cl-316243 and Disease-Models--Animal

[Figure: see text].

Topics: Adipose Tissue, Brown; Adrenergic beta-3 Receptor Agonists; Animals; Apolipoprotein E3; Atherosclerosis; Biomarkers; Cholesterol Ester Transfer Proteins; Dioxoles; Disease Models, Animal; Gene Knockdown Techniques; Humans; Lipids; Lipolysis; Liver; Mice, Inbred C57BL; Mice, Transgenic; Plaque, Atherosclerotic; RNA Interference; RNA, Small Interfering; Scavenger Receptors, Class B

White adipocytes store energy differently than brown and brite adipocytes which dissipate energy under the form of heat. Studies have shown that adipocytes are able to respond to bacteria thanks to the presence of Toll-like receptors at their surface. Despite this, little is known about the involvement of each class of adipocytes in the infectious response. We treated mice for one week with a β3-adrenergic receptor agonist to induce activation of brown adipose tissue and brite adipocytes within white adipose tissue. Mice were then injected intraperitoneally with E. coli to generate acute infection. The metabolic, infectious and inflammatory parameters of the mice were analysed during 48 hours after infection. Our results shown that in response to bacteria, thermogenic activity promoted a discrete and local anti-inflammatory environment in white adipose tissue characterized by the increase of the IL-1RA secretion. More generally, activation of brown and brite adipocytes did not modify the host response to infection including no additive effect with fever and an equivalent bacteria clearance and inflammatory response. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes in response to acute bacterial infection and open a way to characterize their effect along more chronic infection as septicaemia.

Topics: Adipocytes, Beige; Adipocytes, White; Adipose Tissue, Brown; Adrenergic Agonists; Animals; Bacteremia; Dioxoles; Disease Models, Animal; Energy Metabolism; Escherichia coli; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Mice; Receptors, Adrenergic, beta-3; Thermogenesis; Toll-Like Receptors

Brown fat activation accelerates the uptake of cholesterol-enriched remnants by the liver and thereby lowers plasma cholesterol, consequently protecting against atherosclerosis development. Hepatic cholesterol is then converted into bile acids (BAs) that are secreted into the intestine and largely maintained within the enterohepatic circulation. We now aimed to evaluate the effects of prolonged brown fat activation combined with inhibition of intestinal BA reabsorption on plasma cholesterol metabolism and atherosclerosis development.. APOE*3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective β3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged β3-AR agonism reduced faecal BA excretion (-31%), while markedly increasing plasma levels of total BAs (+258%), cholic acid-derived BAs (+295%), and chenodeoxycholic acid-derived BAs (+217%), and decreasing the expression of hepatic genes involved in BA production. In subsequent experiments, mice were additionally treated with the BA sequestrant Colesevelam to inhibit BA reabsorption. Concomitant intestinal BA sequestration increased faecal BA excretion, normalized plasma BA levels, and reduced hepatic cholesterol. Moreover, concomitant BA sequestration further reduced plasma total cholesterol (-49%) and non-high-density lipoprotein cholesterol (-56%), tended to further attenuate atherosclerotic lesion area (-54%). Concomitant BA sequestration further increased the proportion of lesion-free valves (+34%) and decreased the relative macrophage area within the lesion (-26%), thereby further increasing the plaque stability index (+44%).. BA sequestration prevents the marked accumulation of plasma BAs as induced by prolonged brown fat activation, thereby further improving cholesterol metabolism and reducing atherosclerosis development. These data suggest that combining brown fat activation with BA sequestration is a promising new therapeutic strategy to reduce hyperlipidaemia and cardiovascular diseases.

Topics: Adipose Tissue, Brown; Adrenergic beta-3 Receptor Agonists; Animals; Anticholesteremic Agents; Apolipoprotein E3; Atherosclerosis; Bile Acids and Salts; Cholesterol; Cholesterol Ester Transfer Proteins; Colesevelam Hydrochloride; Dioxoles; Disease Models, Animal; Enterohepatic Circulation; Feces; Hyperlipidemias; Intestinal Absorption; Intestinal Elimination; Liver; Mice, Transgenic

Regulation of metabolic activity in adipose tissue is of great concern for treating obesity. This study aimed to evaluate the adrenergic regulation of glucose uptake and the thermogenic program in adipose tissues in mouse models of both type 1 and 2 diabetes mellitus (DM).. Male mice were treated with streptozotocin to induce type 1 (T1) DM, and obese ob/ob mice were used for the type 2 (T2) DM model. After selective β. In T1DM, [. The metabolic response against adrenergic stimulation varied depending on the type of adipose tissue and DM. This could be important for the therapeutic activation of adipose tissue metabolism in obese diabetic patients.

