guanosine-triphosphate and Obesity

The characterisation of receptor sites of hormones to various tissues in vivo and in vitro have introduced new insights for the evaluation of pathogenic mechanisms involved in endocrine and metabolic human diseases. Disorders at the receptor level are characterized by changes in the number of receptor sites, the affinity of the hormone to its specific receptors or by generation of anti-receptor antibodies, which impair hormone binding procedures or post-receptor metabolism. Altered receptor physiology may be of an important value as well for diagnosis and treatment of endocrine, metabolic and neoplastic diseases as for the understanding of their pathogenetic mechanisms.

Topics: Acanthosis Nigricans; Adenosine Triphosphate; Adenylyl Cyclases; Antibodies; Binding, Competitive; Cyclic AMP; Diabetes Complications; Endocrine System Diseases; Enzyme Activation; Graves Disease; Guanosine Triphosphate; Humans; Hypercholesterolemia; Insulin; Insulin Resistance; Lipoproteins, LDL; Metabolic Diseases; Myasthenia Gravis; Obesity; Receptors, Androgen; Receptors, Cell Surface; Receptors, Neurotransmitter

The objective of the current study was to explore the potential mechanism of Ziyang selenium-enriched green tea polysaccharide (Se-GTP) against obesity. The results showed that Se-GTP significantly alleviated obesity and related metabolic disorders caused by high-fat diet (HFD) in mice. 16S rRNA gene sequencing results revealed that Se-GTP improved gut microbiota disturbance of obese mice and facilitated proliferation of probiotics such as

Topics: Animals; Gastrointestinal Microbiome; Guanosine Triphosphate; Mice; Mice, Obese; Obesity; Polysaccharides; RNA, Ribosomal, 16S; Selenium

Green tea polyphenols (GTPs) exhibit beneficial effects towards obesity and intestinal inflammation; however, the mechanisms and association with gut microbiota are unclear. We examined the role of the gut microbiota of GTPs treatment for obesity and inflammation. Canines were fed either a normal diet or high-fat diet with low (0.48% g/kg), medium (0.96% g/kg), or high (1.92% g/kg), doses of GTPs for 18 weeks. GTPs decreased the relative abundance of Bacteroidetes and Fusobacteria and increased the relative abundance of Firmicutes as revealed by 16S rRNA gene sequencing analysis. The relative proportion of Acidaminococcus, Anaerobiospirillum, Anaerovibrio, Bacteroides, Blautia, Catenibactetium, Citrobacter, Clostridium, Collinsella, and Escherichia were significantly associated with GTPs-induced weight loss. GTPs significantly (P<.01) decreased expression levels of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and inhibited induction of the TLR4 signaling pathway compared with high-fat diet. We show that the therapeutic effects of GTPs correspond with changes in gut microbiota and intestinal inflammation, which may be related to the anti-inflammatory and anti-obesity mechanisms of GTPs.

Topics: Animals; Cluster Analysis; Diet, High-Fat; Dietary Supplements; Dogs; Firmicutes; Fusobacteria; Gastrointestinal Microbiome; Guanosine Triphosphate; Inflammation; Intestinal Mucosa; Intestines; Male; Obesity; Phylogeny; Polyphenols; RNA, Ribosomal, 16S; Signal Transduction; Tea; Toll-Like Receptor 4; Weight Gain

