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

Adipocytes produce a variety of molecules that are capable of functioning in both a paracrine and autocrine fashion. Tumor necrosis factor (TNF) is one of the proteins produced by adipocytes that has been shown to regulate adipocyte function. Interestingly, adipocyte expression of TNF increases with increasing adipocyte mass and expression of TNF is increased in adipocytes isolated from several genetic models of rodent obesity and from obese humans. This finding has led to the idea that TNF produced by adipocytes functions as a local "adipostat" to limit fat accumulation. Increased production of TNF by adipocytes, however, may contribute to insulin resistance in obesity and in non-insulin-dependent diabetes mellitus (NIDDM). TNF has been shown to inhibit insulin-simulated tyrosine phosphorylation of both the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and to stimulate downregulation of the insulin-sensitive glucose transporter, GLUT4, in adipocytes. These findings raise the possibility that pharmacological inhibition of TNF may provide a novel therapeutic target to treat patients with NIDDM.
Cytokine Growth Factor Rev 1996 Aug
PMID:Inhibition of insulin receptor signaling by TNF: potential role in obesity and non-insulin-dependent diabetes mellitus. 889 94

Lectins are a family of proteins that stimulate cellular responses after binding to carbohydrate chains on plasma membranes. In the study described here, a mixture of lectins--pokeweed mitogen (PKW)--was shown to have insulinomimetic effects in mice. After receiving PKW (15 mg/kg intraperitoneally [IP]), serum glucose declined from 154 +/- 3 to 23 +/- 10 mg/dL by 24 hours later. Anorexia developed, and by 3 days, there was a significant decline in body weight. Carcass weights were 10% lower, and epididymal fat pad weights were 45% lower. When given for 16 days, PKW 3 mg/kg every other day caused a sustained 10% weight loss. Severe combined immune deficiency (SCID) mice were sensitive to PKW, showing that B and T lymphocytes were not required for the effects to develop. Cytokine antagonists attenuated the hypoglycemia and anorexia, but only by 50%. Further study showed that PKW has insulin-like effects in vitro. Glucose uptake was stimulated when murine C2C12 myotubes were exposed to an enriched fraction of PKW. These results demonstrated that PKW has both insulin-like activity and weight-reducing effects when administered to mice. The development of therapy for adult-onset diabetes or obesity based on lectins from pokeweed may be possible.
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PMID:The metabolic effects of pokeweed mitogen in mice. 944 Apr 81

The discovery of leptin has imparted great impetus to adipose tissue research by demonstrating a more active role for the adipocyte in energy regulation. Besides leptin, however, the adipose tissue also secretes a large number other signals. Cytokine signals, TNFalpha and IL-6, and components of the alternative pathway of complement influence peripheral fuel storage, mobilization and combustion, as well as energy homeostasis. In addition to the acute regulation of fuel metabolism, adipose tissue also influences steroid conversion and sexual maturation. In this way, adipose tissue is an active endocrine organ, influencing many aspects of fuel metabolism through a network of local and systemic signals, which interact with the established neuroendocrine regulators of adipose tissue. Thus, insulin, catecholamines and anterior pituitary endocrine axes interact at multiple levels with both cytokines and leptin. It may be proposed that the existence of this network of adipose tissue signalling pathways, arranged in an hierarchical fashion, constitutes a metabolic repertoire which enables the organism to adapt to a range of different metabolic challenges, including starvation, reproduction, times of physical activity, stress and infection, as well as short periods of gross energy excess. However, the occurrence of more prolonged periods of energy surplus, leading to obesity, is an unusual state in evolutionary terms, and the adipose tissue signalling repertoire, although sophisticated, adapts poorly to these conditions. Rather, the responses of the adipose tissue endocrine network to obesity are maladaptive, and lay the foundations of metabolic disease.
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PMID:Adipose tissue as an endocrine and paracrine organ. 987 49

