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

CART peptides are relatively novel neuropeptides involved in feeding, drug reward and stress. They are formed from a proCART polypeptide that is 89 amino acids in length in the human version. Fragments 42-89 and 49-89 are behaviorally active in feeding and locomotion as well and other functions. These peptides are highly abundant and widely but discretely distributed in the brain, gut, pituitary, adrenals and pancreas. The presence of CART immunoreactivity in specific nuclei of the hypothalamus has led to an examination of icv-injected CART peptides effects on feeding, which have proven to be significantly anorectic. Studies of transgenic animals and humans have also demonstrated a linkage to both obesity and anorexia. Similarly, the localization of CART to sub-regions of the mesolimbic dopamine system has led to demonstration of the effects of CART peptides on locomotor activity and conditioned place preference when injected into the ventral tegmental area (VTA), which are psychostimulant-like in quality. These findings also suggest that CART has the capacity to modulate mesolimbic dopamine, which could have implications for the treatment not only of psychostimulant abuse but also for the treatment of other disorders with mesolimbic dopamine involvement, such as schizophrenia. Other lines of evidence also show that CART peptides are involved in fear and startle behaviors which may have implications for understanding anxiety and stress. An important part of the development of CART mimetics and related drugs would be the identification of CART receptors. At the present time such receptors have not been identified, and much effort should be directed at this problem. Nonetheless, CART peptides offer interesting targets for new drug development for obesity and, potentially, a number of other disorders.
 ...
PMID:CART peptides as targets for CNS drug development. 1276

Adiponectin (Acrp30) is a physiologically active polypeptide hormone secreted by adipose tissue that shows insulin-sensitizing, antiinflammatory, and antiatherogenic properties. In humans, Acrp30 levels are inversely related to the degree of adiposity. In the current study, we tested the long-term weight-reducing and insulin-enhancing effects of Acrp30 cDNA delivered peripherally by a viral vector. To this end, we have generated a series of recombinant adeno-associated virus vectors of serotypes 1 and 5 encoding mouse Acrp30 cDNAs. The long-term expression of recombinant adeno-associated virus-Acrp30 vectors was tested after intramuscular or intraportal injection in female Sprague-Dawley rats with diet-induced obesity. We show that a single peripheral injection of 10(12) physical particles of Acrp30-encoding vectors resulted in sustained (up to 280 days) significant reduction in body weight, concomitant with the reduction in daily food intake. Acrp30 treatment resulted in higher peripheral insulin sensitivity measured by the i.p. glucose tolerance test in fasted animals. Ectopic expression of the Acrp30 transgene resulted in modulation of hepatic gluconeogenesis and lipogenesis, as demonstrated by the reduction of the expression of two key genes: PEPCK (phosphoenolpyruvate carboxykinase) and SREBP-1c (sterol regulatory element-binding protein 1c) in the liver. These data show successful peripheral therapy in a clinically relevant model for human obesity and insulin resistance.
 ...
PMID:Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. 1461 71

Although described initially as an intracellular adipocyte-specific triacylglycerol lipase, it is now clear that HSL (hormone-sensitive lipase) is expressed in multiple tissues and plays a number of roles in lipid metabolism, including that of a neutral cholesteryl ester hydrolase. The major isoform is a single polypeptide with a molecular mass of approx. 84 kDa and which comprises three major domains: a catalytic domain, a regulatory domain encoding several phosphorylation sites and an N-terminal domain involved in protein-protein and protein-lipid interactions. The activity of HSL is regulated acutely by several mechanisms, including reversible phosphorylation by a number of different protein kinases, translocation to different sites within the cell and interaction with a number of proteins, some of which may serve to direct the inhibitory products of HSL away from the protein. It is also apparent from work with HSL null mice that more than one enzyme species may be classified as a hormone-sensitive lipase. The possible presence of HSL in macrophages remains controversial, and the role of the protein in pancreatic beta-cells has yet to be fully elucidated. Altered expression of HSL in different cell types may be associated with a number of pathological states, including obesity, atherosclerosis and Type II diabetes.
 ...
PMID:Hormone-sensitive lipase--new roles for an old enzyme. 1472 7