There is increasing interest in ultrasound-diagnosed non-alcoholic fatty liver disease (NAFLD) in the ambulatory care setting. The aim of this study was to determine the clinical and metabolic features of ultrasound-diagnosed NAFLD.. Fifty ultrasound-diagnosed NAFLD patients who had not consumed alcohol for at least the previous 3 months were matched with 100 controls by age and gender distribution. Clinical, biochemical, and nutritional variables were compared between the ultrasound-diagnosed NAFLD patients and the controls. Conditional logistic regression analyses were used to identify independent factors associated with ultrasound-diagnosed NAFLD.. The ultrasound-diagnosed NAFLD patients had higher values on the anthropometric measurements than those of the controls. Aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), uric acid, and gamma-glutamyl transpeptidase levels were higher in the ultrasound-diagnosed NAFLD patients than those in the controls (p<0.001). The ASAT/ALAT ratio of the ultrasound-diagnosed NAFLD patients was lower than that of the controls (p<0.001). Total cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol, non-HDL-cholesterol, atherogenic index, fasting glucose, systolic blood pressure (BP), diastolic BP, and pulse pressure were higher in the ultrasound-diagnosed NAFLD patients than in the control subjects, while lipoprotein(a) was lower. There were no significant differences in low-density lipoprotein (LDL)-cholesterol levels or nutritional intake between patients and controls. Abnormal ASAT or ALAT, hypertriglyceridemia, lower HDL-cholesterol levels, silent myocardial ischemic pattern on electrocardiogram (ECG), impaired fasting glucose, and obesity were common among the ultrasound-diagnosed NAFLD patients. The only independent factor associated with ultrasound-diagnosed NAFLD was obesity (p<0.001).. Our data suggest that NAFLD diagnosed by ultrasound is associated with hypertriglyceridemia, impaired fasting glucose, silent myocardial ischemic pattern of ECG, obesity, and abnormal liver tests in adults. Among these factors, obesity was the only independent factor associated with ultrasound-diagnosed NAFLD.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Fatty Liver; Guanosine Triphosphate; Humans; Korea; Lipids; Liver Function Tests; Obesity; Odds Ratio; Ultrasonography

Lipolysis and adenylyl cyclase (AC) activation in response to beta-adrenergic agents are abnormally low in white epididymal adipose tissue (WAT) of the ob/ob mouse. The abundance of G-proteins (Gs alpha and Gi alpha) linked to AC is also abnormally low. By contrast, beta-adrenergic receptor (beta-AR) levels were previously found to be normal in WAT and elevated in liver. The relative importance of various forms of the beta-AR in mouse WAT was reassessed in view of the discovery of the beta 3-AR. The results show that (1) the beta 3-AR is mainly responsible for AC activation in lean-mouse WAT; (2) the beta 3-AR is only partly responsible for AC activation in obese mouse WAT; and (3) GTP modulates beta 3--but not beta 1--or beta 2-AR activation of AC in a biphasic manner. Therefore, the beta 3-AR appears responsible for the well-known bimodal effect of GTP on beta-adrenergic receptor-mediated AC activity in WAT.

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclases; Adipocytes; Adipose Tissue; Adrenergic beta-Agonists; Albuterol; Analysis of Variance; Animals; Cell Membrane; Dioxoles; DNA Probes; DNA, Complementary; Enzyme Activation; Epididymis; GTP-Binding Proteins; Guanosine Triphosphate; Isoproterenol; Kinetics; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Propranolol; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Thinness; Virulence Factors, Bordetella

Studies were designed to find the molecular basis for previous observations that lipolysis is less active and A1 adenosine receptor signaling is more active in adipocytes from obese than from lean Zucker rats. With quantitative immunoblot procedures for detection, Gi alpha 1 and Gs alpha 45 levels were found anomalously low in obese compared with lean membranes (50 and 30%, respectively), but other G alpha subunit levels were normal. However, the sensitivity of the receptor-Gi protein to GTP was about 5- to 10-fold higher in obese compared with lean membranes when assessed from 1) the ability of GTP to inhibit forskolin-stimulated adenylyl cyclase in the presence of an adenosine receptor agonist and 2) the ability of a nonhydrolyzable guanine nucleotide analogue to alter A1 adenosine receptor agonist binding. Alkaline phosphatase treatment of isolated adipocyte membranes from obese but not lean animals decreased guanine nucleotide sensitivity of agonist binding. Surprisingly, solubilized adipocyte A1 adenosine receptors from all animals exhibited the same high sensitivity to guanine nucleotides as that of intact obese membranes, and this high sensitivity could be decreased 20-fold by treatment with alkaline phosphatase. These data suggest that protein phosphorylation may regulate coupling of the A1 adenosine receptor in rat adipocyte membranes.