High-fat-fed C57Bl/6J FABP4/aP2 null mice develop obesity but not the related hyperglycemia or hyperinsulinemia characteristic of type II diabetes. FABP4/aP2 protein's function to bind fatty acids in the adipocytes may promote total body energy homeostasis by linking energy depots to the ability to express signaling molecules similar to leptin. To test this hypothesis, proteomic analysis of serum proteins from high-fat-fed wild-type and FABP4/aP2 null mice revealed that the GDF-3/Vgr-2 protein, a bone morphogenetic protein, was upregulated in C57Bl/6J FABP4/aP2 null mice. The increase in serum GDF-3/Vgr-2 protein was correlated with a 27-fold increase in adipose GDF-3/Vgr-2 mRNA. In contrast, leptin expression was unaltered between FABP4/aP2 null and wild-type animals. The expression of GDF-3/Vgr-2 mRNA was not substantially different in adipose tissue of db/db and tb/tb mice compared to wild-type controls. The expression of GDF-3/Vgr-2 mRNA was dependent upon the age and diet of the animals, declining as a function of age in high-fat-fed wild-type animals while increasing in the FABP4/aP2 null strain. These results identify GDF-3/Vgr-2 as an age- and fat-regulated, adipose-derived cytokine suggesting a linkage between adipocyte fatty acid metabolism and the expression of the bone morphogenetic family of differentiation regulators.
Cytokine 2001 May 07
PMID:Upregulation of bone morphogenetic protein GDF-3/Vgr-2 expression in adipose tissue of FABP4/aP2 null mice. 1139 90

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor alpha (TNF-alpha) and several interleukins (IL), notably IL-1beta and IL-6. Other adipocyte products with 'immunological' actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-alpha and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-alpha mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual 'inflammatory' stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-alpha. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-alpha and IL-6 inhibit lipoprotein lipase, and TNF-alpha additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-alpha also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more 'trophic', and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor gamma). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of beta3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-alpha is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-alpha is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.
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PMID:Pro-inflammatory cytokines and adipose tissue. 1168 9

This study was undertaken to review the links between maternal nutrition, offspring's birth weight and the propensity to early insulin resistance and high diabetes rates in Indian adults. Studies included a comparison of maternal size and nutrition with birth weights in Pune, India, and Southampton, UK. In Pune, the growth, insulin resistance and blood pressure of four-year-old children were assessed. Adults >40 years of age, who were resident in rural areas, were compared with adults living in urban areas for size, glucose handling, lipid status and blood pressure. Newly diagnosed diabetic adults living in urban areas were also monitored. Height, weight, head, waist and hip circumferences, skin-fold measurements and blood pressure were routinely measured. Fasting glucose, insulin, total and high-density lipoprotein cholesterol and triglycerides were linked to the glucose and insulin responses during glucose tolerance tests. Cytokine levels were measured in plasma samples of urban and rural adults. Indian babies were lighter, thinner, shorter and had a relatively lower lean tissue mass than the Caucasian babies. However, the subcutaneous fat measurements of these babies were comparable to those of the white Caucasian babies. The Indian mothers were small, but relatively fat mothers produced larger babies. Maternal intake of green vegetables, fruit and milk, and their circulating folate and vitamin C levels, predicted larger fetal size. Rapid childhood growth promoted insulin resistance and higher blood pressure. Rural adults were thin, with a 4% prevalence of diabetes and a 14% prevalence of hypertension, but the risks increased within the normal body mass index (BMI) range. Type 2 diabetes was common in urban adults younger than 35 years of age. Although the average BMI was 23.9 kg m(-2), central obesity and thin limbs were noteworthy. Levels of interleukin-6 and tumour necrosis factor-a were markedly increased in urban dwellers. Hence, there is evidence of a remarkably powerful, intergenerational effect on body size and total and central adiposity. Indians are highly susceptible to insulin resistance and cardiovascular risks, with babies being born small but relatively fat. Insulin resistance is amplified by rapid childhood growth. Dietary factors seem to have profound long-term metabolic influences in pregnancy. Overcrowding with infections and central obesity may amplify cytokine-induced insulin resistance and early diabetes in Indian adults with a low BMI.
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PMID:The lifecycle effects of nutrition and body size on adult adiposity, diabetes and cardiovascular disease. 1216 75

