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

Elevated circulating fatty acid concentration is a hallmark of insulin resistance and is at least in part attributed to the action of adipose tissue-derived tumor necrosis factor-alpha (TNF-alpha) on lipolysis. Cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) belongs to a family of proapoptotic proteins that has five known members in humans and mice. The action of CIDEA is unknown, but CIDEA-null mice are resistant to obesity and diabetes. We investigated CIDEA in adipose tissue of obese and lean humans and mice. The mRNA was expressed in white human fat cells and in brown mouse adipocytes. The adipose mRNA expression of CIDEA in mice was not influenced by obesity. However, CIDEA expression was decreased twofold in obese humans and normalized after weight reduction. Low adipose CIDEA expression was associated with several features of the metabolic syndrome. Human adipocyte depletion of CIDEA by RNA interference stimulated lipolysis and increased TNF-alpha secretion by a posttranscriptional effect. Conversely, TNF-alpha treatment decreased adipocyte CIDEA expression via the mitogen-activated protein kinase c-Jun NH(2)-terminal kinase. We propose an important and human-specific role for CIDEA in lipolysis regulation and metabolic complications of obesity, which is at least in part mediated by cross-talk between CIDEA and TNF-alpha.
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PMID:A human-specific role of cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) in adipocyte lipolysis and obesity. 1591 94

Serotonin 5-HT2C receptors (5-HT(2C)Rs) are almost exclusively expressed in the CNS, and implicated in disorders such as obesity, depression, and schizophrenia. The present study investigated the mechanisms governing the coupling of the 5-HT(2C)R to the extracellular signal-regulated kinases (ERKs) 1/2, using a Chinese hamster ovary (CHO) cell line stably expressing the receptor at levels comparable to those found in the brain. Using the non-RNA-edited isoform of the 5-HT(2C)R, constitutive ERK1/2 phosphorylation was observed and found to be modulated by full, partial and inverse agonists. Interestingly, agonist-directed trafficking of receptor stimulus was also observed when comparing effects on phosphoinositide accumulation and intracellular Ca2+ elevation to ERK1/2 phosphorylation, whereby the agonists, [+/-]-2,5-dimethoxy-4-iodoamphetamine (DOI) and quipazine, showed reversal of efficacy between the phosphoinositide/Ca2+ pathways, on the one hand, and the ERK1/2 pathway on the other. Subsequent molecular characterization found that 5-HT-stimulated ERK1/2 phosphorylation in this cellular background requires phospholipase D, protein kinase C, and activation of the Raf/MEK/ERK module, but is independent of both receptor- and non-receptor tyrosine kinases, phospholipase C, phosphoinositide 3-kinase, and endocytosis. Our findings underscore the potential for exploiting pathway-selective receptor states in the differential modulation of signaling pathways that play prominent roles in normal and abnormal neuronal signaling.
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PMID:Characterization of serotonin 5-HT2C receptor signaling to extracellular signal-regulated kinases 1 and 2. 1593 77

Body fat distribution determines obesity-related morbidity in adults but little is known of the aetiology or pathophysiology in children. This study investigates differences in insulin-mediated metabolism in primary cell cultures of subcutaneous and visceral preadipocytes derived from prepubertal children. The impact of differentiation and responses to TNFalpha exposure was also investigated. Proliferation rates were greater in subcutaneous versus visceral preadipocytes (41 h3 versus 69 h4; P=0.008). Insulin caused a dose-dependent increase in GSK-3 phosphorylation and an increase in MAPK phosphorylation over time, with increased sensitivity in subcutaneous preadipocytes. Post-differentiation, dose-dependent increases in GSK-3 phosphorylation were maintained, while MAPK phosphorylation was identical in both subtypes. No changes were observed in insulin receptor abundance pre-/post-differentiation. GLUT4 abundance was significantly increased in visceral versus subcutaneous adipocytes by 76(4)%; P=0.03), coincidental with increased insulin-stimulated 2-deoxy-glucose transport (+150(26)% versus +79(10)%; P=0.014) and further elevated by acute exposure to TNFalpha (+230(52)%; P=0.019 versus +123(24)%; P=0.025, respectively). TNFalpha also significantly increased basal glucose transport rates (+44(14)%; P=0.006 versus +34(11)%; P=0.007) and GLUT1 localisation to the plasma membrane. These data establish site-specific differences in subcutaneous and visceral fat cells from children. Responses to insulin varied with differentiation and TNFalpha exposure in the two depots, consistent with parallel changes in GLUT1/4 abundance and localisation.
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PMID:Site-specific differences of insulin action in adipose tissue derived from normal prepubertal children. 1593 53