Topics: Adenosine; Adenylyl Cyclases; Adipocytes; Animals; Cell Membrane; Colforsin; Cyclic AMP; Guanine Nucleotides; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Iodine Radioisotopes; Iodobenzenes; Obesity; Phosphorylation; Proteins; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Purinergic P1

Attenuated maximal activations by forskolin, Mn+. NaF or guanosine 5'-[gamma-thio]triphosphate (GTP[S]) were noted for adenylate cyclase activity in adipocytes from obese (fa/fa) Zucker rats compared with their lean (Fa/Fa) littermates. GTP[S] achieved half-maximal activation of adenylate cyclase at some 10-fold lower concentrations in membranes from lean animals compared with those from obese. Levels of the 42 and 45 kDa forms of Gs were some 40-50% lower in membranes from obese animals, and levels of Gi-1 and Gi-3 were some 62-65% lower. No differences in levels of Gi-2 alpha-subunits or G-protein beta-subunits were observed. Gi function, as assessed by inhibiting forskolin-stimulated adenylate cyclase, achieved by prostaglandin E1, nicotinate and phenylisopropyladenosine, was similar in membranes from both lean and obese animals. Levels of beta-adrenoceptors were some 50% lower in membranes from obese animals. It is suggested that the attenuated activation of adenylate cyclase by stimulatory ligands in membranes from obese animals may be caused by decreases in both Gs and receptors, and that this may contribute to the attenuated lipolytic response seen in adipocytes from such animals.

Topics: Adenylyl Cyclases; Adipose Tissue; Animals; Cell Membrane; Cells, Cultured; Glucagon; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Isoproterenol; Kinetics; Macromolecular Substances; Male; Obesity; Rats; Rats, Zucker; Secretin; Thyrotropin

Lipolysis in rat adipocytes is controlled by the hormonally mediated stimulation and inhibition of adenylate cyclase. This dual regulation involves stimulatory (Gs) and inhibitory (Gi) GTP-binding proteins which control cAMP production in a GTP dependent manner. Adenosine, acting via the A1 receptor-Gi complex provides tonic regulation of adenylate cyclase and lipolysis in rat adipocytes. Adipocytes prepared from young obese Zucker (fa/fa) rats exhibit less stimulation (or greater inhibition) in response to adenosine deaminase, alone or in combination with lipolytic hormones, as compared with their lean littermates. Adenylate cyclase, measured in membranes prepared from obese adipocytes, showed decreased sensitivity to activation by low concentrations of GTP and was not inhibited by higher concentrations of the guanine nucleotide which, in lean control rats results in a biphasic activity curve. Adenosine A1 receptor binding, measured in these same membranes, demonstrated an increased sensitivity to activation by the GTP analogue, guanylyl imidodiphosphate. The presence of the analogue results in the dissociation of the receptor-Gi complex and conversion to the low affinity form in a greater proportion of receptors in the obese membranes. These results are consistent with an increased sensitivity to adenosine mediated inhibition of adenylate cyclase and lipolysis in the fat cells of the young obese (fa/fa) Zucker rat.

Topics: Adenosine; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Adipose Tissue; Animals; Awards and Prizes; Cell Membrane; Cyclic AMP; Dietetics; Female; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Isoproterenol; Lipolysis; Obesity; Phenylisopropyladenosine; Rats; Rats, Zucker; Receptors, Purinergic; Societies, Medical; United States

