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

Pathway specific resistance to insulin signaling through PI 3-kinase/Akt/eNOS associated with a normal or hyper-activated MAP kinase signaling in vascular tissues has recently been proposed as a candidate link between cardiovascular disease and insulin resistance. Growth stimulatory pathways other than ERK/MAP kinase, such as JAK/STAT have not yet been investigated in vessels of animal models of insulin resistance. Here we have examined whether insulin is able to activate JAK2/STAT pathway in rat aorta and also the regulation of this pathway in an animal model of obesity/insulin resistance. Our results demonstrate that insulin activates JAK2 tyrosine kinase activity in rat aorta in parallel with the activation of STAT3 and STAT5a/b. Moreover, it is shown that, in obese animals, JAK2/STAT and MAP kinase pathways are hyper-activated in response to insulin, which occurs in association with a reduced activation of PI 3-kinase/Akt pathway in aorta. The results of the present study suggest that, besides ERK/MAP kinase pathway, another potentially pro-atherogenic pathway, JAK2/STAT is hyper-activated in vessels in a state of insulin resistance and this phenomenon, in association with the inhibition of the PI 3-kinase/Akt pathway, may play an important role in the pathogenesis of cardiovascular diseases.
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PMID:Effect of obesity on insulin signaling through JAK2 in rat aorta. 1623 56

Most obese subjects exhibit leptin resistance, thus restricting the value of direct leptin administration for treatment of obesity. Understanding the leptin signalling mechanism has become crucial for design of novel therapeutic strategies for leptin-resistant/obese patients. The SH2-containing cytoplasmic tyrosine phosphatase Shp2 has recently been shown to play a critical role in leptin signalling and functions in hypothalamic control of energy balance and metabolism. Shp2 appears to downregulate the LepRb-STAT3 pathway while promoting extracellular-regulated kinase activation by leptin. Overall, Shp2 is a leptin signal enhancer, as evidenced by the obese and hyperleptinemic phenotype of mutant mice with Shp2 deleted in postmitotic forebrain neurons. Pharmaceutical enhancement of Shp2 activity may be a new approach worthy of consideration in clinical treatment of leptin resistance and obesity. This article discusses the significance of recent experimental data on Shp2 and also the prospects for using Shp2 as a therapeutic target for obese patients.
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PMID:Shp2 as a therapeutic target for leptin resistance and obesity. 1644 Dec 33

Increased visceral adipose tissue results in elevated plasma leptin, which are associated with increased risk of a number of obesity-related cancers. However, research is contradictory regarding the role of elevated plasma leptin in colon cancer risk. Having established that leptin induced proliferation in a murine model of preneoplastic (Apc(Min/+); IMCE) colon epithelial cells but not normal (Apc(+/+); YAMC) cells, we hypothesized that the leptin-associated IMCE cell proliferation was a result of autocrine interleukin-6 (IL-6) production and ensuing IL-6 receptor (IL-6R) signaling. Here we show, for the first time, that leptin induces elevated IL-6 production in IMCE cells but not in YAMC cells. IL-6 treatment induced cell proliferation in IMCE cells, but not in YAMC cells, in a concentration-dependent manner from 0.1 to 100 ng/ml (P < 0.05). Interleukin-6-induced IMCE cell proliferation was blocked by the addition of a neutralizing anti-IL-6R antibody. In addition, leptin-induced IMCE cell proliferation was blocked by the addition of an anti-IL-6R neutralizing antibody. Further, we elucidate a novel mechanism by which leptin activates TACE/ADAM17-associated IL-6R shedding and trans-IL-6 signaling in IMCE by induction of IL-6 production. IL-6 treatment of IMCE cells was associated with STAT3, ERK, p38, MEK and JAK2 activation and associated STAT3 nuclear activation and translocation. These data implicate leptin-induced IL-6 production, signaling and subsequent STAT3 activation as early events promoting the survival/proliferation of colon epithelial preneoplastic cells. The elucidation of the leptin-initiated mechanism of preneoplastic cell proliferation establishes a biologically plausible link between the adipocyte-specific cytokine leptin and obesity-associated colon cancer.
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PMID:Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line. 1659 43

AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance and of the effects of leptin on food intake and fatty acid oxidation. Obesity is usually associated with resistance to the effects of leptin on food intake and body weight. To determine whether diet-induced obesity (DIO) impairs the AMPK response to leptin in muscle and/or hypothalamus, we fed FVB mice a high fat (55%) diet for 10-12 weeks. Leptin acutely decreased food intake by approximately 30% in chow-fed mice. DIO mice tended to eat less, and leptin had no effect on food intake. Leptin decreased respiratory exchange ratio in chow-fed mice indicating increased fatty acid oxidation. Respiratory exchange ratio was low basally in high fat-fed mice, and leptin had no further effect. Leptin (3 mg/kg intraperitoneally) increased alpha2-AMPK activity 2-fold in muscle in chow-fed mice but not in DIO mice. Leptin decreased acetyl-CoA carboxylase activity 40% in muscle from chow-fed mice. In muscle from DIO mice, acetyl-CoA carboxylase activity was basally low, and leptin had no further effect. In paraventricular, arcuate, and medial hypothalamus of chow-fed mice, leptin inhibited alpha2-AMPK activity but not in DIO mice. In addition, leptin increased STAT3 phosphorylation 2-fold in arcuate of chow-fed mice, but this effect was attenuated because of elevated basal STAT3 phosphorylation in DIO mice. Thus, DIO in FVB mice alters alpha2-AMPK in muscle and hypothalamus and STAT3 in hypothalamus and impairs further effects of leptin on these signaling pathways. Defective responses of AMPK to leptin may contribute to resistance to leptin action on food intake and energy expenditure in obese states.
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PMID:Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. 1668 13

An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal basis and include breast, prostate, endometrium, colon and gall-bladder cancers. 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. Therefore, it is plausible that leptin acts to promote cancer growth by acting as a mitogenic agent. However, a direct role for leptin in endometrial cancer has not been demonstrated. In this study, we analyzed the proliferative role of leptin and the mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of ECC1 and Ishikawa cells. The promotion of endometrial cancer cell proliferation by leptin involves activation of STAT3 and ERK2 signaling pathways. Moreover, leptin-induced phosphorylation of ERK2 and AKT was dependent on JAK/STAT activation. Therefore blocking its action at the JAK/STAT level could be a rational therapeutic strategy for endometrial carcinoma in obese patients. We also found that leptin potently induces invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of JAK/STAT (AG490) and phosphatidylinositol 3-kinase (LY294002). Taken together these data indicate that leptin promotes endometrial cancer growth and invasiveness and implicate the JAK/STAT and AKT pathways as critical mediators of leptin action. Our findings have potential clinical implications for endometrial cancer progression in obese patients.
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PMID:Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways. 1672 88

Epidemiological studies show that the obstructive sleep apnea syndrome (OSAS) is strongly associated with obesity, hypertension and diabetes, the three conditions characteristic of the metabolic syndrome. Since metabolic disorders usually involve altered homeostatic mechanisms both centrally and peripherally, it is likely that so it is in OSAS, but the underlying mechanisms remain largely unknown. We used an established rodent model to test whether chronic intermittent hypoxia (CIH) similar to that experienced by OSAS patients leads to distinct and relevant for metabolic regulation transcriptional changes in the posterior hypothalamus. Using quantitative reverse transcription-polymerase chain reaction, we found that rats exposed to CIH for 35 days (n=9) had twice higher levels of the adrenergic alpha2A receptor mRNA than the rats simultaneously submitted to a matching sham treatment (n=9). The mRNA levels of three members of the family of signal transducers and activators of transcription, STAT1, STAT3 and STAT5b, were also increased 2-4 times. The increases occurred only in the perifornical region, whereas no changes were detected in the ventromedial region comprising the ventromedial and arcuate nuclei or the dorsomedial region comprising the dorsomedial and paraventricular nuclei. These results show that, at least at the transcriptional level, CIH exerts a distinct and regionally selective central effect on the expression of selected mRNAs involved in metabolic regulation through adrenergic, leptinergic and inflammatory pathways.
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PMID:Chronic intermittent hypoxia alters hypothalamic transcription of genes involved in metabolic regulation. 1673 Feb 40

Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.
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PMID:Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. 1673 81

The mechanisms of leptin resistance observed in most cases of human obesity are poorly understood. Therefore, we evaluated the effects of nitric oxide (NO) on the leptin-induced activation of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathways and on the leptin receptor (LEPR) expression using SH-SY5Y cells. Here, we show that the NO donor spermine/NONOate inhibited leptin-induced activation of STAT3 in vitro. The inhibition of leptin-mediated STAT3 phosphorylation caused by excessive NO was partially prevented by a sulfhydryl reducing agent, ascorbic acid. Cellular experiments show that reduced expression of long form leptin receptor (LEPR-b) and STAT3 protein instability induced by NO may be mechanisms of the NO-mediated inhibition of leptin-STAT3 signaling. We also present data showing that the hypothalamic NO content of high-fat (HF)-diet-induced obese mice was higher than that of control mice; this is likely caused by decreased caveolin-1 expression and increased nNOS expression induced by HF diet over 19 weeks. Concurrently with the overproduction of NO, the decrease of hypothalamic LEPR-b in obese mice also supports these in vitro data. Combined results suggest that excess of NO can induce the attenuation of leptin-mediated STAT3 activation through reduced expression of LEPR-b mRNA and instability of STAT3 protein at least in part. Furthermore, our in vivo data indicate that long-term HF diet induces hypothalamic overproduction of NO, which may be related with leptin insensitivity. However, further study is required to warrant direct in vivo evidence of a causal relationship between endogenous excess of hypothalamic NO and central leptin resistance.
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PMID:Excessive nitric oxide attenuates leptin-mediated signal transducer and activator of transcription 3 activation. 1709 87

One of the major manifestations of obesity is an increased production of the adipocyte-derived 16-kDa peptide leptin, which acts mainly on hypothalamic leptin receptors. Leptin receptors are widely distributed in various tissues, including the heart. Whereas increased plasma leptin levels have been reported in patients with congestive heart failure, systemic alterations induced by obesity can affect cardiac hypertrophy, and the direct effects of leptin on cardiac structure and function still remain to be determined. We first exposed primary cardiac myocytes from neonatal rats to leptin for 48 h. This resulted in a significant increase in myocyte long-axis length (P < 0.05 at 50 ng/ml) but not in the short-axis width. Leptin induced the rapid phosphorylation of STAT3 and its DNA binding in cardiac myocytes. Administration of a JAK2 inhibitor, AG-490, completely inhibited all of these effects by leptin. Furthermore, we examined the effect of continuous infusion of leptin for 4 wk following myocardial infarction in mice. Echocardiography demonstrated that left ventricular fractional shortening in the leptin-infused group (28.4 +/- 2.8%) was significantly higher than that in the PBS-infused group (18.4 +/- 2.2%) following myocardial infarction. Interestingly, left ventricular diastolic dimension in the leptin-infused group (4.56 +/- 0.12 mm) was also higher than that in the PBS-infused group (4.13 +/- 0.09 mm). These results demonstrate that leptin induces the elongation of cardiac myocytes via a JAK/STAT pathway and chronic leptin infusion causes eccentric dilatation with augmented systolic function after myocardial infarction.
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PMID:Leptin induces elongation of cardiac myocytes and causes eccentric left ventricular dilatation with compensation. 1722 Jan 91

Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNFalpha and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation.
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PMID:The dual function of hepatic SOCS3 in insulin resistance in vivo. 1729 35


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