Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

In animal models, STAT3 action in the hypothalamus and liver appears essential for normal body weight and glucose homeostasis in response to insulin. We hypothesized that variation in the STAT3 gene may be associated with body fat and/or insulin resistance in the general population. Five tagging SNPs spanning the STAT3 gene, rs8074524, rs2293152, rs2306580, rs6503695, and rs7211777 were genotyped in 2776 white female twins (mean age, 47.4+/-12.5 yrs) from the St Thomas' United Kingdom Adult Twin Registry (Twins UK). Minor allele frequencies were as follows: rs8074524 (0.19), rs2293152 (0.37), rs2306580 (0.06), rs6503695 (0.35), and rs7211777 (0.34). The minor allele of rs2293152 was associated with higher homeostasis model assessment index of insulin resistance (p=0.013) in the full cohort and confirmed in sib-transmission/disequilibrium test (TDT): (p=0.015; n=60). However, there were no associations with fasting serum insulin or glucose or with obesity variables. Although defective STAT3 action results in obesity and insulin resistance in animal models, we failed to establish any indicative associations with common SNPs in this human study.
Obesity (Silver Spring) 2007 Jul
PMID:Common STAT3 variants are not associated with obesity or insulin resistance in female twins. 1763 79

Maternal food restriction during pregnancy results in intrauterine growth-restricted (IUGR) newborns with significantly decreased plasma leptin levels. When nursed by ad libitum-fed controls, IUGR offspring exhibit hyperphagia with adult obesity, marked by increased percentage body fat and plasma leptin, suggesting altered anorexigenic pathways. The authors examined leptin signaling pathways and food intake responses to 2 putative anorexic effectors (leptin and sibutramine, a serotonin reuptake inhibitor) in IUGR offspring. From 10 days to term gestation and through lactation, control pregnant rats received ad libitum food, whereas study rats were 50% food restricted. Following birth, litter size was standardized, and all offspring were nursed by control dams. At 3 weeks of age, offspring were weaned to ad libitum laboratory chow. At ages 1 day and 3 weeks, hypothalamic leptin receptor (Ob-Rb) mRNA and total STAT3 protein expression were determined. In addition, phosphorylated STAT3 was measured in 1-day-old offspring administered peripheral leptin. In prepubescent and adult offspring, anorexic effects of leptin and sibutramine were determined. At 1 day of age, IUGR pups showed increased hypothalamic Ob-Rb mRNA and total STAT3 protein expression though reduced leptin activated phosphorylated STAT3. At 3 weeks of age, IUGR offspring had decreased hypothalamic Ob-Rb mRNA expression, although with continued elevated STAT3 protein levels. The IUGR offspring demonstrated resistance to anorexigenic agents, leptin (6 weeks and 6 months), and sibutramine (8 months), as evidenced by less reduction in food intake and less body weight loss than controls. The IUGR offspring demonstrate suppressed leptin-induced STAT3 phosphorylation and impaired anorexigenic response to 2 factors in the central satiety pathway. This reduced anorexigenic function, together with normal or perhaps enhanced orexigenic function, contributes to the development of programmed obesity in IUGR rat offspring.
...
PMID:Programmed hyperphagia due to reduced anorexigenic mechanisms in intrauterine growth-restricted offspring. 1764 5

Obesity is a risk factor for thoracic ossification of ligament flavum (TOLF) that is characterized by ectopic bone formation in the spinal ligaments. Hyperleptinemia is a common feature of obese people, and leptin, an adipocyte-derived cytokine with proliferative and osteogenic effects in several cell types, is believed to be an important factor in the pathogenesis of TOLF. However, how leptin might stimulate cell osteogenic differentiation in TOLF is not totally understood. We reported here that leptin-induced osteogenic effect in TOLF cells is associated with activation of signaling molecules STAT3, JNK, and ERK1/2 but not p38. Blocking STAT3 phosphorylation with a selective inhibitor, AG490, significantly abolished leptin-induced osteogenic differentiation of TOLF cells, whereas blocking ERK1/2 and JNK phosphorylation with their selective inhibitors PD98059 and SP600125, respectively, had only marginal effects. In addition, we showed that STAT3 interacted with Runt-related transcription factor 2 (Runx2) in the nucleus, and STAT3, Runx2, and steroid receptor coactivator steroid receptor coactivator-1 were components of the transcription complex recruited on Runx2 target gene promoters in response to leptin treatment. Our experiments identified STAT3, Runx2, and steroid receptor coactivator-1 as critical molecules in mediating leptin-stimulated cell osteogenesis in TOLF.
...
PMID:Mechanistic roles of leptin in osteogenic stimulation in thoracic ligament flavum cells. 1770 47