The abundance of the alpha and beta subunits of the GTP-binding proteins (G-proteins) that transduce hormonal messages to adenylate cyclase was assessed in adipocyte membranes from lean (+/+) and obese (ob/ob) mice, using ADP-ribosylation with bacterial toxin and immunodetection. Both methods revealed two Gs alpha species (48 and 42 kDa) in the membranes. Compared with those of lean mice, the membranes from obese mice contained substantially less of the 48 kDa species of Gs alpha, as assessed by both methods. ADP-ribosylation by pertussis toxin showed that only half as much ADP-ribose was incorporated into Gi alpha in the membranes from obese as compared with lean mice. Immunodetection revealed two separate Gi alpha peptides (39 and 40 kDa) and showed that the 40 kDa species was less abundant in the membranes from obese mice, whereas the amount of the 39 kDa species was similar in membranes from both lean and obese animals. Based on ADP-ribosylation assays, in membranes from lean mice the ratio Gs alpha/Gi alpha was 1:16, whereas in the membranes from obese mice it was 1:10. Similar amounts of immunodetectable beta peptide were found in both types of membranes. On the basis of the currently accepted dissociation model of adenylate cyclase activation, the decrease in the abundance of the Gi alpha subunit in adipocyte membranes from obese mice could account for the abnormal kinetics of the enzyme in these membranes.

Topics: 5'-Nucleotidase; Adenosine Diphosphate Ribose; Adenylate Cyclase Toxin; Adenylyl Cyclases; Adipose Tissue; Animals; Cell Membrane; GTP-Binding Proteins; Guanosine Triphosphate; Immunoblotting; Macromolecular Substances; Male; Mice; Mice, Inbred C57BL; Obesity; Pertussis Toxin; Sodium-Potassium-Exchanging ATPase; Virulence Factors, Bordetella

Adenylate cyclase activity was determined in membranes of liver, muscle, white adipose tissue, and brown adipose tissue (BAT) of lean (Fa/) and obese (fa/fa) Zucker rats. Responses were monitored following beta-adrenergic receptor stimulation and addition of GTP, GTP gamma S, or forskolin. beta-Adrenergic responses in liver, white adipose tissue, and BAT were lower in obese than in lean animals. No such difference was observed in muscle membranes. Production of cAMP after addition of guanine nucleotides was lower in liver and white adipose tissue membranes from obese rats compared with their lean littermates. Synthesis of cAMP in muscle membranes of obese animals after addition of GTP was either not different, or slightly higher, than that observed in muscle membranes from lean animals. Furthermore, production of cAMP after forskolin addition to muscle membranes of obese rats was significantly higher than that observed from lean rats under the same conditions. Interestingly, BAT membranes of obese rats were significantly more sensitive to guanine nucleotide activation than those of lean animals. The results confirm recent findings indicating inferior function of G proteins in liver plasma membranes of obese Zucker rats, and extend this observation to adipose tissue. The present results further suggest that the "nonreceptor" components (e.g., G proteins) responsible for the activation of adenylate cyclase in BAT membranes of obese rats are more responsive to stimulation than those of lean animals. Such sensitivity may be related to and perhaps compensate for the reduced thermogenic activity in the obese Zucker rat during the development of obesity.

Topics: Adenylyl Cyclases; Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Colforsin; Cyclic AMP; Dose-Response Relationship, Drug; Female; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Isoproterenol; Liver; Muscles; Norepinephrine; Obesity; Organ Size; Rats; Rats, Zucker; Receptors, Adrenergic, beta

Adenylate cyclase activity and its modulation by guanine nucleotides and isoproterenol were assessed in adipocyte membranes of mice with mutations causing different genetic obesity syndromes. The object was to determine whether the defect in inhibitory modulation observed in the obese (ob/ob) mouse was also present in the diabetes (db/db) mouse. The data show that adipocyte adenylate cyclase in both the ob/ob and the db/db mouse is resistant to activation by isoproterenol. The response to guanosine triphosphate (GTP) differed between the two mutants, such that an inhibitory phase was visible in the db/db but not in the ob/ob membranes. Moreover, pertussis toxin attenuated the inhibitory effect of GTP and significantly stimulated cyclase activity in the db/db but not in the ob/ob membranes. The data show that the two mutations affect the expression of adenylate cyclase activity via different mechanisms.

