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)

Glucose, one of the most important nutrients for animals, acts as a regulatory signal that controls the secretion of hormones, such as insulin, by endocrine tissues. However, how organisms respond to extracellular glucose and how glucose controls nutrient homeostasis remain unknown. Here, we show that a putative Drosophila melanogaster G protein-coupled receptor, previously identified as Bride of sevenless (BOSS), responds to extracellular glucose and regulates sugar and lipid metabolism. We found that BOSS was expressed in the fat body, a nutrient-sensing tissue equivalent to mammalian liver and adipose tissues, and in photoreceptor cells. Boss null mutants had small bodies, exhibited abnormal sugar and lipid metabolism (elevated circulating sugar and lipid levels, impaired lipid mobilization to oenocytes), and were sensitive to nutrient deprivation stress. These phenotypes are reminiscent of flies defective in insulin signaling. Consistent with these findings are the observations that boss mutants had reduced PI3K activity and phospho-AKT levels, which indicates that BOSS is required for proper insulin signaling. Because human G protein-coupled receptor 5B and the seven-transmembrane domain of BOSS share the same sequence, our results also have important implications for glucose metabolism in humans. Thus, our study provides insight not only into the basic mechanisms of metabolic regulation but also into the pathobiological basis for diabetes and obesity.
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PMID:A Drosophila orphan G protein-coupled receptor BOSS functions as a glucose-responding receptor: loss of boss causes abnormal energy metabolism. 1883 80

The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an increased risk of cardiovascular disease and diabetes. The metabolic syndrome can be defined as a cluster of cardiovascular disease risk factors including visceral obesity, insulin resistance, dyslipidemia, increased blood pressure, and hypercoagulability. The farnesoid X receptor (FXR) belongs to the superfamily of ligand-activated nuclear receptor transcription factors. FXR is activated by bile acids, and FXR-deficient (FXR(-/-)) mice display elevated serum levels of triglycerides and high-density lipoprotein cholesterol, demonstrating a critical role of FXR in lipid metabolism. In an opposite manner, activation of FXR by bile acids (BAs) or nonsteroidal synthetic FXR agonists lowers plasma triglycerides by a mechanism that may involve the repression of hepatic SREBP-1c expression and/or the modulation of glucose-induced lipogenic genes. A cross-talk between BA and glucose metabolism was recently identified, implicating both FXR-dependent and FXR-independent pathways. The first indication for a potential role of FXR in diabetes came from the observation that hepatic FXR expression is reduced in animal models of diabetes. While FXR(-/-) mice display both impaired glucose tolerance and decreased insulin sensitivity, activation of FXR improves hyperglycemia and dyslipidemia in vivo in diabetic mice. Finally, a recent report also indicates that BA may regulate energy expenditure in a FXR-independent manner in mice, via activation of the G protein-coupled receptor TGR5. Taken together, these findings suggest that modulation of FXR activity and BA metabolism may open new attractive pharmacological approaches for the treatment of the metabolic syndrome and type 2 diabetes.
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PMID:Role of bile acids and bile acid receptors in metabolic regulation. 1912 57

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor mainly expressed in the central nervous system of vertebrates. Activation of the MC4R leads to a decrease in food intake, whereas inactivating mutations are a genetic cause of obesity. The binding of agouti-related protein (AGRP) reduces not only agonist-stimulated cAMP production (competitive antagonist) but also the basal activity of the receptor, as an inverse agonist. Transgenic zebrafish overexpressing AGRP display increased food intake and linear growth, indicative of a physiological role for the melanocortin system in the control of the energy balance in fish. We report on the cloning, pharmacological characterization, tissue distribution, and detailed brain mapping of a sea bass (Dicentrarchus labrax) MC4R ortholog. Sea bass MC4R is profusely expressed within food intake-controlling pathways of the fish brain. However, the activity of the melanocortin system during progressive fasting does not depend on the hypothalamic/pituitary proopiomelanocortin (POMC) and MC4R expression, which suggests that sea bass MC4R is constitutively activated and regulated by AGRP binding. We demonstrate that AGRP acts as competitive antagonist and reduces MTII-induced cAMP production. AGRP also decreases the basal activity of the receptor as an inverse agonist. This observation suggests that MC4R is constitutively active and supports the evolutionary conservation of the AGRP/MC4R interactions. The inverse agonism, but not the competitive antagonism, depends on the presence of a phosphodiesterase inhibitor (IBMX). This suggests that inverse agonism and competitive antagonism operate through different intracellular signaling pathways, a view that opens up new targets for the treatment of melanocortin-induced metabolic syndrome.
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PMID:Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax). 1922 41

Type 2 diabetes (T2D) and associated obesity have reached epidemic proportions, and there is an increasing need for orally effective agents that regulate glucose homeostasis with a concurrent reduction in body weight. GPR119, a class-A (rhodopsin-like) G protein-coupled receptor, expressed primarily in the human pancreas and gastrointestinal tract, has attracted considerable interest as a T2D drug target in the last three to five years. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion and increased levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide). In rodent models, orally available GPR119-specific agonists have been shown to attenuate blood glucose levels with a simultaneous body weight loss. This review summarizes the research leading to the identification of GPR119 as a potential drug target for T2D and related metabolic disorders. In addition, an overview of the recent progress made in the discovery of orally active GPR119 agonists is provided.
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PMID:GPR119 agonists: a promising new approach for the treatment of type 2 diabetes and related metabolic disorders. 1956 48

