Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in lipid metabolism have been reported under treatment of various skin disorders with oral retinoids. In 36 patients, mostly psoriatics, under administration of aromatic retinoid (Ro 10-9359) in various dosages serum triglycerides and cholesterol were estimated; in 25 out of 36 patients lipid analysis of the lipoproteins and apoproteins A (HDL) and B (LDL) has been performed. To reveal possible similarities of lipid changes under the two main retinoids we determined the same parameter in 10 patients with conglobate acne treated orally with 13-cis-retinoic acid (isotretinoin/Ro 4-3780 1mg/kg b.w.). Under both drugs serum triglyceride and cholesterol levels were significantly increased. In contrast to the results under the aromatic derivate the HDL- and LDL-cholesterol fractions were changed under isotretinoin. The apoprotein A (HDL) was found significantly increased under aromatic retinoid. Elevated serum lipids mostly occurred in patients having risk factors such as preexisting lipid abnormalities, obesity, diabetes mellitus, heavy smoking, alcohol abuse and hyperlipemia-inducing drugs. Patients to be treated with these drugs should be carefully followed up in order to minimize the risk for atheromatosis.
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PMID:[Changes in serum lipid fractions as a side effect of oral retinoids]. 621 75

Retinoids, especially all-trans retinoic acid (RA), have been shown to inhibit the differentiation of preadipose cells. It is important to human health, especially to obesity, that the regulatory system for the differentiation of adipocytes is well defined. Previously, we have shown that retinoic acid receptor (RAR) gamma 2 gene expression is up-regulated by RA in 3T3-L1 preadipose cells. In this study, the RAR system was dissected and the RA-regulated function in 3T3-L1 cells was assigned to one given receptor. We used three synthetic retinoids; (1) Ro 41-5253, a selective RAR alpha antagonist, (2) Ch 55, an RAR alpha, beta and gamma agonist, and (3) Am 80, an RAR alpha and beta agonist, which has less affinity to RAR gamma. Ro 41-5253 reverted RA-induced inhibition of the differentiation of 3T3-L1 cells. However, there was no significant reversion in RA-induced RAR gamma mRNA level by treatment with Ro 41-5253. In the case of RAR agonists, both Am 80 and Ch 55 strongly inhibited the differentiation of 3T3-L1 cells. However, Am 80 weakly increased RAR gamma mRNA content less than did Ch 55. These findings suggest, that RAR alpha is involved in the prevention of adipose differentiation by RA in 3T3-L1 cells. Moreover, there seems no causal relationship between the prevention of adipose differentiation by RA and the up-regulation of RAR gamma 2 gene expression by RA in 3T3-L1 cells. We have shown the functional heterogeneity of RA action through different RARs in 3T3-L1 cells.
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PMID:The prevention of adipose differentiation of 3T3-L1 cells caused by retinoic acid is elicited through retinoic acid receptor alpha. 793 25

Metabolic disorders including diabetes mellitus, glucose intolerance, dyslipidemias, hyperuricemia, and hypervitaminosis A have often been mentioned in association with diffuse idiopathic skeletal hyperostosis (DISH). Production of bone under the influence of insulin or retinol has been suggested as a possible mechanism for this disease. We prospectively studied metabolic disorders in 25 patients with DISH and 25 controls matched for age, sex, and body mass index. Correlations between simultaneously evaluated parameters were looked for. Obesity was prevalent in both groups. Serum levels of glucose, insulin, glycated hemoglobin, total cholesterol, HDL cholesterol, triglycerides, uric acid, retinol, and retinol binding protein were similar in the two groups. A positive correlation was found between body mass index and serum insulin. We found no correlation between serum levels of insulin and retinol. None of the metabolic parameters studied showed alterations likely to explain the development of hyperostosis. Other growth factors such as retinoic acid or insulin-like growth factor 1, perhaps produced on a paracrine basis, may be the cause of increased bone at enthesis production.
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PMID:[Forestier disease and metabolism disorders. A prospective controlled study of 25 cases]. 816 24

Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that are expressed in a highly tissue-specific manner and bind to fatty acids such as oleic and retinoic acid. Mice with a null mutation in aP2, the gene encoding the adipocyte FABP, were developmentally and metabolically normal. The aP2-deficient mice developed dietary obesity but, unlike control mice, they did not develop insulin resistance or diabetes. Also unlike their obese wild-type counterparts, obese aP2-/- animals failed to express in adipose tissue tumor necrosis factor-alpha (TNF-alpha), a molecule implicated in obesity-related insulin resistance. These results indicate that aP2 is central to the pathway that links obesity to insulin resistance, possibly by linking fatty acid metabolism to expression of TNF-alpha.
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PMID:Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. 891 Feb 78

Uncoupling protein (UCP) is essential to the thermogenic function of brown adipose tissue (BAT). The thermogenic role of this protein is due to its capacity to uncouple oxidative phosphorylation in a regulated manner. The thermogenic potential of BAT is determined by its content of UCP. The gene encoding this protein is under complex regulation. Catecholamines, via cAMP, thyroid hormone and retinoic acid, directly stimulate the gene acting upon an upstream (-2.28/-2.49 kb) enhancer sequence, but cAMP may act upon other sequences of the gene as well. CCAAT enhancer binding proteins and peroxisome proliferation activator receptor (PPAR) gamma 2 have also been implicated in the regulation of the gene acting on discrete sequences. While the thyroid hormone response and retinoic acid response elements (TRE and RARE) have been well defined, the cAMP response elements (CRE) remain elusive. The two TREs are 27 bp apart between -2.33 kb and -2.39 kb. The synergism between cAMP and thyroid hormone seems to reside in a 39 bp sequence downstream (-2.28/-2.32 kb). The most important CRE, the RARE, a cell-specific enhancer and a putative PPAR element are all concentrated in a 90 bp regulatory element of great complexity (-2.40/-2.49 kb). Other hormones, such as insulin and glucocorticoids, and IGF-I also modulate the expression of the gene but their effects seem to be largely indirect. Understanding the regulation of the UCP gene expression may facilitate the development of interventions in obesity and related disorders.
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PMID:Regulation of the uncoupling protein gene expression. 910 May 46

Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate transcription. We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors? We demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating RXR: PPARgamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARgamma is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of noninsulin-dependent diabetes mellitus (NIDDM) and obesity, RXR agonists function as insulin sensitizers and can decrease hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. This antidiabetic activity can be further enhanced by combination treatment with PPARgamma agonists, such as thiazolidinediones. These data suggest that the RXR:PPARgamma heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance. Activation of the RXR:PPARgamma dimer with rexinoids may provide a new and effective treatment for NIDDM.
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PMID:Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. 912 58

Cancer is a common life-threatening disease. Prevention and therapy of the disease are the desire of everybody. This paper summarizes our attempt to the tough challenge. Chronologically we began the study of carcinogenesis, and then turned to the research of anticancer agents. Identification of food mutagens was extensively studied. Once they were identified, the mechanism of nucleic acid modifications by these mutagens had been studied. The modification study gave information on the nucleic acid modification by mitomycin and bleomycin. The structure-activity relationship study of phorbol esters and teleocidines whose tumor promotion is epigenetic, was extensively studied. On the other hand, retinoic acid, a vitamin A metabolite, suppresses the epigenetic tumor promotion. This suggests that an epigenetically active compound rather than a cytotoxic anticancer agent can be used for tumor suppression. In the retinoid research, we found a number of characteristic new active substances which may be of therapeutic use: some of them are in the clinical trial stages in the field of dermatology and cancer. During the chemical study of retinoids, we encountered the retinoic acid receptor, coded by the retinoic acid receptor (RAR) gene which had just reported. Further retinoid research yielded retinoids antagonists, and then RXR(retinoic acid-X-receptor)-agonists and RXR-antagonists. These ligands have a big potential in the therapy of diabetes and obesity.
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PMID:[From cancer prevention to cancer treatment]. 1108 9

