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)

We have investigated the effects of tyrosine on alternation behavior and hippocampal adrenergic and cholinergic tone in a model of self-induced weight loss caused by separation stress. Separation decreased body weight in mice (P < .001) and spontaneous alternations in the T-maze (P < .001). This impairment was associated with depletion of both norepinephrine (NE, P < .001) and dopamine (P < .01) while increasing MHPG (P < .05) and the ratio of MHPG/NE (P < .05). Increasing tyrosine availability restored performance to control levels (P < .001) and repleted dopamine (P < .05) and presumably also NE (indicated by increases in both MHPG, P < .001, and MHPG/NE, P < .05). Stress increased adrenergic alpha(2)-receptor density (P < .001) without changing its K(d) and the B(max) and K(d) of beta-receptors, suggesting that it decreased NE transmission through action on alpha(2)-receptors. The balance between beta- and alpha(2)-receptors appeared to be related to alternation behavior as shown by the decrease (P < .01) and increase (P < .05) in their ratios induced by stress and tyrosine, respectively. With regard to cholinergic tone, separation stress increased M1 receptor density (P < .05) and its mRNA signal (P < .001). Tyrosine further increased M1 receptor density of stressed mice (P < .05). Tyrosine might be a potential therapy for cognitive and mood problems associated with the maintenance of a reduced body weight in the treatment of obesity and in the extreme case of anorexia nervosa.
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PMID:Separation-induced body weight loss, impairment in alternation behavior, and autonomic tone: effects of tyrosine. 1126 32

The role of leptin and its receptor on the regulation of appetite and body fat was summarized. Leptin directly exerts its anorexigenic effects on arcuate nucleus via proopiomelanocortin and neuropeptide Y neurons. The anorexia and sympathetic nerve activation result in the reduction of body fat. But physiological concentrations of leptin could not reduce body fat in obese people, while genetic loss of central leptin effects induces obesity in children. Melanin concentrating hormone, orexin, and corticotropin-releasing hormone may be directly regulated by leptin. Serotonergic neurons may be separate from leptin effects. Phosphorylation of 985- and 1138-tyrosine of long-form leptin receptor activates SHP-2 and STAT3, respectively. Soluble leptin receptor concentrations in serum are negatively correlated with BMI. Clinical usefulness of leptin is now in progress.
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PMID:[Role of leptin and its receptor in the regulation of appetite and body fat]. 1126 87

Leptin is a 16 kDa protein secreted by fat cells which regulates body weight and thermogenesis at sites within the brain. Blood-borne leptin reaches those brain sites because of a saturable transport system located at the blood-brain barrier (BBB). Impaired transport occurs in obese rodents and likely underlies the resistance to the actions of peripheral leptin seen in obesity. Here, we show that leptin transport into the brain is enhanced 2-3-fold by epinephrine and other agents which are more specific for the alpha1 adrenergic receptor. Epinephrine had no effect on the transport across the BBB of insulin or tumor necrosis factor, on BBB integrity, or on the size of the vascular space of the brain. Dopamine, acetylcholine, histamine, serotonin, thyroid hormones, and phentolamine were without effect. Of several amino acids tested, only the catecholamine precursor tyrosine had an effect on leptin transport. Epinephrine was effective after intravenous or intraperitoneal injection, but neither epinephrine nor any of the other monoamines given by intracerebroventricular injection had an effect on leptin transport. These results show that epinephrine likely acts at a site on the luminal surface of the BBB. In conclusion, epinephrine works at an alpha1-like adrenergic, luminal side to enhance the transport of leptin across the BBB.
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PMID:Enhanced leptin transport across the blood-brain barrier by alpha 1-adrenergic agents. 1131 82

Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insulin resistance associated with obesity, a major risk factor for the development of type 2 diabetes. The insulin resistance induced by TNF-alpha is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. The aim of the current study was to dissect the mechanism whereby pioglitazone, one of the TZDs, ameliorates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes. Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was reduced by TNF-alpha, with concomitant restorations in tyrosine phosphorylation and protein levels of insulin receptor (IR) and insulin receptor substrate (IRS)-1, as well as association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase phosphorylation site (hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored TNF-alpha-induced decrease of triglyceride in adipocytes as effectively as pioglitazone. Overexpression of the PPAR-gamma proteins in TNF-alpha-treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. These results indicate that the ability of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-alpha-induced insulin resistance, may be independent of the adipogenic activity of PPAR-gamma that regulates protein levels of IR/IRS-1.
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PMID:Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma. 1133 12