The adipose tissue-derived hormone leptin acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. LRb signaling via STAT3 and a number of other pathways is required for the totality of leptin action. The failure of elevated leptin levels to suppress feeding and mediate weight loss in common forms of obesity defines a state of so-called leptin resistance. A number of mechanisms, including the leptin-stimulated phosphorylation of Tyr(985) on LRb and the suppressor of cytokine signaling 3, attenuate leptin signaling and promote a cellular leptin resistance in obesity. Several unique features of the arcuate nucleus of the hypothalamus may contribute to the severity of cellular leptin resistance in this region. Other mechanisms that govern feeding behavior and food reward may also underlie the inception of obesity.
...
PMID:Mechanisms of leptin action and leptin resistance. 1793 1

Obesity is a major global health problem and is associated with low-grade inflammation and, in a number of cases, poor iron status. We speculated that the adipokine leptin might play a role in regulating iron metabolism in the overweight population because it shares a number of common biological features with IL-6, a major factor in the development of the anemia of chronic disease via its stimulatory actions on the production and release of the iron regulatory hormone hepcidin. To test this hypothesis, we exposed HuH7 human hepatoma cells to leptin and measured hepcidin mRNA expression by quantitative PCR. HuH7 cells were also transfected with a hepcidin promoter-luciferase reporter gene construct to investigate transcriptional regulation of hepcidin. In leptin-treated cells, hepcidin mRNA expression was enhanced significantly. Preincubation with a Janus kinase (JAK) 2 inhibitor significantly diminished this response. Hepcidin promoter activity was also increased in the presence of leptin. This effect was decreased either by mutation of the signal transducer and activator of transcription (STAT) 3 binding motif in the hepcidin promoter or by coexpressing a dominant-negative STAT3 mutant. These data suggest that leptin upregulates hepatic hepcidin expression through the JAK2/STAT3 signaling pathway. As a consequence, the increased production of leptin in overweight individuals might be a major contributor to the aberrant iron status observed in these population groups.
...
PMID:Leptin increases the expression of the iron regulatory hormone hepcidin in HuH7 human hepatoma cells. 1795 71

The proinflammatory cytokine interleukin (IL)-6 has been proposed to be one of the mediators that link obesity-derived chronic inflammation with insulin resistance. Signaling through the mammalian target of rapamycin (mTOR) has been found to impact insulin sensitivity under various pathological conditions, through serine phosphorylation and inhibition of insulin receptor substrate by the downstream effector of mTOR, ribosomal S6 kinase 1 (S6K1). However, an involvement of mTOR in IL-6-induced insulin resistance has not yet been reported. Here we show that rapamycin, the inhibitor of mTOR signaling, rescues insulin signaling and glycogen synthesis from IL-6 inhibition in HepG2 hepatocarcinoma cells as well as in mouse primary hepatocytes. IL-6 activates S6K1 in these cells, but unexpectedly, S6K1 is not involved in IL-6 inhibition of insulin signaling, since the effect of IL-6 persists in cells with drastically reduced S6K1 levels induced by RNA interference, suggesting that the function of mTOR signaling is through a mechanism different from the prevailing model of S6K1 phosphorylation of insulin receptor substrate-1. Interestingly, we find that the phosphorylation of STAT3 on Ser(727) and STAT3 transcriptional activity are regulated by mTOR upon IL-6 stimulation and that STAT3 is required for IL-6 inhibition of insulin signaling. Furthermore, IL-6-induced SOCS3 expression is inhibited by rapamycin, and ectopic expression of SOCS3 blocks the ability of rapamycin to enhance insulin sensitivity in the presence of IL-6. Taken together, we propose that mTOR plays a key role in IL-6-induced hepatic insulin resistance by regulating STAT3 activation and subsequent SOCS3 expression.
...
PMID:Regulation of interleukin-6-induced hepatic insulin resistance by mammalian target of rapamycin through the STAT3-SOCS3 pathway. 1799 46