Topics: Adenylyl Cyclases; Adipose Tissue; Animals; Cell Membrane; Diabetes Mellitus, Experimental; Enzyme Activation; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Isoproterenol; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Obesity

The modulation of adenylate cyclase by guanosine triphosphate (GTP) and hormones was examined in liver membranes of lean and ob/ob mice, to determine whether a defective regulation of cyclase similar to that found in adipocyte membranes was present. In conjunction with GTP, glucagon was a powerful stimulant of cyclase in both types of membranes. In contrast, GTP alone or in conjunction with isoproterenol and norepinephrine stimulated significantly less in the membranes of the lean than in those of the obese mouse. In addition, low concentrations of norepinephrine elicited an inhibitory response in membranes of the lean mouse, but not in those of the obese. This inhibitory effect of norepinephrine was abolished by the alpha 2-antagonist yohimbine and by treatment with pertussis toxin, but not by propranolol or treatment with cholera toxin. These data show that it is possible to demonstrate inhibitory effects of guanine nucleotides on cyclase in the membranes from lean but not those from obese mice and suggest a defect in inhibitory regulation in the tissue of the obese.

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclases; Animals; Cell Membrane; Cholera Toxin; Enzyme Activation; Glucagon; Guanosine Triphosphate; Isoproterenol; Liver; Magnesium; Magnesium Chloride; Male; Mice; Mice, Inbred C57BL; Norepinephrine; Obesity; Pertussis Toxin; Propranolol; Virulence Factors, Bordetella; Yohimbine

Adipocytes can be readily isolated from intact adipose tissue. In adipocytes from hamster and human white adipose tissue it is possible to demonstrate beta, alpha 1, and alpha 2 adrenoceptors. Alpha 2 adrenoceptor activation inhibits while beta adrenoceptor activation stimulates cyclic AMP accumulation and lipolysis. The effects of catecholamines on cyclic AMP accumulation are mediated through regulation of adenylate cyclase activity, which is activated through beta adrenoceptors and inhibited through alpha 2 adrenoceptors. Activation of alpha 1 adrenergic receptors has been shown to be associated with elevations of cytosol calcium and increased turnover of phosphatidylinositol. In white adipocytes, the only known alpha 1 adrenergic effects are inhibition of glycogen synthase and stimulation of glycogen phosphorylase via mechanisms distinct from those by which cyclic AMP produces similar end effects. In brown adipocytes, alpha 1 adrenoceptor activation stimulates respiration. Thyroid hormones primarily regulate the sensitivity of adipocytes to beta-adrenergic amines while having little effect on alpha adrenoceptor sensitivity.

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclases; Adipose Tissue; Adipose Tissue, Brown; Animals; Bacterial Toxins; Calcium; Catecholamines; Cyclic AMP; Diet; Enzyme Activation; Guanosine Triphosphate; Humans; Insulin; Lipolysis; Obesity; Phosphatidylinositols; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Sodium; Thyroid Hormones; Virulence Factors, Bordetella

Experimental obesity syndromes are characterized by considerable fat accretion which may be the result of hyperinsulinemia. Adipose tissue accretion may be the result both of the excessive synthesis of triglycerides and a defect in their mobilization from adipose tissue stores. The adenylate cyclase system which appears to be the site of the defect in mobilization is studies in more detail.

Topics: Adenylyl Cyclases; Adipose Tissue; Animals; Cell Membrane; Disease Models, Animal; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Kinetics; Lipolysis; Liver; Mice; Mice, Obese; Obesity; Rats; Rats, Inbred Strains; Rats, Zucker

Topics: Adenosine Triphosphate; Animals; Bucladesine; Butyrates; Cyclic AMP; Cyclic GMP; Cytosine Nucleotides; Drug Synergism; Female; Glucose; Guanosine Triphosphate; Hyperglycemia; In Vitro Techniques; Inosine Nucleotides; Insulin; Insulin Antibodies; Insulin Secretion; Iodine Radioisotopes; Islets of Langerhans; Mice; Nucleotides, Cyclic; Obesity; Uracil Nucleotides