up to 11- and 4.8-fold, respectively, in a time-dependent fashion with significant stimulation observed at concentrations as low as 10 nM dexamethasone and 1 ng/ml IL-6. In contrast, insulin, isoproterenol and growth hormone did not influence SAA3 synthesis. Inhibitor studies suggested that the positive effect of IL-6 on SAA3 expression is at least in part mediated by Janus kinase 2. Taken together, our results show a differential regulation of SAA3 by glucocorticoids and IL-6 supporting an integrative role of this acute-phase reactant in the pathogenesis of insulin resistance and its link to obesity and cardiovascular disease.
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PMID:Serum amyloid A3 expression is stimulated by dexamethasone and interleukin-6 in 3T3-L1 adipocytes. 1559 Sep 82

An elevated circulating level of the adipocyte-derived satiety hormone leptin is an independent risk factor for cardiovascular disease. Because thrombus formation is a major cause of acute coronary events and leptin was shown previously to facilitate ADP-induced platelet aggregation, we chose to define the signaling events involved in leptin-mediated platelet activation. Using pharmacological, biochemical, and cell biological approaches, we show that leptin-induced platelet activation required activation of a signaling cascade that included the long form of the leptin receptor, three kinases [Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (PKB/Akt)], the insulin receptor substrate-1 (IRS-1), and the major human platelet cAMP phosphodiesterase phosphodiesterase 3A (PDE3A). Moreover, we identify a role for an intraplatelet LEPR/JAK2/IRS-1/PI3K/PKB/PDE3A molecular complex that allows for the selective leptin-mediated activation of platelets. Our data demonstrate that leptin promotes platelet activation, provides a mechanistic basis for the prothrombotic effect of this hormone, and identifies a potentially novel therapeutic avenue to limit obesity-associated cardiovascular disease.
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PMID:Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex. 1588 25

The effects of leptin, in concentrations seen in obesity, on collagen production and turnover in non-immortalized human hepatic stellate cell (HSC), were unknown. The profibrogenic effects of leptin in these cells were studied. Hepatic stellate cells were obtained from resected livers. Collagen I/III gene expression and protein production were measured by quantitative real-time polymerase chain reaction and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, respectively. The signal transduction pathways involved were evaluated by specific blockers of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase kinase (MEK), and Janus kinase 2 (JAK2). The effects on matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were assessed by their gene transcript levels, collagenolytic activity of cell culture supernatants, and MMP-1 protein levels. At concentrations seen in nonobese individuals ([leptin] < 10 ng/mL), leptin did not affect collagen production. At concentrations seen in obesity (30-50 ng/mL), leptin increased collagen I and III messenger RNA (mRNA) transcript levels by 286% +/- 55% (P < .001) and 167% +/- 62% (P < .007) and protein production by 45.8% +/- .02% and 84.39% +/- .01%, respectively. These effects were blocked by JAK2 inhibition as well as PI3K inhibition. Although MEK inhibition blocked leptin-induced procollagen I and III mRNA levels, there were no significant effects on collagen I and III protein levels. Leptin (10-50 ng/mL) had no significant effects on MMP-1 or TIMP-1 mRNA levels, collagenolytic activity, or MMP-1 protein levels. In conclusion, leptin, at levels seen in obese individuals, produces an increase in collagen production by HSC acting through the JAK and PI3K pathways. At these concentrations, leptin does not affect MMP-1 or TIMP-1 expression or collagenolytic activity of HSC.
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PMID:Physiologic concentrations of leptin increase collagen production by non-immortalized human hepatic stellate cells. 1697 1

Adipose tissue plays a critical role in energy homeostasis, not only in storing triglycerides, but also responding to nutrient, neural, and hormonal signals and secreting adipokines that control feeding, thermogenesis, immunity, and neuroendocrine function. A rise in leptin signals satiety to the brain through receptors in hypothalamic and brainstem neurons. Leptin activates tyrosine kinase, Janus kinase 2, and signal transducer and activator of transcription 3, leading to increased levels of anorexigenic peptides, e.g., alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and inhibition of orexigenic peptides, e.g., neuropeptide Y and agouti-related peptide. Obesity is characterized by hyperleptinemia and hypothalamic leptin resistance, partly caused by induction of suppressor of cytokine signaling-3. Leptin falls rapidly during fasting and potently stimulates appetite, reduces thermogenesis, and mediates the inhibition of thyroid and reproductive hormones and activation of the hypothalamic-pituitary-adrenal axis. These actions are integrated by the paraventicular hypothalamic nucleus. Leptin also decreases glucose and stimulates lipolysis through central and peripheral pathways involving AMP-activated protein kinase (AMPK). Adiponectin is secreted exclusively by adipocytes and has been linked to glucose, lipid, and cardiovascular regulation. Obesity, diabetes, and atherosclerosis have been associated with reduced adiponectin levels, whereas adiponectin treatment reverses these abnormalities partly through activation of AMPK in liver and muscle. Administration of adiponectin in the brain recapitulates the peripheral actions to increase fatty acid oxidation and insulin sensitivity and reduce glucose. Although putative adiponectin receptors are widespread in peripheral organs and brain, it is uncertain whether adiponectin acts exclusively through these targets. As with leptin, adiponectin requires the central melanocortin pathway. Furthermore, adiponectin stimulates fatty acid oxidation and reduces glucose and lipids, at least in part, by activating AMPK in muscle and liver.
Obesity (Silver Spring) 2006 Aug
PMID:Adipose tissue as an endocrine organ. 1702 75