Leptin is produced in adipose tissue and acts in the hypothalamus to regulate food intake. However, recent evidence also indicates a potential for direct roles for leptin in peripheral tissues, including those of the immune system. In this study, we provide direct evidence that macrophages are a target tissue for leptin. We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin. Leptin also stimulates both phosphoinositide 3-kinase (PI 3-kinase) activity and tyrosine phosphorylation of JAK2 and STAT3 in these cells. We investigated the effects of leptin on hormone-sensitive lipase (HSL), which acts as a neutral cholesterol esterase in macrophages and is a rate-limiting step in cholesterol ester breakdown. Leptin significantly increased HSL activity in J774.2 macrophages, and these effects were additive with the effects of cAMP and were blocked by PI 3-kinase inhibitors. Conversely, insulin inhibited HSL in macrophages, but unlike adipocytes, this effect did not require PI 3-kinase. These results indicate that leptin and insulin regulate cholesterol-ester homeostasis in macrophages and, therefore, defects in this process caused by leptin and/or insulin resistance could contribute to the increased incidence of atherosclerosis found associated with obesity and type 2 diabetes.
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PMID:Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways. 1133 38

Apolipoprotein A-IV (apo A-IV) is a glycoprotein synthesized by the human intestine. In rodents, both the small intestine and liver secrete apo A-IV, but the small intestine is the major organ responsible for the circulating apo A-IV. Intestinal apo A-IV synthesis is markedly stimulated by fat absorption and appears not to be mediated by the uptake or reesterification of fatty acids to form triglycerides. Rather, the formation of chylomicrons acts as a signal for the induction of intestinal apo A-IV synthesis. Intestinal apo A-IV synthesis is also enhanced by a factor from the ileum, probably peptide tyrosine-tyrosine. The inhibition of food intake by apo A-IV is mediated centrally. The stimulation of intestinal synthesis and the secretion of apo A-IV by lipid absorption are rapid; thus, apo A-IV likely plays a role in the short-term regulation of food intake. Other evidence suggests that apo A-IV may also be involved in the long-term regulation of food intake and body weight. Chronic ingestion of a high-fat diet blunts the intestinal apo A-IV response to lipid feeding and may explain why the chronic ingestion of a high-fat diet predisposes both animals and humans to obesity.
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PMID:The role of apolipoprotein A-IV in the regulation of food intake. 1137 36

Vanadium, a potent nonselective inhibitor of protein tyrosine phosphatases, has been shown to mimic many of the metabolic actions of insulin both in vivo and in vitro. The mechanism(s) of the effect of vanadium on the decrease in appetite and body weight in Zucker fa/fa rats, an insulin-resistant model, is still unclear. Because insulin may inhibit hypothalamic neuropeptide Y (NPY), which is known to be related to appetite, and increase leptin secretion in adipose tissue, we studied the possibility that the changes in appetite produced by vanadium may be linked to altered NPY levels in the hypothalamus. We also examined effects of vanadium on leptin. Zucker lean and fatty rats were chronically treated with bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, in the drinking water. Plasma and adipose tissue leptin levels were measured by radioimmunoassay and immunoblotting, respectively. Hypothalamic NPY mRNA and peptide levels were measured using in situ hybridization and immunocytochemistry, respectively. BMOV treatment significantly reduced food intake, body fat, body weight, plasma insulin levels, and glucose levels in fatty Zucker rats. Fifteen minutes after insulin injection (5 U/kg, intravenous [IV]), circulating leptin levels (+100%) and adipose leptin levels (+60%) were elevated in BMOV-treated fatty rats, although these effects were not observed in untreated fatty rats. NPY mRNA levels in the arcuate nucleus (ARC) (-29%), NPY peptide levels in ARC (-31%), as well as in the paraventricular nucleus (PVN) (-37%) were decreased with BMOV treatment in these fatty rats. These data indicate that BMOV may increase insulin sensitivity in adipose tissue and decrease appetite and body fat by decreasing NPY levels in the hypothalamus. BMOV-induced reduction in appetite and weight gain along with normalized insulin levels in models of obesity, suggest its possible use as a therapeutic agent in obesity.
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PMID:Effect of vanadium on insulin sensitivity and appetite. 1139 43