Topics: Adipose Tissue; Adrenergic Agents; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dioxoles; Disease Models, Animal; Glucose; Male; Mice, Inbred ICR; Uncoupling Protein 1

According to recent studies, kidney stones are associated with metabolic syndrome. We focused on brown adipocytes and β

Topics: Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Adrenergic beta-3 Receptor Agonists; Animals; Calcium-Binding Proteins; Chemokine CCL2; Crystallization; Dioxoles; Disease Models, Animal; Glyoxylates; Inflammation Mediators; Kidney Calculi; Male; Mice, Inbred C57BL; Receptors, Adrenergic, beta-3; Receptors, G-Protein-Coupled; Signal Transduction; Superoxide Dismutase-1

Previous studies have shown that degeneration of retinal capillaries occurs following N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity, but it is unclear whether vasodilatory mechanisms are altered in retinal blood vessels. The purpose of the present study was to determine whether retinal vasodilator responses are affected in a rat model of NMDA-induced retinal damage. At 14 days after a single intravitreal injection of NMDA (200 nmol), retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in fundus images. Acetylcholine-induced vasodilation of retinal arterioles was significantly reduced in NMDA-treated retinas, whereas retinal vasodilatory effects of the nitric oxide (NO) donor NOR3, the β2-adrenoceptor agonist salbutamol, and the β3-adrenoceptor agonist CL316243 were unaltered. The vasodilator response to acetylcholine observed under the combined blockade of NO synthase and cyclooxygenase with N(G)-nitro-L-arginine methyl ester (30 mg/kg, i.v.) plus indomethacin (5 mg/kg, i.v.), possibly an endothelium-derived hyperpolarizing factor-mediated response, was also reduced. These results suggest that endothelium-dependent vasodilatory mechanisms in retinal blood vessels are impaired in the rat model of NMDA-induced retinal degeneration. Glutamate-induced neurotoxicity is implicated in several retinal diseases; therefore, abnormal retinal circulation would contribute to the progression of the diseases.

Topics: Acetylcholine; Adrenergic beta-3 Receptor Agonists; Animals; Dioxoles; Disease Models, Animal; Endothelial Cells; Male; N-Methylaspartate; Rats, Wistar; Receptors, Adrenergic, beta-3; Retinal Artery; Retinal Degeneration; Vasodilation

Obesity produces a chronic inflammatory state involving the NFκB pathway, resulting in persistent elevation of the noncanonical IκB kinases IKKε and TBK1. In this study, we report that these kinases attenuate β-adrenergic signaling in white adipose tissue. Treatment of 3T3-L1 adipocytes with specific inhibitors of these kinases restored β-adrenergic signaling and lipolysis attenuated by TNFα and Poly (I:C). Conversely, overexpression of the kinases reduced induction of Ucp1, lipolysis, cAMP levels, and phosphorylation of hormone sensitive lipase in response to isoproterenol or forskolin. Noncanonical IKKs reduce catecholamine sensitivity by phosphorylating and activating the major adipocyte phosphodiesterase PDE3B. In vivo inhibition of these kinases by treatment of obese mice with the drug amlexanox reversed obesity-induced catecholamine resistance, and restored PKA signaling in response to injection of a β-3 adrenergic agonist. These studies suggest that by reducing production of cAMP in adipocytes, IKKε and TBK1 may contribute to the repression of energy expenditure during obesity. DOI: http://dx.doi.org/10.7554/eLife.01119.001.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue, White; Adrenergic beta-3 Receptor Agonists; Aminopyridines; Animals; Catecholamines; Chlorocebus aethiops; COS Cells; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 3; Dioxoles; Disease Models, Animal; Energy Metabolism; Enzyme Activation; HEK293 Cells; Humans; I-kappa B Kinase; Inflammation; Ion Channels; Lipolysis; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Phosphorylation; Poly I-C; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Receptors, Adrenergic, beta; Signal Transduction; Sterol Esterase; Time Factors; Transfection; Tumor Necrosis Factor-alpha; Uncoupling Protein 1

