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

Transgenic mice overexpressing transforming growth factor alpha (TGF-alpha) under control of the metallothionein promoter had, on average, 20% reductions in body and carcass weights compared to nontransgenic littermates. This loss resulted from significant decreases in the comparative weights of bone, muscle, and especially fat. Transgenic epididymal fat pads were reduced by 40-80%, and total body fat content by 50%, relative to control animals. Distal hindlimb muscle weights were 20% below normal, and other skeletal muscles were visibly smaller in size. Weight reductions were accompanied by decreases in the cellularity of transgenic fat pads and muscles and by decreases in the number and area of striated muscle fibers. These findings were not obviously attributable to differences in metabolic rates since transgenic and control mice displayed similar levels of energy expenditure per unit lean body mass. The effects of TGF-alpha on the development of these tissues could be mimicked in culture for fat but not muscle. Thus, TGF-alpha did not inhibit the differentiation of the mouse skeletal myoblast cell line C2C12 as evidenced by the expression of muscle-specific actin and fusion to form multinucleated myotubes. However, TGF-alpha repressed the differentiation of the preadipocyte cell line 3T3-F442A in a dose-dependent and reversible manner as judged by morphological conversion and diminished expression of mRNAs encoding the adipocyte-specific markers adipsin and glycerophosphate dehydrogenase. This repression, which occurred without marked stimulation of proliferation, was incomplete even in the presence of high concentrations of growth factor. Despite its effects on adipose development, introduction of the metallothionein-TGF-alpha transgene into the ob/ob genetic background did not suppress the marked obesity characteristic of this mutation. Finally, endogenous TGF-alpha epidermal growth factor receptor mRNAs were detected in normal adipose tissue, suggesting that regulation of adipogenesis by this growth factor may be physiological.
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PMID:Regulation of fat and muscle development by transforming growth factor alpha in transgenic mice and in cultured cells. 846 58

Mice with a temporally regulatable ovine metallothionein 1a--ovine growth hormone transgene (oMT1a-oGH) were utilized to study the effects of withdrawal of elevated circulating levels of growth hormone (GH) on growth and body composition. The transgene was activated from 21-42 days of age by provision of zinc sulfate in the drinking water. At 42 days, mice were allocated to either activated transgenic (remain on zinc sulfate) or inactivated transgenic (removal of zinc sulfate) groups, and to receive either ad libitum or restricted (80-90% of ad libitum) access to feed. Non-transgenic control mice were treated similarly. Body weights and intakes were recorded weekly. Mice were killed at 70 d and epididymal and subcutaneous fat pads, trimmed hind carcass and various organs were weighed. The main findings of this study are: (1) food-restricted mice possessing an activated oMT1a-oGH transgene fail to demonstrate increased growth, but exhibit significantly reduced levels of fat (P < 0.05) relative to all other genotype x feed level combinations; and (2) inactivation of the oMT1a-oGH transgene, following a period of elevated GH levels, leads to development of obesity as evidenced by two to three fold increases in epididymal and subcutaneous fat pad weights (P < 0.01) relative to both activated transgenic and non-transgenic control mice. These large increases in fat deposition also occurred when intake was restricted to 80-90% of ad libitum levels, indicating that metabolic changes independent of intake occur in these inactivated transgenic mice. It is possible that highly elevated production of GH in activated oMT1a-oGH transgenic mice leads to (1) enhanced promotion of preadipocyte differentiation, leading to increased numbers of adipocytes that, upon cessation of oGH production, are available for lipid deposition resulting in obesity, or (2) alterations in production of or responsiveness to insulin, leading to increased fat deposition upon removal of the chronic anti-lipogenic actions of GH. The oMT1a-oGH transgenic mouse line should provide a new genetic model with which to investigate the mechanisms by which growth hormone affects obesity.
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PMID:Development of obesity following inactivation of a growth hormone transgene in mice. 858 37