Aging is associated with low-grade increases in circulating levels of TNF-alpha and IL-6. A wide range of factors, including smoking, obesity, infections, the decline in sex hormones, and the genotype, induce and modify this age-related inflammatory activity, which on the other hand may cause age-related pathology. Several classical risk factors are indeed controlled by TNF-alpha and IL-6. TNF-alpha induces insulin resistance and endothelial dysfunction, IL-6 promotes procoagulant changes and both cytokines cause dyslipidaemia. Moreover, systemic low-grade elevations in both cytokines have been related to cardiovascular diseases and TNF-alpha has been associated with Alzheimer's disease and type 2 diabetes mellitus. TNF-alpha and IL-6 are also differently and independently of each other associated with mortality in elderly populations, indicating points of distinction in the biological effects of the two cytokines. Moreover, the association between cytokines and mortality is independent of co-morbidity, suggesting that low-grade increases in circulating cytokines are strong, independent risk factors of morbidity and mortality in old populations, although life style factors and co-morbidity may modulate levels.
Eur Cytokine Netw
PMID:Effects of tumor necrosis factor-alpha and interleukin-6 in elderly populations. 1251 24

In mammals, the pleiotropic biological functions of tumor necrosis factor alpha (TNF-alpha) may include important effects on human reproductive physiology. Thus, chronic anovulation, oligo or amenorrhea, infertility, hyperandrogenism, obesity, insulin resistance and increased TNFalpha serum levels have been observed in women affected by polycystic ovary syndrome (PCOS). Whole blood short - term cell cultures (WBSC) are simple systems where the capacity to produce TNF-alpha by circulating leukocytes, mainly of the macrophage/monocyte lineage, can be accurately quantified. Given the relevance of monocytes/macrophages in the production of TNF-alpha, in this study, in a control-case approach, WBSC from women with PCOS were analyzed in their basal and lipolysaccharide (LPS)- stimulated capacity to produce the cytokine. These measurements did not correlate with the increased serum levels of the cytokine and the normal levels of cortisol, found in PCOS women. Increased serum TNF-alpha levels in PCOS women correlated positively with body mass index and negatively with insulin sensitivity. In spite of the increased serum TNF-alpha levels in PCOS women, basal and LPS stimulated production of the cytokine, by the ex vivo WBSC from these patients, were within normal values.
Eur Cytokine Netw
PMID:Evaluation of tumor necrosis factor alpha production in ex vivo short term cultured whole blood from women with polycystic ovary syndrome. 1251 26

We and others have previously shown that leptin has direct effects on the function of monocytes and macrophages. Since obesity is associated with an increased cardiovascular risk, as well as with markedly elevated circulating leptin levels, we examined whether leptin has any pro-inflammatory effects on the function of monocytes. Leptin strongly enhanced the expression and secretion of the interferon-gamma-inducible protein (IP-10) in a human monocytic cell line, as well as in peripheral blood mononuclear cells. In contrast, no significant effect on other inflammatory proteins was observed, such as metalloproteinases and other chemokines. In summary, we have demonstrated that leptin selectively induces the expression and secretion of IP-10 in human monocytic cells, potentially contributing to the vascular complications associated with hyperleptinemic obesity in humans.
Cytokine 2003 Jan 07
PMID:IP-10, but not RANTES, is upregulated by leptin in monocytic cells. 1266 59

Insulin resistance is a fundamental defect that precedes the development of the full insulin resistance syndrome as well as beta cell failure and type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha), a paracrine/autocrine factor highly expressed in adipose tissues of obese animals and human subjects, is implicated in the induction of insulin resistance seen in obesity and type 2 diabetes. Here, we review several molecular aspects of adipose tissue physiology, and highlight the direct effects of TNF-alpha on the functions of adipose tissue including induction of lipolysis, inhibition of insulin signaling, and alterations in expression of adipocyte important genes through activation of NF-kappaB, as well as their pertinence to insulin sensitivity of adipocytes. We also review the ability of TNF-alpha to inhibit synthesis of several adipocyte-specific proteins including Acrp30 (adiponectin) and enhance release of free fatty acids (FFAs) from adipose tissue, and discuss how these factors may act as systemic mediators of TNF-alpha and affect whole body energy homeostasis and overall insulin sensitivity. On the basis of these mechanisms, we examine the therapeutic potential of blocking specific autocrine/paracrine signaling pathways in adipocytes, particularly those involving NF-kappaB, in the treatment of type 2 diabetes.
Cytokine Growth Factor Rev 2003 Oct
PMID:Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. 1294 26


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