The plasma lactate concentration in patients with obesity and type 2 diabetes is often higher than that in nondiabetic individuals. Although it is known that increased lactate concentration is an independent risk factor for developing type 2 diabetes, the underlying mechanisms are not well understood. Because inflammation plays an important role in the development of type 2 diabetes, we postulated that increased lactate level might contribute to the pathogenesis of type 2 diabetes by enhancing inflammation. In the present study, we demonstrated that preexposure of U937 macrophage-like cells to sodium lactate increased LPS-stimulated matrix metalloproteinase (MMP)-1, IL-1beta, and IL-6 secretion. Augmentation of LPS-stimulated MMP-1 secretion was diminished when sodium lactate was replaced by lactic acid that reduced pH in the culture medium. Furthermore, quantitative real-time PCR indicated that the increased secretion of MMP-1, IL-1beta, and IL-6 was due to increased mRNA expression. To explore the underlying signaling mechanism, blocking studies using specific inhibitors for NF-kappaB and MAPK cascades were performed. Results showed that blocking of either NF-kappaB or MAPK pathways led to the inhibition of MMP-1, IL-1beta, and IL-6 expression stimulated by sodium lactate, LPS, or both. Finally, electrophoretic mobility shift assays showed a synergy between sodium lactate and LPS on AP-1 and NF-kappaB transcriptional activities. In conclusion, this study has demonstrated for the first time that sodium lactate and LPS exert synergistic effect on MMP and cytokine expression through NF-kappaB and MAPK pathways and revealed a novel mechanism potentially involved in the development of type 2 diabetes and its complications.
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PMID:Sodium lactate increases LPS-stimulated MMP and cytokine expression in U937 histiocytes by enhancing AP-1 and NF-kappaB transcriptional activities. 1594 82

Accumulating evidence suggests that high concentrations of leptin observed in obesity and diabetes may contribute to their adverse effects on cardiovascular health. Metformin monotherapy is associated with reduced macrovascular complications in overweight patients with type 2 diabetes. It is uncertain whether such improvement in the cardiovascular outcome is related to specific vasculoprotective effects of this drug. In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters. Incubation of HASMCs with leptin enhanced the proliferation and MMP-2 expression in these cells and increased the generation of intracellular reactive oxygen species (ROS). These effects were abolished by vitamin E. Inhibition of NAD(P)H oxidase and protein kinase C (PKC) suppressed the effect of leptin on ROS production. In HASMCs, leptin induced PKC, extracellular signal-regulated kinase (ERK)1/2, and nuclear factor-kappaB (NF-kappaB) activation and inhibition of these signaling pathways abrogated HASMC proliferation and MMP-2 expression induced by this hormone. Treatment of HASMCs with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-kappaB. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKC-dependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-kappaB pathways and that therapeutic metformin concentrations effectively inhibit these biological effects. These results suggest a new mechanism by which metformin may improve cardiovascular outcome in patients with diabetes.
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PMID:Signaling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2 expression induced by leptin: inhibitory effect of metformin. 1598 26

Obesity has reached epidemic proportions in several regions of the world. General changes in lifestyle, including consumption of fat-rich food, are among the most important factors leading to an unprecedented increase in the prevalence of this disease. Weight gain results from an imbalance between caloric intake and energy expenditure. Both of these parameters are under the tight control of specialized neurons of the hypothalamus that respond to peripheral anorexigenic and adipostatic signals carried by leptin and insulin. Here we show, by macroarray analysis, that high-fat feeding [hyperlipidic diet (HL)] induces the expression of several proinflammatory cytokines and inflammatory responsive proteins in hypothalamus. This phenomenon is accompanied by increased activation of c-Jun N-terminal kinase and nuclear factor-kappaB. In addition, HL feeding leads to impaired functional and molecular activation of the insulin-signaling pathway, which is paralleled by increased serine phosphorylation of the insulin receptor and insulin receptor substrate-2. Intracerebroventricular treatment of HL rats with a specific inhibitor of c-Jun N-terminal kinase (SP600125) restores insulin signaling and leads to a reduced caloric intake and weight loss. We conclude that HL feeding induces a local proinflammatory status in the hypothalamus, which results in impaired anorexigenic insulin signaling.
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PMID:Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. 1616 30