The consequences of a 42 d exposure to elevated growth hormone (GH) on adipose tissue were assessed using the regulatable ovine metallothionein- ovine GH (oMt1a-oGH) transgene in male and female GH transgenic (TG) mice. Activation of transgene expression at 21 d of age followed by inactivation of transgene expression at 63 d of age (TG-on/off) increased individual white adipose tissue (WAT) depots and total body lipid stores in both males and females. WAT, expressed as a percentage of fasted body weight, did not differ in wildtype (WT) and continuously activated TG males and females up to 105 d of age, but was increased approximately 270% following inactivation of the transgene. Inguinal depot adipocytes were more numerous in both male and female TG +/- relative to WT or TG animals. The ensuring obesity was not accompanied by a decrease in thermogenic capacity of brown adipose tissue, as indexed by uncoupling protein quantity. GH transgene expression was accompanied by elevated insulin levels that were restored to WT levels upon cessation of transgene expression (p > 0.1). Early, transient exposure to elevated GH increased total body lipid by nearly threefold independent of gender; the increased lipid content was sustained and reflected WAT hypertrophy and hyperplasia. The oMt1a-oGH mouse provides a novel model of induced obesity in response to inactivation of a GH-transgene by the withdrawal of the transgene stimulus.
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PMID:Body composition of inactivated growth hormone (oMt1a-oGH) transgenic mice: generation of an obese phenotype. 954 8

Thanks to progress in zinc research, it is now possible to describe in more detail how zinc ions (Zn++) and nitrogen monoxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, help to regulate immune responses to antigens. NO appears to be able to liberate Zn++ from metallothionein (MT), an intracellular storage molecule for metal ions such as zinc (Zn++) and copper (Cu++). Both Zn++ and Cu++ show a concentration-dependent inactivation of a protease essential for the proliferation of the AIDS virus HIV-1, while zinc can help prevent diabetes complications through its intracellular activation of the enzyme sorbitol dehydrogenase (SDH). A Zn++ deficiency can lead to a premature transition from efficient Th1-dependent cellular antiviral immune functions to Th2-dependent humoral immune functions. Deficiencies of Zn++, NO and/or GSH shift the Th1/Th2 balance towards Th2, as do deficiencies of any of the essential nutrients (ENs) - a group that includes methionine, cysteine, arginine, vitamins A, B, C and E, zinc and selenium (Se) - because these are necessary for the synthesis and maintenance of sufficient amounts of GSH, MT and NO. Via the Th1/Th2 balance, Zn++, NO, MT and GSH collectively determine the progress and outcome of many diseases. Disregulation of the Th1/Th2 balance is responsible for autoimmune disorders such as diabetes mellitus. Under Th2, levels of interleukin-4 (II-4), II-6, II-10, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are raised, while levels of II-2, Zn++, NO and other substances are lowered. This makes things easier for viruses like HIV-1 which multiply in Th2 cells but rarely, if ever, in Th1 cells. AIDS viruses (HIVs) enter immune cells with the aid of the CD4 cell surface receptor in combination with a number of co-receptors which include CCR3, CCR5 and CXCR4. Remarkably, the cell surface receptor for LTB4 (BLTR) also seems to act as a co-receptor for CD4, which helps HIVs to infect immune cells. The Th2 cytokine II-4 increases the number of CXCR4 and BLTR co-receptors, as a result of which, under Th2, the HIV strains that infect immune cells are precisely those that are best able to accelerate the AIDS disease process. The II-4 released under Th2 therefore not only promotes the production of more HIVs and the rate at which they infect immune cells, it also stimulates selection for the more virulent strains. Zn++ inhibit LTB4 production and numbers of LTB4 receptors (BLTRs) in a concentration-dependent way. Zn++ help cells to keep their LTB4 'doors' shut against the more virulent strains of HIV. Moreover, a sufficiency of Zn++ and NO prevents a shift of the Th1/Th2 balance towards Th2 and thereby slows the proliferation of HIV, which it also does by inactivating the HIV protease. Research makes it look likely that deficiencies of ENs such as zinc promote the proliferation of Th2 cells at the expense of Th1 cells. Zinc deficiency also promotes cancer. Under the influence of Th1 cells, zinc inhibits the growth of tumours by activating the endogenous tumour-suppressor endostatin, which inhibits angiogenesis. The modern Western diet, with its excess of refined products such as sugar, alcohol and fats, often contains, per calorie, a deficiency of ENs such as zinc, selenium and vitamins A, B, C and E, which results in disturbed immune functions, a shifted Th1/Th2 balance, chronic (viral) infections, obesity, atherosclerosis, autoimmunity, allergies and cancer. In view of this, an optimization of dietary composition would seem to give the best chance of beating (viral) epidemics and common (chronic) diseases at a realistic price.
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PMID:Modern diets and diseases: NO-zinc balance. Under Th1, zinc and nitrogen monoxide (NO) collectively protect against viruses, AIDS, autoimmunity, diabetes, allergies, asthma, infectious diseases, atherosclerosis and cancer. 1049 17