We have previously reported that β(3)-adrenoceptor agonists dilate retinal blood vessels, but their effects on retinal neurons have been unclear. In this study, we examined the action of the β(3)-adrenoceptor agonist CL316243 against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats. CL316243 was injected into the vitreous cavity before, with, or after intravitreal NMDA injection. Seven days after NMDA injection, cell loss in the ganglion cell layer (GCL) and thinning of the inner plexiform layer were observed. The reduction in the number of cells in the GCL was diminished by injection of CL316243 at 15, 30, 60, or 120 min after NMDA injection, whereas no significant protective effect was observed when CL316243 was administered 240 min after NMDA injection. Neither preinjection of CL316243 30 min before NMDA nor simultaneous injection of CL316243 with NMDA exerted any protective effect. The β(3)-adrenoceptor antagonist L748337 almost completely abolished the protection conferred by CL316243 injection 120 min after NMDA injection. The number of parvalbumin-positive amacrine cells was decreased in eyes examined 1 day after NMDA treatment, but this was prevented by CL316243 injection at 120 min after NMDA injection. These results suggest that CL316243 exerts protective effects against NMDA-induced damage by stimulation of β(3)-adrenoceptors. β(3)-adrenoceptor agonists may be effective candidates for the treatment of retinal diseases associated with glutamate-induced excitotoxicity, including glaucoma and diabetic retinopathy.

Topics: Adrenergic beta-3 Receptor Agonists; Aminophenols; Animals; Dioxoles; Disease Models, Animal; Intravitreal Injections; Male; N-Methylaspartate; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Retinal Diseases; Retinal Ganglion Cells; Sulfonamides; Time Factors

To compare the potency and ureteral selectivity of the selective β(2)/β(3)-adrenoceptor agonist KUL-7211 with those of the nonselective β-adrenoceptor agonist isoproterenol, selective β(2)-adrenoceptor agonist terbutaline, and selective β(3)-adrenoceptor agonist CL-316243, we performed the study using an isolated porcine ureter and a porcine model of acute unilateral ureteral obstruction.. The effects of the drugs on the 80-mM KCl-induced contraction of the ureteral segments isolated from male pigs were evaluated using a functional experimental technique. Anesthetized male miniature pigs with complete obstruction of the left lower ureter were used to evaluate the effects of the cumulative intravenous drug administration on the elevated intraureteral pressure and mean blood pressure.. The KCl-induced contractions in the isolated ureter were concentration-dependently attenuated by KUL-7211, isoproterenol, terbutaline, and CL-316243, with a rank order of potency of 6.26, 6.98, 5.41, and 5.41, respectively. In the anesthetized pigs, all 4 drugs reduced the unilateral ureteral obstruction-induced elevated intraureteral pressure in a dose-dependent manner, with KUL-7211 reducing it with a lower hypotensive effect than either isoproterenol or terbutaline. The ureteral selectivity (defined as the ratio of the effective dose to decrease the mean blood pressure by 25% to the effective dose to decrease the intraureteral pressure by 50%) of KUL-7211 (1.5) was significantly greater than that of isoproterenol (0.04) or terbutaline (0.43).. The present results have demonstrated that in pigs, KUL-7211 is a potent ureteral relaxant with a relatively small hypotensive effect. A selective β(2)/β(3)-adrenoceptor agonist, such as KUL-7211, warrants additional investigation as a potentially useful drug for the promotion of stone passage in patients with urolithiasis.

Topics: Acetates; Acute Disease; Adrenergic beta-Agonists; Animals; Dioxoles; Disease Models, Animal; Injections, Intravenous; Isoproterenol; Male; Swine; Terbutaline; Ureter; Ureteral Obstruction

Accumulation of the neurotoxic beta-amyloid protein (Abeta) in the brain is a key step in the pathogenesis of Alzheimer's disease (AD). Although transgenic mouse models of AD have been developed, there is a clear need for a validated animal model of Abeta-induced amnesia which can be used for toxicity testing and drug development. Intracranial injections of Abeta(1-42) impaired memory in a single trial discriminative avoidance learning task in chicks. Memory inhibition was closely associated with the state of aggregation of the Abeta peptide, and a scrambled-sequence of Abeta(1-42) peptide failed to impair memory. Abeta had little effect on labile (short-term and intermediate) memory, but blocked consolidation of memory into long-term storage mimicking the type of anterograde amnesia that occurs in early AD. Since noradrenaline exerts a modulatory influence on labile memory in the chick, we examined the effects of two beta-adrenoceptor (AR) agonists on Abeta-induced amnesia. A beta(3)-AR agonist (CL316243), but not a beta(2)-AR agonist, rescued Abeta-induced memory loss, suggesting the need for further studies on the role of beta(3)-ARs in AD.