The central melanocortin receptors, melanocortin-4 (MC4R) and melanocortin-3 (MC3R), are involved in the regulation of satiety and energy homeostasis. The MC4R in particular has become a pharmaceutical industry drug target due to its direct involvement in the regulation of food intake and its potential therapeutic application for the treatment of obesity-related diseases. The melanocortin receptors are stimulated by the native ligand, alpha-melanocyte stimulating hormone (alpha-MSH). The potent and enzymatically stable analogue NDP-MSH (Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH(2)) is a lead peptide for the identification of melanocortin amino acids important for receptor molecular recognition and stimulation. We have synthesized nine peptide fragments of NDP-MSH, deleting N- and C-terminal amino acids to determine the "minimally active" sequence of NDP-MSH. Additionally, five peptides were synthesized to study stereochemical inversion at the Phe 7 and Trp 9 positions in attempts to increase tetra- and tripeptide potencies. These peptide analogues were pharmacologically characterized at the mouse melanocortin MC1, MC3, MC4, and MC5 receptors. This study has identified the Ac-His-DPhe-Arg-Trp-NH(2) tetrapeptide as possessing 10 nM agonist activity at the brain MC4R. The tripeptide Ac-DPhe-Arg-Trp-NH(2) possessed micromolar agonist activities at the MC1R, MC4R, and MC5R but only slight stimulatory activity was observed at the MC3R (at up to 100 microM concentration). This study has also examined to importance of both N- and C-terminal NDP-MSH amino acids at the different melanocortin receptors, providing information for drug design and identification of putative ligand-receptor interactions.
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PMID:Characterization of melanocortin NDP-MSH agonist peptide fragments at the mouse central and peripheral melanocortin receptors. 1140 61

Protein tyrosine phosphatases (PTPs) form a large family of enzymes that serve as key regulatory components in signal transduction pathways. Recent gene knockout studies in mice identify PTP1B as a promising target for anti-diabetes/obesity drug discovery. PTPs are also implicated in a wide variety of other disorders, including cancer. Significant progress has been made in identifying small molecules that simultaneously bind both the active site and a unique adjacent site that enables specific inhibition of individual PTP isoenzymes. As a consequence, there are compelling reasons to believe that PTP inhibitors may ultimately serve as powerful therapeutic weapons in our arsenal for battling human diseases.
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PMID:Protein tyrosine phosphatases: prospects for therapeutics. 1147 Jun 5

This article has attempted to point out some of the relationships between 5-HT and catecholamine (NE, DA) neurons in brain and the control of appetite and food intake. At least two bodies of evidence support this connection. The first is pharmacologic, and demonstrates that drugs that stimulate transmission across 5-HT and/or catecholamine synapses suppress hunger and food intake. The second is physiologic and metabolic, and reveals that the ingestion of foods, on either an acute (single meal) or chronic basis, can reliably modify the uptake of TRP and TYR into brain (and hypothalamus), and directly alter the synthesis of their transmitters (5-HT and the catecholamines, respectively). The synthesis of these two bodies of information has led to models by which (1) changes in dietary carbohydrate ingestion, by modifying brain TRP uptake and 5-HT production, may cause like changes in 5-HT release, and in the stimulation of 5-HT receptors in brain circuits that control carbohydrate appetite, and (2) dietary protein intake, by altering brain TYR uptake, directly influences DA and NE synthesis (notably in hypothalamus), perhaps providing a signal to brain circuits monitoring dietary protein adequacy regarding protein intake. In this case, one might imagine that stimulating DA and/or NE receptors in such circuits might suppress protein intake, a possibility we are now examining in rats. As indicated in the Introduction, the broader issue being touched upon in this article concerns the body's need to acquire and maintain an optimal (or adequate) nutritional balance (for growth and ultimately, reproductive success). Rats and humans evolved in an environment that does not provide continuous access to all essential nutrients, and one that presents nutrients in a complex matrix (other animals, plants) that can also include toxic compounds. Together with the fact that animals and humans do not carry a guidebook to healthy eating, we must presume that the brain mechanisms that have evolved to optimize the acquisition of essential nutrients are 'automatic' (i.e., not conscious) and quite complex. In this context, the relationships described here must be viewed as rudimentary, touching only a small portion of this complex regulatory mechanism. The hope is, as further insights develop, that we will gain a better understanding of the workings of these mechanisms, and also be able to apply this knowledge to the development of better pharmacologic (and other) aids for controlling appetite and obesity in our modern, man-made environment.
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PMID:Diet, monoamine neurotransmitters and appetite control. 1151 Apr 34


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