The traditional role attributed to white adipose tissue is energy storage, fatty acids being released when fuel is required. The metabolic role of white fat is, however, complex. For example, the tissue is needed for normal glucose homeostasis and a role in inflammatory processes has been proposed. A radical change in perspective followed the discovery of leptin; this critical hormone in energy balance is produced principally by white fat, giving the tissue an endocrine function. Leptin is one of a number of proteins secreted from white adipocytes, which include angiotensinogen, adipsin, acylation-stimulating protein, adiponectin, retinol-binding protein, tumour neorosis factor a, interleukin 6, plasminogen activator inhibitor-1 and tissue factor. Some of these proteins are inflammatory cytokines, some play a role in lipid metabolism, while others are involved in vascular haemostasis or the complement system. The effects of specific proteins maybe autocrine or paracrine, or the site of action maybe distant from adipose tissue. The most recently described adipocyte secretory proteins are fasting-induced adipose factor, a fibrinogen-angiopoietin-related protein, metallothionein and resistin. Resistin is an adipose tissue-specific factor which is reported to induce insulin resistance, linking diabetes to obesity. Metallothionein is a metal-binding and stress-response protein which may have an antioxidant role. The key challenges in establishing the secretory functions of white fat are to identify the complement of secreted proteins, to establish the role of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production with alterations in adiposity (obesity, fasting, cachexia). There is already considerable evidence of links between increased production of some adipocyte factors and the metabolic and cardiovascular complications of obesity. In essence, white adipose tissue is a major secretory and endocrine organ involved in a range of functions beyond simple fat storage.
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PMID:Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. 1168 7

We have previously established that ATP binds to mammalian metallothionein-2 (MT). The interaction between ATP and MT and the associated conformational change of the protein affect the sulfhydryl reactivity and zinc transfer potential of MT [Jiang, L.-J., Maret, W., and Vallee, B. L. (1998) The ATP-metallothionein complex. Proc. Natl. Acad. Sci. U.S.A. 95, 9146-9149]. NMR spectroscopic investigations have now provided further evidence for the interaction. (35)Cl NMR spectroscopy has further identified chloride as an additional biological MT ligand, which can interfere with the interaction of ATP with MT. (1)H NMR/TOCSY spectra demonstrate that ATP binding affects the N- and C-terminal amino acids of the MT molecule. Scanning tunneling microscopy recorded images of single MT molecules in buffered solutions. Moreover, this technique demonstrates that the otherwise nearly linear MT molecule bends by about 20 degrees at its central hinge region between the domains in the presence of ATP. These results may bear on the development of mild obesity in MT null mice and the role of MT in the regulation of energy balance. The interaction suggests a mechanism for the cellular translocation, retention, and reactivity of the ATP*MT complex in the mitochondrial intermembrane space. Both MT and ATP are localized there, and MT and thionein alternately bind and release zinc, thereby affecting mitochondrial respiration.
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PMID:The ATP/metallothionein interaction: NMR and STM. 1181 64

Obesity and its associated disorders are increasing in companion animals, particularly in dogs. We have investigated whether genes encoding key adipokines, some of which are implicated in the pathologies linked to obesity, are expressed in canine adipose tissues. Using RT-PCR, mRNAs encoding the following adipokines were detected in dog white adipose tissue: adiponectin, leptin, angiotensinogen, plasminogen activator inhibitor-1, IL-6, haptoglobin, metallothionein-1 and 2, and nerve growth factor. The adipokine mRNAs were present in all fat depots examined. Fractionation of adipose tissue by collagenase digestion showed that each gene was expressed in mature adipocytes. The mRNA for TNFalpha was not evident in adipose tissue, but was detected in isolated adipocytes. Fibroblastic preadipocytes from gonadal white fat were differentiated into adipocytes in primary culture and adipokine expression examined before and after differentiation (days 0 and 11, respectively). Each adipokine gene expressed in dog white adipocytes was also expressed in the differentiated cells. These results demonstrate that dog white adipose tissue expresses major adipokine genes, expression being in the adipocytes. Investigation of adipokine production and function will provide insight into the mechanisms involved in obesity-related pathologies in dogs and serve as a model for the related human diseases.
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PMID:Adipokine gene expression in dog adipose tissues and dog white adipocytes differentiated in primary culture. 1613 59