Topics: Adrenergic Agonists; Adrenergic beta-3 Receptor Agonists; Alzheimer Disease; Amnesia, Anterograde; Amyloid beta-Peptides; Animals; Avoidance Learning; Brain; Brain Chemistry; Chickens; Dioxoles; Disease Models, Animal; Memory Disorders; Neuropsychological Tests; Peptide Fragments; Receptors, Adrenergic, beta-3; Treatment Outcome

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia has been identified as a major factor linking these two diseases. Thus, we hypothesized that pharmacological reduction of elevated insulin levels would attenuate type 2 diabetes-mediated mammary tumor progression.. We studied mammary tumor development in MKR(+/+) mice, a nonobese, hyperinsulinemic mouse model of type 2 diabetes. MKR(+/+) mice were either crossed with mice expressing the polyoma virus middle T oncogene specifically in the mammary gland or inoculated orthotopically with the mouse mammary tumor cell lines Met-1 and MCNeuA. MKR(+/+) or control mice harboring tumors were treated with CL-316243, a specific beta3-adrenergic receptor agonist, which sensitizes insulin action but has no direct effect on the mouse mammary epithelium or Met-1 and MCNeuA cells.. CL-316243 treatment significantly reduced the elevated insulin levels in MKR(+/+) mice and, as a consequence, attenuated mammary tumor progression in the three tumor models tested. This effect was accompanied by reductions in phosphorylation of insulin and IGF-I receptors in transformed mammary tissue.. Insulin-sensitizing treatment is sufficient to abrogate type 2 diabetes-mediated mammary tumor progression. Therefore, early administration of insulin-sensitizing therapy may reduce breast cancer risk and mortality in patients with type 2 diabetes.

Topics: Animals; Body Composition; Cell Line, Tumor; Comorbidity; Diabetes Mellitus, Type 2; Dioxoles; Disease Models, Animal; Disease Progression; Eating; Epithelial Cells; Female; Hyperinsulinism; Hypoglycemic Agents; Insulin; Lipids; Male; Mammary Glands, Animal; Mammary Neoplasms, Animal; Mice; Mice, Inbred Strains; Mice, Transgenic; Polyomavirus; Risk Factors

inhibition of L-type Ca(2+) current contributes to negative inotropy of β(3) adrenergic receptor (β(3) AR) activation, but effects on other determinants of excitation-contraction coupling are not known. Of these, the Na(+)-K(+) pump is of particular interest because of adverse effects attributed to high cardiac myocyte Na(+) levels and upregulation of the β(3) AR in heart failure.. we voltage clamped rabbit ventricular myocytes and identified electrogenic Na(+)-K(+) pump current (I(p)) as the shift in holding current induced by ouabain. The synthetic β(3) AR agonists BRL37344 and CL316,243 and the natural agonist norepinephrine increased I(p). Pump stimulation was insensitive to the β(1)/β(2) AR antagonist nadolol and the protein kinase A inhibitor H-89 but sensitive to the β(3) AR antagonist L-748,337. Blockade of nitric oxide synthase abolished pump stimulation and an increase in fluorescence of myocytes loaded with a nitric oxide-sensitive dye. Exposure of myocytes to β(3) AR agonists decreased β(1) Na(+)-K(+) pump subunit glutathionylation, an oxidative modification that causes pump inhibition. The in vivo relevance of this was indicated by an increase in myocardial β(1) pump subunit glutathionylation with elimination of β(3) AR-mediated signaling in β(3) AR(-/-) mice. The in vivo effect of BRL37344 on contractility of the nonfailing and failing heart in sheep was consistent with a beneficial effect of Na(+)-K(+) pump stimulation in heart failure.. the β(3) AR mediates decreased β(1) subunit glutathionylation and Na(+)-K(+) pump stimulation in the heart. Upregulation of the receptor in heart failure may be a beneficial mechanism that facilitates the export of excess Na(+).

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Dioxoles; Disease Models, Animal; Ethanolamines; Glutathione; Heart Failure; Mice; Mice, Knockout; Myocardial Contraction; Myocytes, Cardiac; Nadolol; Oxidative Stress; Patch-Clamp Techniques; Rabbits; Receptors, Adrenergic, beta-3; Sheep; Sodium; Sodium-Potassium-Exchanging ATPase

We investigated the effects of beta(3)-adrenoceptor agonist, 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316,243) in obese diabetic KKAy mice. Two weeks' subcutaneous administration of CL-316,243 reduced serum levels of glucose, insulin, triglyceride, free fatty acid and tumor necrosis factor-alpha (TNF-alpha), and increased adiponectin. Adiponectin, adiponectin receptors and beta(3)-adrenoceptor mRNA expressions were reduced in epididymal white adipose tissue in KKAy mice, and CL-316,243 recovered these mRNA expressions. Meanwhile, CL-316,243 suppressed the overexpressed mRNA level of TNF-alpha in both epididymal white adipose tissue and brown adipose tissue. These data suggest that the normalization of adiponectin, adiponectin receptors and TNF-alpha may result in the amelioration of obesity-induced insulin resistance.