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

Endocrine-disrupting chemicals (EDC) are commonly considered to be compounds that mimic or block the transcriptional activation elicited by naturally circulating steroid hormones by binding to steroid hormone receptors. For example, the Food Quality Protection Act of 1996 defines EDC as those, that "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate." The definition of EDC was later expanded to include those that act on the estrogen, androgen, and thyroid hormone receptors. In this minireview, we discuss new avenues through which xenobiotic chemicals influence these and other hormone-dependent signaling pathways. EDC can increase or block the metabolism of naturally occurring steroid hormones and other xenobiotic chemicals by activating or antagonizing nuclear hormone receptors. EDC affect the transcriptional activity of nuclear receptors by modulating proteasome-mediated degradation of nuclear receptors and their coregulators. Xenobiotics and environmental contaminants can act as hormone sensitizers by inhibiting histone deacetylase activity and stimulating mitogen-activated protein kinase activity. Some endocrine disrupters can have genome-wide effects on DNA methylation status. Others can modulate lipid metabolism and adipogenesis, perhaps contributing to the current epidemic of obesity. Additional elucidation of these new modes of endocrine disruption will be key in understanding the nature of xenobiotic effects on the endocrine system.
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PMID:New modes of action for endocrine-disrupting chemicals. 1603 29

Fatty acids and their metabolites regulate gene expression and immunological pathways. Furthermore, obese individuals frequently have increased circulating fatty acid concentrations, and localized inflammation in adipose tissue may facilitate the systemic inflammation associated with the insulin resistance of obesity. Although palmitate induces inflammation (i.e., activates proinflammatory pathways) in myotubes, the effects of fatty acids on inflammatory processes in adipocytes have not been established. Therefore, we examined the potential for palmitate, laurate, and docosahexaenoic acid (DHA) to modulate inflammation in 3T3-L1 adipocytes. Palmitate, but not DHA or laurate, induced nuclear factor kappaB (NF-kappaB)-driven luciferase activity and interleukin-6 (IL-6) expression (P < 0.05). Inhibition of fatty acyl Co-A synthase (FACS) with triacsin C suppressed palmitate-induced NF-kappaB activation (P < 0.05), but caused an additive increase in palmitate-induced IL-6 expression (P < 0.05). Disrupting mitogen-activated protein kinase/Erk kinase (MEK) and protein kinase C (PKC) activity with U0126 and Bisindolylmaleimide (Bis), respectively, suppressed palmitate-induced IL-6 expression (P < 0.05), but had no effect on NF-kappaB reporter gene activity (P > 0.05). However, the phosphoinositide-3 kinase (PI3K) inhibitor, wortmannin, alone and additively with palmitate, activated the NF-kappaB reporter gene and induced IL-6 expression (P < 0.05). Palmitate also induced the mRNA expression of tumor necrosis factor alpha (TNFalpha) (P < 0.05), but the increase in mRNA abundance was not reflected in a greater protein concentration in the media (P > 0.05). These data indicate that palmitate induces inflammation in adipocytes, and that this is not a generalized effect of all SFA. Furthermore, PI3K may act constitutively to suppress inflammation. Consequently, inhibition of this enzyme may promote and exacerbate the inflammation in adipose tissue that is associated with obesity and insulin resistance.
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PMID:Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3T3-L1 adipocytes. 1604 6

Increased activity of proinflammatory/stress pathways has been implicated in the pathogenesis of insulin resistance in obesity. However, the effects of obesity on the activity of these pathways in skeletal muscle, the major insulin-sensitive tissue by mass, are poorly understood. Furthermore, the mechanisms that activate proinflammatory/stress pathways in obesity are unknown. The present study addressed the effects of diet-induced obesity (DIO; 6 wk of high-fat feeding) and acute (6-h) hyperlipidemia (HL) in rats on activity of IKK/IkappaB/NF-kappaB c-Jun NH(2)-terminal kinase, and p38 MAPK in three skeletal muscles differing in fiber type [superficial vastus (Vas; fast twitch-glycolytic), soleus (Sol; slow twitch-oxidative), and gastrocnemius (Gas; mixed)]. DIO decreased the levels of the IkappaBalpha in Vas (24 +/- 3%, P = 0.001, n = 8) but not in Sol or Gas compared with standard chow-fed controls. Similar to DIO, HL decreased IkappaBalpha levels in Vas (26 +/- 5%, P = 0.006, n = 6) and in Gas (15 +/- 4%, P = 0.01, n = 7) but not in Sol compared with saline-infused controls. Importantly, the fiber-type-dependent effects on IkappaBalpha levels could not be explained by differential accumulation of triglyceride in Sol and Vas. HL, but not DIO, decreased phospho-p38 MAPK levels in Vas (41 +/- 7% P = 0.004, n = 6) but not in Sol or Gas. Finally, skeletal muscle c-Jun NH(2)-terminal kinase activity was unchanged by DIO or HL. We conclude that diet-induced obesity and acute HL reduce IkappaBalpha levels in rat skeletal muscle in a fiber-type-dependent manner.
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PMID:Diet-induced obesity and acute hyperlipidemia reduce IkappaBalpha levels in rat skeletal muscle in a fiber-type dependent manner. 1608 81


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