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)

As ovariectomy induces obesity in rats, we have investigated the influence of ovariectomy and hormone replacement on the proliferation and differentiation capacities of rat cultured preadipocytes removed from different fat depots (femoral sc, parametrial, and perirenal). Ovariectomy induced increased proliferation and differentiation as well as high mitogen-activated protein (MAP) kinase activity and c-fos protein induction in both confluent and differentiated preadipocytes from perirenal fat depots. In parametrial preadipocytes, ovariectomy also increased proliferation and c-fos protein induction, but failed to alter the capacities of these cells to differentiate. Treatment of ovariectomized rats with estradiol and progesterone reversed the promoting effect of ovariectomy on proliferation, differentiation, and c-fos induction in perirenal preadipocytes, but not the MAP kinase activation observed during the proliferative phase. This treatment also reversed the promoting effect of ovariectomy on proliferation and c-fos induction seen in confluent parametrial preadipocytes. In contrast, sc preadipocytes were totally insensitive to ovarian status in terms of proliferation and differentiation capacities, MAP kinase activity, and c-fos induction. This study demonstrates that adipogenesis is site-specifically controlled by the ovarian status in the rat. It also suggests that ovariectomy-induced obesity (mainly abdominal) could be related to changes in some of the signaling pathways controlling adipogenesis in intraabdominal preadipocytes.
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PMID:Control of rat preadipocyte adipose conversion by ovarian status: regional specificity and possible involvement of the mitogen-activated protein kinase-dependent and c-fos signaling pathways. 920 10

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

Several recent studies indicate that type 2 diabetes, arterial hypertension, lipid disorders as well as visceral obesity are coronary risk factors which might belong to a syndrome which is caused by decreased insulin sensitivity with compensatory hyperinsulinaemia. More than 50% of patients with essential hypertension have some degree of insulin resistance, but in contrast to dyslipoproteinaemia and glucose intolerance the causal relation between insulin resistance and elevated arterial blood pressure appears not to be as evident. One explanation is that the link between blood pressure and insulin sensitivity might be mainly related to concomitant obesity. Accordingly, obesity can be associated with an increased activity of the sympathetic nervous system, elevated plasma levels of the vasoconstrictor endothelin-1, and decreased insulin-induced endothelium-dependent vasodilation. Furthermore, adipocytes can secrete vasogenic peptides, such as angiotensinogen. Since insulin resistance is a polygenic disorder, the two basic genetic approaches we follow is to identify genetic defects of insulin action in cells of patients with inherited syndromes of insulin resistance and to characterize molecular mechanisms of insulin regulated gene expression. The results show that insulin can affect the expression rate of various genes, e.g. involved in cholesterol and fatty acid metabolism, by modulating the activity of transcription factors coupled to the MAP kinase cascade and that a genetic postreceptor defect in these intracellular signaling pathways might have a pleiotropic effect on cell metabolism and clinical phenotype.
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PMID:Metabolic syndrome and hypertension: pathophysiology and molecular basis of insulin resistance. 983 75

Insulin resistance is central to the pathophysiology of type 2 diabetes. It has been known for some time that down-regulation and reduced kinase activity of the insulin receptor play a role in insulin resistance; however, it has recently emerged that defects in the intracellular responses to insulin are also very important. We studied the molecular basis of insulin resistance in mice in which injection with gold thioglucose led to the development of hyperphagia, obesity and insulin resistance over a 4-month period. We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. Similarly, we investigated insulin-stimulated PI3-kinase activation in the isolated soleus muscle of lean and obese mice, and found a marked reduction in the PI3-kinase activation of obese animals. The magnitude of the effect was greater than the reduction in insulin receptor activation, suggesting that impairment of PI3-kinase activation is a very important element in the development of insulin resistance in obese mice. In keeping with this, we found that the defect in PI3-kinase activation developed in young obese mice before the emergence of overt insulin resistance. We investigated different mechanisms by which defects in the components of the insulin signalling cascade could emerge, including down-regulation and abnormal phosphorylation of signal molecules. In adipocytes from young obese mice in which insulin resistance had not yet developed, we found that there were already marked defects in IRS-1 tyrosine phosphorylation. Increased IRS-1 phosphorylation on serine and threonine residues affects tyrosine phosphorylation. Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. We found that brief exposure of 3T3-L1 adipocytes to platelet-derived growth factor led to IRS-1 serine/threonine phosphorylation through a PI3-kinase-dependent pathway, and that this prevented phosphorylation of the tyrosine residues of IRS-1. Such a mechanism, induced by growth factors, TNF-alpha or some other agent, may play an important role in the development of insulin resistance in obese mice.
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PMID:Molecular mechanisms of insulin action in normal and insulin-resistant states. 1032 50