Obesity serves as an important risk factor for incidences of both cirrhotic and non-cirrhotic hepatocellular carcinoma (HCC), which is the third leading cause of cancer death worldwide. Leptin, the obesity biomarker molecule secreted systemically by body fat mass and locally by activated hepatic stellate cells, is proposed to play a certain role in HCC growth. Here, we show both proliferative and anti-apoptotic effects of leptin in HCC cells. Leptin stimulated cyclin D1 promoter activity to increase cyclin D1 protein expression, which accelerated the cell cycle progression. The reduced ratio between anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) Bcl-2 family proteins by transforming growth factor (TGF)-beta 1 caused HCC cells degradation of poly(ADP-ribose) polymerase and consequential apoptosis; whereas, leptin protected cells from apoptosis by reversing TGF-beta 1-reduced Bcl-2/Bax ratio as a result of down-regulating Bax. Any inhibitor specific for Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase 1/2 (ERK1/2) blocked these leptin functions. When intrahepatocytic JAK2 was activated by leptin, the active JAK2 afterward triggered a signaling cascade involving activations of PI3K/Akt and MEK/ERK1/2 in order of occurrence. As yet, in most cases, the crosstalks among signaling pathways primarily studied in diverse cancer cell types for mediating somatotropic effect of leptin are not well clarified and seem to be cell-type dependent. For the first time, our results demonstrate the direct effects of leptin on HCC growth and define its signal pathway with a crosstalking JAK2-PI3K/Akt-MEK/ERK1/2 connection. The identified hierarchy of intrahepatocytic leptin signaling pathway provides a clear basis potentially beneficial to make accurate and effectual strategies for facing both cirrhotic and non-cirrhotic liver carcinogenesis.
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PMID:Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway. 1763 64

The leptin signal is transduced via the JAK2-STAT3 (Janus kinase 2-signal transducer and activator of transcription-3) pathway at the leptin receptor. JAK2 also phosphorylates insulin receptor substrate, integral to insulin and leptin action and is required for optimum adenosine triphosphate-binding cassette transporter A1 (ABCA1)-dependent transport of lipids from cells to apolipoprotein A-1 (apoA-I). We hypothesized that common variation in the JAK2 gene may be associated with body fat, insulin sensitivity, and modulation of the serum lipid profile in the general population. Ten tagging single-nucleotide polymorphisms (SNPs) spanning the gene were genotyped in 2,760 white female twin subjects (mean age 47.3 +/- 12.6 years) from the St Thomas' UK Adult Twin Registry. Minor allele frequencies were between 0.170 and 0.464. The major allele of rs7849191 was associated with higher central fat (P = 0.030), percentage of central fat (P = 0.014) and waist circumference (P = 0.027) the major allele of rs3780378 with higher serum apoA (P = 0.026), total cholesterol (P = 0.014), low-density lipoprotein (LDL) cholesterol (P = 0.012) and lower triglyceride (P = 0.023). However, no associations were significant at a level which took account of multiple testing. Although JAK2 is a critical element in leptin and insulin signaling and has a role in cellular cholesterol transport, we failed to establish associations of common SNPs with relevant phenotypes in this human study.
Obesity (Silver Spring) 2008 Feb
PMID:Association of common JAK2 variants with body fat, insulin sensitivity and lipid profile. 1823 66

Levels of the obese gene product leptin are often elevated in obesity and may contribute to obesity-induced cardiovascular complications. However, the role of leptin in obesity-associated cardiac abnormalities has not been clearly defined. This study was designed to determine the influence of high-fat diet-induced obesity on cardiac contractile response of leptin. Mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix system in cardiomyocytes from adult rats fed low- and high-fat diets for 12 weeks. Cardiomyocyte contractile and intracellular Ca(2+) properties were examined including peak shortening, duration and maximal velocity of shortening/relengthening (TPS/TR(90), +/-dl/dt), Fura-2-fluorescence intensity change (DeltaFFI), and intracellular Ca(2+) decay rate (tau). Expression of the leptin receptor (Ob-R) was evaluated by western blot analysis. High-fat diet increased systolic blood pressure and plasma leptin levels. PS and +/-dl/dt were depressed whereas TPS and TR(90) were prolonged after high-fat diet feeding. Leptin elicited a concentration-dependent (0-1,000 nmol/l) inhibition of PS, +/-dl/dt, and DeltaFFI in low-fat but not high-fat diet-fed rat cardiomyocytes without affecting TPS and TR(90). The Janus kinase 2 (JAK2) inhibitor AG490, the mitogen-activated protein kinase (MAPK) inhibitor SB203580, and the nitric oxide synthase (NOS) inhibitor L-NAME abrogated leptin-induced cardiomyocyte contractile response in low-fat diet group without affecting the high-fat diet group. High-fat diet significantly downregulated cardiac expression of Ob-R. Elevation of extracellular Ca(2+) concentration nullified obesity-induced cardiomyocyte mechanical dysfunction and leptin-induced depression in PS. These data indicate presence of cardiac leptin resistance in diet-induced obesity possibly associated with impaired leptin receptor signaling.
Obesity (Silver Spring) 2008 Nov
PMID:High-fat diet-induced obesity leads to resistance to leptin-induced cardiomyocyte contractile response. 1871 78


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