The traditional function attributed to white adipose tissue of energy storage in the form of triglycerides has been challenged by results from recent studies, showing that adipose tissue is, in fact, a highly active metabolic and endocrine organ. A radical change in perspective followed the discovery of a large number of proteins secreted from white adipocytes, such as leptin, resistin, adiponectin, adipsin, acylation-stimulating protein, angiotensinogen, tumour necrosis factor a, interleukin-6, retinol-binding protein, plasminogen activator inhibitor-1, tissue factor, fasting-induced adipose factor, fibrinogen/angiopoetin-related protein, and metallothionein. The effects of specific proteins may be either autocrine or paracrine, meaning that they might act in adipose tissue itself or in more distant target tissues. Some of these proteins induce insulin resistance, some play a role in glucose and lipid metabolism, some are inflammatory cytokines, while others are involved in vascular haemostasis. The key challenges for future investigations of adipose tissue's secretory functions will be to identify all of its secreted proteins, to establish the function of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production due to problems, such as obesity, fasting, or diabetes mellitus type 2.
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PMID:[Adipose tissue as an endocrine organ]. 1664 Jan 91

To understand the molecular mechanisms involved in the effect of exercise training, we examined hepatic transcriptional profiles using cDNA microarrays in exercise-trained and untrained mice with diet-induced obesity. C57BL/6J male mice (n = 10/group) were fed with a normal diet, high-fat diet (HFD), or HFD with exercise training for 12 weeks. The expression level of approximately 10,000 transcripts in liver tissues from each group was assessed using cDNA microarray analysis. Exercise training improved lipid profiles and hepatic steatosis and decreased body fat mass induced by the HFD. Seventy-three genes were differentially expressed in the HFD- and/or HFD with exercise training-treated groups, compared with the normal diet- and HFD-fed groups, respectively. Interestingly, the expression profiles involved in metabolism, such as elongation of very long chain fatty acids-like 2, lipin, and malic enzyme, were changed by exercise training. In addition, expression of genes altered by exercise training related to defense and stress response, including metallothionein 1 and 2 and heat shock protein, showed interesting findings. Our study showed beneficial effects of exercise training in preventing the development of obesity and metabolic disorders in mice with diet-induced obesity.
Obesity (Silver Spring) 2006 Aug
PMID:Effect of exercise on hepatic gene expression in an obese mouse model using cDNA microarrays. 1698 71

Pathogenesis of diabetic cardiomyopathy (DCM) is a complicate and chronic process that is secondary to acute cardiac responses to diabetes. One of the acute responses is cardiac cell death that plays a critical role in the initiation and development of DCM. Besides hyperglycemia, inflammatory response in the diabetic heart is also a major cause for cardiac cell death. Diabetes or obesity often causes systemic and cardiac increases in tumor necrosis factor-alpha, interleukin-18 and plasminogen activator inhibitor-1. However, how these cytokines cause cardiac cell death remains unclear. It has been considered to relate to oxidative and/or nitrosative stress. We have demonstrated that metallothionein as a potent antioxidant or stress protein significantly protected the heart from oxidative damage and cell death caused by these cytokines, leading to effective prevention of DCM. The direct link of the inhibition of oxidative stress and damage to the prevention of cardiac cell death was defined by addition of superoxide or peroxynitrite specific inhibitor to completely prevent cytokine-induced cardiac cell death. Cardiac cell death is induced by the inflammatory cytokines that is increased in response to diabetes. Inflammatory cytokine-induced cardiac cell death is mediated by oxidative stress and is also the major initiator for DCM development.
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PMID:Diabetes/obesity-related inflammation, cardiac cell death and cardiomyopathy. 1721 12


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