The blood-brain barrier (BBB) used to be considered impermeable to polypeptides. However, this view has evolved rapidly over the past two decades. Not only do polypeptides have the potential to serve as carriers for selective therapeutic agents, but they themselves may directly cross the BBB after delivery into the bloodstream to become potential treatments for a variety of CNS disorders, including neurodegeneration, autoimmune diseases, stroke, depression, and obesity. The interactions of polypeptides with the BBB can take many forms, such as simple diffusion, saturable transport, or facilitation of entry of another peptide or protein. In some instances, interactions in the blood compartment (outside the BBB) or within the endothelial cells (at the BBB level) can significantly impede the passage of polypeptides across the BBB. We shall review the different aspects of interactions between peptides/proteins and the BBB that affect their delivery as potential drugs in their natural form, and discuss recent advances in the cell biology of polypeptide transport across the BBB. Better understanding of the BBB will provide insight and direction for future research in the treatment of CNS disorders.
 ...
PMID:Polypeptide delivery across the blood-brain barrier. 1507 88

Obesity is one of the greatest threats to the health of the developed world. In order to design effective drugs to treat the alarming increase in obesity, it is essential to understand the physiology of normal appetite control and the pathophysiology of obesity. The hypothalamus interprets and integrates neural and humoral inputs to provide a coordinated feeding and energy expenditure response. Recent evidence suggests that certain gut hormones - ghrelin, polypeptide YY, pancreatic polypeptide, glucagon-like-peptide 1 and oxyntomodulin - have a physiological role in governing satiety via the hypothalamus. Gut hormone appetite-regulatory systems represent a potential target for the design of antiobesity drugs.
 ...
PMID:Gut hormones in the control of appetite. 1518 57

Adiponectin (Adipocyte Complement-Related Protein of 30 kDa, ACRP30) and resistin are adipocyte-derived polypeptide hormones playing a role in metabolic homeostasis. Their plasma levels are inversely (adiponectin) or directly (resistin) correlated to obesity and they have opposite effects on insulin sensitivity. Adipose tissue hormones such as leptin have been shown to modulate neurotransmitters which control feeding in the hypothalamus. We have studied the effects of adiponectin and resistin on dopamine, norepinephrine and serotonin release from hypothalamic neuronal endings (synaptosomes) in vitro. We have found that adiponectin does not modify either basal or depolarization-induced amine release, while resistin inhibits the stimulated release of dopamine and norepinephrine, leaving unaffected serotonin release. We can conclude that, similarly to leptin, but differently from adiponectin, the adipose tissue hormone resistin could affect the central mechanisms of feeding by inhibiting catecholamine release in the hypothalamus.
 ...
PMID:Resistin, but not adiponectin, inhibits dopamine and norepinephrine release in the hypothalamus. 1518 62

The 42 amino acid polypeptide glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is released from intestinal K-cells in response to nutrient ingestion. Based on animal studies, the peptide was initially assumed to act as an endogenous inhibitor of gastric acid secretion. Later it was found that GIP is capable of augmenting glucose-stimulated insulin secretion, and subsequent studies provided evidence that, in humans, the peptide predominantly acts as an incretin hormone. A role for GIP in the regulation of lipid homeostasis and in the development of obesity has been inferred from different animal studies. While GIP strongly stimulates insulin release in healthy humans, the peptide has almost completely lost its insulinotropic effect in patients with type 2 diabetes. This is different from the actions of glucagon-like peptide 1, which stimulates insulin secretion even in the later stages of type 2 diabetes. This suggests that a diminished insulinotropic effect of GIP may contribute to the pathogenesis of type 2 diabetes. This review will summarize the actions of GIP in human physiology and discuss its role in the pathogenesis of type 2 diabetes, as well as the therapeutic options derived from these findings.
 ...
PMID:Clinical endocrinology and metabolism. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. 1553 77