There is a very close interrelationship between the metabolic disorders such as obesity and diabetes mellitus and cardiovascular diseases such as hypertension and atherosclerosis, with insulin resistance and endothelial dysfunction as common features. Insulin has vasculoprotective effects through production of nitric oxide in the endothelial cells, while it produces atherogenic effects by stimulating proliferation and migration of vascular smooth muscle cells(VSMC). The insulin-activated pathway is the phosphatidylinositol 3-kinase pathway in the endothelial cells and MAP kinase pathway in the VSMC. Insulin resistance and hyperinsulinemia may result in the attenuation of the endothelium-mediated action and stimulation of the VSMC-mediated action. Insulin resistance and endothelial dysfunction are related to each other and may cause vicious cycle, leading to the metabolic and cardiovascular diseases.
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PMID:[Insulin resistance and vascular function]. 1070 56

Cross-talk between insulin and the adrenergic system is important in the regulation of energy homeostasis. In cultured, differentiated mouse brown adipocytes, beta3-adrenergic stimulation induced a 4.5-fold increase in uncoupling protein-1 (UCP-1) expression, which was diminished by 25% in the presence of insulin. Beta3-adrenergic stimulation also activated mitogen-activated protein (MAP) kinase by 3.5-fold and caused a decrease in basal phosphoinositide (PI) 3-kinase activity detected in p110gamma- and Gbeta-subunit-immunoprecipitates in a time-dependent manner, whereas insulin stimulated p110alpha- and phosphotyrosine-associated PI 3-kinase activity. Inhibition of MAP kinase or PI 3-kinase potentiated the beta3-adrenergic effect on UCP-1 expression, both alone and in the presence of insulin. Thus, insulin inhibits beta3-adrenergic stimulation of UCP-1, and both MAP kinase and PI 3-kinase are negative regulatory elements in the beta3-adrenergic control of UCP-1 expression. Cross-talk between the adrenergic and insulin signaling systems and impaired regulation of UCP-1 might contribute to the development of a reduced energy balance, resulting in obesity and insulin resistance.
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PMID:Insulin and the beta3-adrenoceptor differentially regulate uncoupling protein-1 expression. 1084 79

Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.
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PMID:Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. 1101 58

Tumor necrosis factor-alpha (TNFalpha) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. Previous studies have demonstrated that TNFalpha confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFalpha-stimulated IRS-1 serine phosphorylation. In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFalpha. Additional experiments show that MEK1/2 activity is required for TNFalpha-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling. We observe that TNFalpha requires 2.5-4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. Although TNFalpha activates p42/44 MAP kinase, maximal stimulation is observed within 10-30 min. To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFalpha-induced p42/44 activity. Chronic TNFalpha treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. We observe that this longer term TNFalpha-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways. This study suggests that TNFalpha-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway.
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PMID:Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. 1104 72

The beta-adrenergic receptors (betaARs) are members of the large family of G protein-coupled receptors. There are three betaAR subtypes (beta1AR, beta2AR beta3AR), each of which is coupled to Galphas and the stimulation of intracellular cAMP levels. While beta1AR and beta2AR are broadly expressed throughout tissues of the body, beta3AR is found predominantly in adipocytes. Stimulation of the betaARs leads to lipolysis in white adipocytes and nonshivering thermogenesis in brown fat. However, in essentially all animal models of obesity, the betaAR system is dysfunctional and the ability to stimulate lipolysis and thermogenesis is impaired. Nevertheless, we and others have shown that selective beta3AR agonists are able to prevent or reverse obesity and the loss of betaAR expression and to stimulate thermogenesis. This chapter will review the current understanding of the role of the sympathetic nervous system and the adipocyte betaARs in models of obesity; the physiologic impact of changes in betaAR expression on body composition and thermogenesis; and the regulation and unique properties of betaAR subtypes in brown and white adipocytes. The latter includes our recent discovery of novel signal transduction mechanisms utilized by beta3AR to activate simultaneously the protein kinase A and MAP kinase pathways. The impact of understanding these pathways and their potential role in modulating adaptive thermogenesis is discussed.
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PMID:The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. 1123 19

Leptin regulates cardiovascular function. Leptin levels are elevated in obesity and hypertension and may play a role in cardiovascular dysfunctions in these comorbidities. This study was designed to determine the influence of hypertension on the cardiac contractile response of leptin. Mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix system in ventricular myocytes from spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats. The contractile properties included peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR(90), +/-dL/dt), and fura-fluorescence intensity change (DeltaFFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the (3)H-arginine/citrulline conversion assays, respectively. The leptin receptor (Ob-R) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were evaluated by Western blot analysis. SHR animals displayed significantly elevated blood pressure and plasma leptin levels. Leptin elicited a concentration-dependent inhibition of PS and DeltaFFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR(90), or +/- dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), but not by elevated extracellular Ca(2+). Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes. SHR myocytes displayed similar Ob-R protein abundance and basal NO levels, a blunted leptin-induced increase in NOS activity as well as enhanced basal STAT3 levels compared with the WKY group. These data indicate that the leptin-induced cardiac contractile response is abolished by spontaneous hypertension, possibly because of mechanisms involving altered JAK/STAT, MAP kinase signaling, and NO response.
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PMID:Abrogated leptin-induced cardiac contractile response in ventricular myocytes under spontaneous hypertension: role of Jak/STAT pathway. 1179 81

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