Circulating adiponectin levels fall whereas leptin levels rise with obesity, suggesting that regulation of these two adipocyte-derived hormones may be simultaneously influenced by common obesity-related factors. We examined adiponectin mRNA levels in WAT and in some instances, brown adipose tissue (BAT) following fasting and refeeding, acute and chronic administration of a beta(3)-adrenergic agonist, acute treatment with retinoic acid (RA) and a glucocorticoid, and following chronic infusion of leptin and compared the expression of adiponectin to that of leptin in each circumstance. Serum concentrations of adiponectin were also reported for most of the treatments. Fasting diminished and refeeding reversed both adiponectin and leptin gene expression. Peripheral injection of the beta(3)-adrenergic agonist, CL316,243, suppressed both leptin and adiponectin expression in WAT. A small but significant reduction in adiponectin expression in BAT was also observed following this treatment. Although CL316,23 lowered serum leptin levels markedly, it did not affect serum adiponectin levels. A chronic 7-day infustion of CL316,243 resulted in an elevation of adiponectin expression in WAT and serum concentrations in contrast to suppressions in both mRNA and serum levels of leptin by a similar treatment as previously reported. Chronic administration of leptin did not alter adiponectin synthesis in WAT compared to controls, but prevented the reduction in adiponectin synthesis associated with pair feeding. Food restriction through pair feeding also diminished adiponectin expression in BAT. Collectively, although leptin and adiponectin are inversely correlated with obesity, leptin does not appear to participate directly in adiponectin synthesis. The short-term regulation of the two adipokine expression in WAT is somewhat similar, perhaps subjective to common control of energy balance. The long-term regulation of adiponectin expression in WAT appears to be the opposite of that of leptin and may be more sensitive to changes in adiposity or insulin sensitivity.
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PMID:Regulation of adiponectin and leptin gene expression in white and brown adipose tissues: influence of beta3-adrenergic agonists, retinoic acid, leptin and fasting. 1238 94

Neuropeptide Y (NPY) and the related receptors represent a widely diffused system that is involved in the regulation of multiple biological functions. NPY, a 36-aminoacid peptide expressed in several areas of the nervous system, is a pleiotropic factor participating to the control of some physiological processes, such as cognitive functions, eating behavior, circadian rhythms, neuroendocrine mechanisms, reproductive and cardiovascular functions. NPY acts through a series of G-protein-associated membrane receptors (NPY-Rs), characterized by different tissue distribution and affinity for the ligand. The expression and secretion of NPY and the expression of NPY-R isoforms are controlled by a very wide range of agents, acting in an endocrine and/or paracrine fashion. NPY and NPY-Rs appear to be strongly involved in the control of eating behavior; their expression is modulated by changes of food intake and energy balance and is disrupted in several animal models of obesity and diabetes. Moreover, the hypothalamic NPY system appears to integrate signals of energy balance in the modulation of the reproductive axis. Agents that stimulate their expression include activators of intracellular signalling pathways (protein kinase A and C), classical neurotransmitters, steroid and peptide hormones and growth factors, while other agents (leptin, insulin and retinoic acid) have been shown to be inhibitory. Interestingly, some agents, like retinoic acid, have been shown to modulate the expression of both NPY and NPY-Rs in the same direction, thus providing a fine mechanism for the tuning of the system. The regulation of NPY/NPY-R expression and function appears to be part of a complex system controlling multiple physiological functions, and its disruption might be relevant in the pathophysiology of disease states such as obesity.
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PMID:Hormonal control of the neuropeptide Y system. 1257 Jul 84

The ongoing global explosion in the incidence of obesity has focused attention on the development of adipose cells. Severe obesity is the result of an increase in fat cell size in combination with increased fat cell number. New fat cells arise from a pre-existing pool of adipose stem cells that are present irrespective of age. The development of established preadipocyte cell lines has facilitated the study of different steps leading to terminal differentiation. However, these systems are limited for studying early events of differentiation as they represent cells which are already determined for the adipogenic lineage. In vitro differentiation of mouse embryonic stem (ES) cells towards the adipogenic lineage provides an alternative source of adipocytes for study in tissue culture and offers the possibility to investigate regulation of the first steps of adipose cell development. In this review, we describe the sequential requirement of retinoic acid and PPARgamma during adipogenesis in ES cells. Stimulation of ES cells with synthetic retinoids which are selective ligands of the retinoic acid receptor isotypes allowed the investigation of the contribution of the different retinoic receptors on the RA-dependent differentiation. The effects of thiazolidinediones, a new class of pharmacological agents used for the treatment of type 2 diabetes, and of statins, drugs used in therapy for lowering cholesterol, on the differentiation of ES cells into adipocytes or osteoblasts are described. Finally, we propose a model in which PPARgamma plays a key role in the decision of stem cells to undergo differentiation into adipocytes or osteoblasts, two closely related lineages.
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PMID:Differentiation of embryonic stem cells for pharmacological studies on adipose cells. 1264 82


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