Insulin-like growth factor II (IGF-II) is a polypeptide that plays a key role in mammalian growth, influencing fetal cell division, differentiation, and possibly metabolic regulation. In adult humans, polymorphisms of the IGF2 gene have been associated with predisposition to obesity. In the present study, we tested the association between IGF2/ApaI genotype and Body Mass Index (BMI) in 294 healthy volunteers (95 men and 199 women; 18-30y) and correlated the results with their birth weights (BW) in order to investigate the relationship between this polymorphic site, fetal life and adult BMI. Blood samples were obtained for DNA extraction, PCR and genotyping. The statistical analyses were performed by the Chi-square, Kolmogorov-Smirnov normality, and Tukey post hoc tests. Although the IGF2 genotype was not significantly associated with BMI and/or BW, we observed a statistically significant correlation of 0.33 (p < 0.023) between BW and BMI in GG subjects whose BW was higher than 3.5 kg (n = 47). We hypothesize that high BWs associated with homozygosis for the G allele of IGF2/ApaI is not a null factor and might be associated with predisposition to high BMI in young adults.
 ...
PMID:Association between birth weight, body mass index and IGF2/ApaI polymorphism. 1610 92

Resistin is a member of a class of cysteine-rich proteins collectively termed resistin-like molecules. Resistin has been implicated in the pathogenesis of obesity-mediated insulin resistance and T2DM (Type II diabetes mellitus), at least in rodent models. In addition, resistin also appears to be a pro-inflammatory cytokine. Taken together, resistin, like many other adipocytokines, may possess a dual role in contributing to disease risk. However, to date there has been considerable controversy surrounding this 12.5 kDa polypeptide in understanding its physiological relevance in both human and rodent systems. Furthermore, this has led some to question whether resistin represents an important pathogenic factor in the aetiology of T2DM and cardiovascular disease. Although researchers still remain divided as to the role of resistin, this review will place available data on resistin in the context of our current knowledge of the pathogenesis of obesity-mediated diabetes, and discuss key controversies and developments.
 ...
PMID:Role of resistin in obesity, insulin resistance and Type II diabetes. 1610 44

Targeted deletion of the gene encoding the neuronal and endocrine secreted peptide precursor called VGF (nonacronymic) produces a lean, hypermetabolic, hyperactive mouse. Because VGF mutant mice are resistant to specific forms of diet-, lesion-, and genetically induced obesity, we investigated the role that this polypeptide plays in glucose homeostasis. We report that VGF mutant mice have increased insulin sensitivity by hyperinsulinemic euglycemic clamp analysis, and by insulin and glucose tolerance testing. Blunted counterregulatory responses in VGF-deficient mice were likely influenced by their significantly lower liver glycogen levels. VGF deficiency lowered circulating glucose and insulin levels in several murine models of obesity that are also susceptible to adult onset diabetes mellitus, including A(y)/a agouti, ob/ob, and MC4R(-)/MC4R(-) mice. Interestingly, ablation of Vgf in ob/ob mice decreased circulating glucose and insulin levels but did not affect adiposity, whereas MC4R(-)/MC4R(-) mice that are additionally deficient in VGF have improved insulin responsiveness at 7-8 wk of age, when lean MC4R(-)/MC4R(-) mice already have impaired insulin tolerance but are not yet obese. VGF mutant mice also resisted developing obesity and hyperglycemia in response to a high-fat/high-carbohydrate diet, and after gold thioglucose treatment, which is toxic to hypothalamic glucose-sensitive neurons. Lastly, circulating adiponectin, an adipose-synthesized protein the levels of which are correlated with improved insulin sensitivity, increased in VGF mutant compared with wild-type mice. Modulation of VGF levels and/or VGF signaling may consequently represent an alternative means to regulate circulating glucose levels and insulin sensitivity.
 ...
PMID:VGF ablation blocks the development of hyperinsulinemia and hyperglycemia in several mouse models of obesity. 1614 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>