In this issue of Cell Metabolism, Thomas et al. (2009) show that specific activation of the bile-acid-activated G protein-coupled receptor TGR5 improves pancreatic and hepatic function and impairs the development of obesity following administration of a high-fat diet.
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PMID:Bile acids have the gall to function as hormones. 1972 93

TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies in vivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6alpha-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777), a specific TGR5 agonist, is linked to an increase of the intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization. Altogether, these data show that the TGR5 signaling pathway is critical in regulating intestinal GLP-1 secretion in vivo, and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.
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PMID:TGR5-mediated bile acid sensing controls glucose homeostasis. 2039 10

TGR5 is a G protein-coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. In the present study, we evaluated the ability of bile alcohols, which are structurally and physiologically similar to bile acids and are produced as the end products of cholesterol catabolism in evolutionarily primitive vertebrates, to act as TGR5 agonists. In a cell-based reporter assay and a cAMP production assay performed in vitro, most bile alcohols with a side chain containing hydroxyl group(s) were highly efficacious agonists for TGR5 comparable to its most potent ligand in the naturally occurring bile acid, lithocholic acid. However, the abilities of the bile alcohols to activate TGR5 varied with the position and number of the hydroxyl substituent in the side chain. Additionally, the conformation of the steroidal nucleus of bile alcohols is also important for its activity as a TGR5 agonist. Thus, we have provided new insights into the structure-activity relationships of bile alcohols as TGR5 agonists.
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PMID:Bile alcohols function as the ligands of membrane-type bile acid-activated G protein-coupled receptor. 2002 5

The human cannabinoid 1 receptor (hCB1), a ubiquitous G protein-coupled receptor (GPCR), transmits cannabinergic signals that participate in diverse (patho)physiological processes. Pharmacotherapeutic hCB1 targeting is considered a tractable approach for treating such prevalent diseases as obesity, mood disorders, and drug addiction. The hydrophobic nature of the transmembrane helices of hCB1 presents a formidable difficulty to its direct structural analysis. Comprehensive experimental characterization of functional hCB1 by mass spectrometry (MS) is essential to the targeting of affinity probes that can be used to define directly hCB1 binding domains using a ligand-assisted experimental approach. Such information would greatly facilitate the rational design of hCB1-selective agonists/antagonists with therapeutic potential. We report the first high-coverage MS analysis of the primary sequence of the functional hCB1 receptor, one of the few such comprehensive MS-based analyses of any GPCR. Recombinant C-terminal hexa-histidine-tagged hCB1 (His6-hCB1) was expressed in cultured insect (Spodoptera frugiperda) cells, solubilized by a procedure devised to enhance receptor purity following metal-affinity chromatography, desalted by buffer exchange, and digested in solution with (chymo)trypsin. "Bottom-up" nanoLC-MS/MS of the (chymo)tryptic digests afforded a degree of overall hCB1 coverage (>94%) thus far reported for only two other GPCRs. This MS-compatible procedure devised for His6-hCB1 sample preparation, incorporating in-solution (chymo)trypsin digestion in the presence of a low concentration of CYMAL-5 detergent, may be applicable to the MS-based proteomic characterization of other GPCRs. This work should help enable future ligand-assisted structural characterization of hCB1 binding motifs at the amino-acid level using rationally designed and targeted covalent cannabinergic probes.
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PMID:Mass spectrometry-based GPCR proteomics: comprehensive characterization of the human cannabinoid 1 receptor. 2013 67

TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies invivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6alpha-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777), a specific TGR5 agonist, is linked to an increase of the intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization. Altogether, these data show that the TGR5 signaling pathway is critical in regulating intestinal GLP-1 secretion invivo, and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.
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PMID:A new life for bile acids. 1972 93

The newly discovered G protein-coupled receptor GPR120 has recently been shown to stimulate secretion of the gut hormones glucagon-like peptide-1 and cholecystokinin upon binding of free fatty acids, thrusting it to the forefront of drug discovery efforts for treatment of type 2 diabetes as well as satiety and obesity. Although sequences for two alternative splice variants of the human GPR120 receptor have been reported, there have been no studies which directly compare the signaling of these isoforms. We have identified an additional 16 amino acid gap containing four phospho-labile serine/threonine residues which is localized to the third intracellular loop of the GPR120-long (GPR120-L) isoform. Based on this finding, we hypothesized that the agonist-stimulated phosphorylation profiles of this isoform would be distinct from that of the short isoform (GPR120-S). Using a clonal HEK293 cell model, we examined agonist-mediated phosphorylation of GPR120-S and GPR120-L with the omega-3 fatty acids alpha-linolenic acid (ALA) and docosahexaenoic acid (DHA). Our results show rapid phosphorylation of both isoforms following agonism by either ALA or DHA. Moreover, we show no significant difference in the degree or rate of phosphorylation of both isoforms upon agonism with either ALA or DHA, suggesting that the additional gap in the longer variant is not phosphorylated. Importantly, our results demonstrate that the shorter variant exhibits significantly more pronounced basal phosphorylation in the absence of agonist, suggesting that the additional gap in the long variant may contribute to masking of constitutive phosphorylation sites. These are the first results which demonstrate specific phosphorylation of GPR120 isoforms upon agonism by free fatty acids and the first which distinguish the phosphorylation profiles of the two GPR120 isoforms.
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PMID:Agonism with the omega-3 fatty acids alpha-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human GPR120 receptor. 2047 68


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