Leptin enhances agonist-induced platelet aggregation, and human platelets have been reported to express the leptin receptor. However, the pathways and mediators lying downstream of leptin binding to platelets remain, with few exceptions, unknown. In the present study, we sought to gain further insight into the possible role of leptin as a platelet agonist. Stimulation of platelets with leptin promoted thromboxane generation and activation of alpha(IIb)beta(3), as demonstrated by PAC-1 binding. Furthermore, it increased the adhesion to immobilised fibrinogen (p<0.001) and induced cytoskeletal rearrangement of both platelets and Meg01 cells. Leptin time- and dose-dependently phosphorylated the intracellular signalling molecules JAK2 and STAT3, although the importance of STAT3 for leptin-induced platelet activation remains to be determined. Important intracellular mediators and pathways activated by leptin downstream of JAK2 were found to include phosphatidylinositol-3 kinase, phospholipase Cgamma2 and protein kinase C, as well as the p38 MAP kinase-phospholipase A(2) axis. Accordingly, incubation with the specific inhibitors AG490, Ly294002, U73122, and SB203580 prevented leptin-mediated platelet activation. These results help delineate biologically relevant leptin signalling pathways in platelets and may improve our understanding of the mechanisms linking hyperleptinaemia to the increased thrombosis risk in human obesity.
...
PMID:Leptin signalling and leptin-mediated activation of human platelets: importance of JAK2 and the phospholipases Cgamma2 and A2. 1800 Jun 12

Phosphatidylinositol 3-kinase (PI3K) pathway of leptin signaling plays an important role in transducing leptin action in the hypothalamus. Obesity is usually associated with resistance to the effect of leptin on food intake and energy homeostasis. Although central leptin resistance is thought to be involved in the development of diet-induced obesity (DIO), the mechanism behind this phenomenon is not clearly understood. To determine whether DIO impairs the effect of leptin on hypothalamic PI3K signaling, we fed 4-wk-old FVB/N mice a high-fat diet (HFD) or low-fat diet (LFD) for 19 wk. HFD-fed mice developed DIO in association with hyperleptinemia, hyperinsulinemia, and impaired glucose and insulin tolerance. Leptin (ip) significantly increased hypothalamic PI3K activity and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) levels in LFD-fed mice but not in DIO mice. Immunocytochemical study confirmed impaired p-STAT3 activation in various hypothalamic areas, including the arcuate nucleus. We next tested whether both PI3K and STAT3 pathways of leptin signaling were impaired during the early period of DIO. Leptin failed to increase PI3K activity in DIO mice that were on a HFD for 4 wk. However, leptin-induced p-STAT3 activation in the hypothalamus measured by Western blotting and immunocytochemistry remained comparable between LFD- and HFD-fed mice. These results suggest that the PI3K pathway but not the STAT3 pathway of leptin signaling is impaired during the development of DIO in FVB/N mice. Thus, a defective PI3K pathway of leptin signaling in the hypothalamus may be one of the mechanisms of central leptin resistance and DIO.
...
PMID:Hypothalamic phosphatidylinositol 3-kinase pathway of leptin signaling is impaired during the development of diet-induced obesity in FVB/N mice. 1804 92

Sympatho-adrenergic activity and the renin-angiotensin system are considered critical regulators of obesity and hypertension. The novel angiotensin II type 1 receptor-associated protein (ATRAP) has been demonstrated to modulate angiotensin II signalling in smooth muscle cells and cardiomyocytes. Adipose tissue expresses important renin angiotensin system components and contributes to cardiometabolic disease. However, ATRAP expression and regulation in adipocytes are unknown. We investigated expression of this novel modulator of angiotensin signalling and its regulation by beta-adrenergic receptors. We found ATRAP to be expressed in differentiated brown and white adipocytes. Stimulation of beta-adrenoceptors strongly suppressed ATRAP expression. We hypothesised a role for JAK/STAT signalling elements. Indeed, beta3-adrenergic stimulation robustly stimulated both STAT1 and STAT3 phosphorylation in a time- and dose-dependent manner. This effect was abrogated by inhibition of PKA and JAK2 signalling. Moreover, inhibition of JAK/STAT and PKA signalling reversed the beta3-adrenergic suppression of ATRAP expression. This study provides the first evidence for expression and adrenergic regulation of the angiotensin II signalling modulator ATRAP in adipocytes. Further, it indicates a novel regulatory link between beta-adrenergic and JAK/STAT signalling.
...
PMID:Expression of ATRAP in adipocytes and negative regulation by beta-adrenergic stimulation of JAK/STAT. 1823 61

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


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---