Topics: Adiponectin; Adipose Tissue; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Dietary Fats; Dioxoles; Disease Models, Animal; Eating; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Resistance; Lipids; Male; Mice; Obesity; Receptors, Adiponectin; Receptors, Adrenergic, beta-3; Tumor Necrosis Factor-alpha

Methylsulfonamide substituted 2,4-thiazolidinedione 22c is a potent (EC50=0.01 microM, IA=1.19) and selective (more than 110-fold over beta1 and beta2 agonist activity) beta3 agonist. This compound has also been proven to be active and selective in an in vivo mode.

Topics: Adrenergic beta-3 Receptor Agonists; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Mice; Mice, Knockout; Mice, Transgenic; Obesity; Structure-Activity Relationship; Thiazoles; Thiazolidinediones

Chronic stimulation of the beta3-adrenergic receptor (AR) in obese animals resulted in a reduced adiposity associated with an increased expression of thermogenic uncoupling protein (UCP)1 in adipose tissues. In this study, the mRNA expression of newly cloned UCP isoforms (UCP2 and UCP3) were examined in obese yellow KK and C57BL control mice. UCP2 mRNA was found in all tissues examined, with higher levels in adipose tissues and skeletal muscle of the obese mice. UCP3 mRNA was expressed in skeletal muscle, heart and brown adipose tissue similarly in the two mouse strains. Daily injection of a selective beta3-adrenergic agonist, CL316,243 (0.1 mg/kg), for 10 days resulted in a marked reduction of white fat pad weight and 1.8-4.8-fold increase in the mRNA levels of UCP2 and UCP3 in skeletal muscle of obese mice. No noticeable change in the UCP2 and 3 mRNA levels was found in brown and white adipose tissues. It was also found that CL316,243 injection produced a marked and sustained elevation of the plasma free fatty acid level. These results, together with our previous findings of the fatty acid-induced UCP expression in a myocyte cell line in vitro, suggest that the beta3-AR agonist-induced UCP expression in skeletal muscle may be mediated through the elevated plasma free fatty acids. It was also suggested that anti-obesity effect of beta3-AR agonists is attributable to increased thermogenesis not only by UCP1 but also by UCP2 and UCP3.

Topics: Adipose Tissue, Brown; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Blood Glucose; Blotting, Northern; Carrier Proteins; Dioxoles; Disease Models, Animal; Fatty Acids; Female; Ion Channels; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondrial Proteins; Muscle, Skeletal; Protein Biosynthesis; Proteins; RNA, Messenger; Uncoupling Protein 2; Uncoupling Protein 3; Up-Regulation

To assess the effect of chronic treatment with a beta 3-adrenoceptor agonist, CL 316,243 (CL) on serum leptin concentration in rats with diet-induced obesity (DIO) or with genetic obesity (fa/fa Zucker).. Leptin concentration was measured in serum of young control rats, young rats with DIO and old control or genetically obese fa/fa Zucker rats, that were treated chronically with CL for 2-4 weeks in our previous studies.. Treatment with CL reduced elevated leptin concentrations in young rats with DIO and in old mildly obese control rats to the low concentration of young lean rats. It did not alter the grossly elevated concentration in fa/fa rats. This effect of CL correlated well with its effect to reduce white adipocyte size, except in fa/fa rats. In CL-treated fa/fa rats, despite reductions in body fat mass and in white adipocyte size, and despite normalization of both hyperglycemia and hyperinsulinemia, the leptin concentration did not change.. The reason for lack of change in leptin concentrations in fa/fa rats, despite shrinking of white adipocytes and partial reversal of the obesity, may be due to another defect. The large increase in white adipocyte number in these animals was not reversed by the treatment and might have contributed to elevated leptin production. In addition, all forms of leptin receptor are known to be defective in fa/fa rats. Since leptin is rapidly excreted in urine and leptin receptors (including a form known to be involved in leptin transport) are expressed in the kidney, we suggest that leptin excretion is impaired in the fa/fa rat. This impairment contributes to maintenance of an elevated concentration of leptin in its blood and prevents treatment with a beta 3-adrenoceptor agonist from reducing this elevated concentration despite reversal of both obesity and diabetes. In addition, we suggest that CL-induced suppression of hyperphagia in fa/fa rats is leptin-independent and due to the large increase in thermogenesis.

Topics: Adipocytes; Adrenergic beta-Agonists; Animals; Cohort Studies; Dioxoles; Disease Models, Animal; Leptin; Male; Obesity; Proteins; Rats; Rats, Sprague-Dawley; Rats, Zucker; Time Factors