Kinin B1 and B2 receptor deficiency protects against obesity induced by a high-fat diet and improves glucose tolerance in mice

The kallikrein-kinin system is well known for its role in pain and inflammation, and has been shown recently by our group to have a role also in the regulation of energy expenditure. We have demonstrated that B1 receptor knockout (B1KO) mice are resistant to obesity induced by a high-fat diet (HFD) and that B1 receptor expression in adipocytes regulates glucose tolerance and predisposition to obesity. However, it is also known that in the absence of B1 receptor, the B2 receptor is overexpressed and can take over the function of its B1 counterpart, rendering uncertain the role of each kinin receptor in these metabolic effects. Therefore, we investigated the impact of ablation of each kinin receptor on energy metabolism using double kinin receptor knockout (B1B2KO) mice. Our data show that B1B2KO mice were resistant to HFD-induced obesity, with lower food intake and feed efficiency when compared with wild-type mice. They also had lower blood insulin and leptin levels and higher glucose tolerance after treatment with an HFD. Gene expression for tumor necrosis factor-alpha and C-reactive protein, which are important genes for insulin resistance, was reduced in white adipose tissue, skeletal muscle, and the liver in B1B2KO mice after the HFD. In summary, our data show that disruption of kinin B1 and B2 receptors has a profound impact on metabolic homeostasis in mice, by improving glucose tolerance and preventing HFD-induced obesity. These novel findings could pave the way for development of new pharmacological strategies to treat metabolic disorders such as insulin resistance and obesity

Role of endothelial kinin B(1) receptor on the membrane potential of transgenic rat aorta

The kinin receptors are classically involved in inflammation, pain and sepsis. The effects of the kinin B(1) receptor agonist des-Arg(9)-bradykinin (DBK) and lipopolysaccharide (LPS) were investigated by comparing the membrane potential responses of aortic rings from transgenic rats overexpressing the kinin B1 receptor (B1R) in the endothelium (TGR(Tie2B1)) and Sprague Dawley (SD) rats. No difference in the resting membrane potential in the aorta's smooth muscle from the transgenic and SD rats was observed. The aorta rings from SD rats hyperpolarized only to LPS but not to DBK, whereas the aorta rings from TGR(Tie2B(1)) responded by the administration of both drugs. DBK and LPS responses were inhibited by the B(1) receptor antagonist R715 and by iberiotoxin in both cases. Thapsigargin induced a hyperpolarization in the smooth muscle of SD rats that was not reversed by R715, but was reversed by iberiotoxin and this hyperpolarization was further augmented by DBK administration. These results show that the model of overexpression of vascular B(1) receptors in the TGR(Tie2B(1)) rats represent a good model to study the role of functional B(1) receptors in the absence of any pathological stimulus. The data also show that K(Ca) channels are the final mediators of the hyperpolarizing responses to DBK and LPS. In addition, we suggest an interaction between the B1R and TLR4, since the hyperpolarization induced by LPS could be abolished in the presence of R715

Kinin B1 receptor gene ablation affects hypothalamic CART production

A role for the kinin B1 receptor in energy-homeostatic processes was implicated by previous works. Notably the studies where kinin B1 receptor knockout mice (B1-/-) are observed to have impaired adiposity, impaired leptin and insulin production, lower feed efficiency, protection from liver steatosis and diet induced obesity when fed a high fat diet (HFD). More particularly, in a model where the B1 receptor is expressed exclusively in the adipose tissue, it rescues the plasma insulin concentration and the weight gain seen in wild type mice. Taking into consideration that leptin participates in the formation of hypothalamic nuclei, which modulate energy expenditure, and feeding behavior, we hypothesized that these brain regions could also be altered in B1-/- mice. We observed for the first time a difference in the gene expression pattern of CART (cocaine-and-amphetamine related transcript) in the LHA (lateral hypothalamic area) resulting from the deletion of the kinin B1 receptor gene. The correlation between CART expression in the LHA and the thwarting of diet-induced obesity corroborates independent correlations between CART and obesity. Further it seems to indicate that the mechanism underlying the 'lean' phenotype of B1-/- mice is not solely stemming from changes in peripheral tissues but may also receive contributions from changes in the hypothalamic machinery involved in energy homeostasis processes

Kinin b(1) receptor in adipocytes regulates glucose tolerance and predisposition to obesity

BACKGROUND: Kinins participate in the pathophysiology of obesity and type 2 diabetes by mechanisms which are not fully understood. Kinin B(1) receptor knockout mice (B(1) (-/-)) are leaner and exhibit improved insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that kinin B(1) receptors in adipocytes play a role in controlling whole body insulin action and glucose homeostasis. Adipocytes isolated from mouse white adipose tissue (WAT) constitutively express kinin B(1) receptors. In these cells, treatment with the B(1) receptor agonist des-Arg(9)-bradykinin improved insulin signaling, GLUT4 translocation, and glucose uptake. Adipocytes from B(1) (-/-) mice showed reduced GLUT4 expression and impaired glucose uptake at both basal and insulin-stimulated states. To investigate the consequences of these phenomena to whole body metabolism, we generated mice where the expression of the kinin B(1) receptor was limited to cells of the adipose tissue (aP2-B(1)/B(1) (-/-)). Similarly to B(1) (-/-) mice, aP2-B(1)/B(1) (-/-) mice were leaner than wild type controls. However, exclusive expression of the kinin B(1) receptor in adipose tissue completely rescued the improved systemic insulin sensitivity phenotype of B(1) (-/-) mice. Adipose tissue gene expression analysis also revealed that genes involved in insulin signaling were significantly affected by the presence of the kinin B(1) receptor in adipose tissue. In agreement, GLUT4 expression and glucose uptake were increased in fat tissue of aP2-B(1)/B(1) (-/-) when compared to B(1) (-/-) mice. When subjected to high fat diet, aP2-B(1)/B(1) (-/-) mice gained more weight than B(1) (-/-) littermates, becoming as obese as the wild types. CONCLUSIONS/SIGNIFICANCE: Thus, kinin B(1) receptor participates in the modulation of insulin action in adipocytes, contributing to systemic insulin sensitivity and predisposition to obesity

Low-cost inorganic cation exchange membrane for electrodialysis: optimum processing temperature for the cation exchanger

The optimum temperature for fixing zirconium phosphate, obtained by precipitation, on a low-cost ceramic support was determined in order to obtain an inorganic cation exchange membrane for electrodialysis. Zirconium phosphate ion exchange capacity maximised between 450 and 550°C, thus it was considered the optimum processing temperature. The origin of this maximum was investigated by means of X-ray diffraction and termogravimetry and evolved gas analysis. Zirconium phosphate formation by precipitation in the porous network of the support was verified by scanning electron microscopy and energy dispersive X-ray analysis and mercury intrusion porosimetry. The membrane obtained after thermal treatment at 450°C displayed selectivity to the cations present in the spent rinse water of the chromium plating process. This property allows the recovery of chromium by removing the cations through the cation exchange ceramic membrane.The authors wish to express their gratitude to the Spanish Ministry of Science and Innovation for the support given to the research study (National Basic Research Programme, Ref. CTQ2008-06750-C02-02), as well as for the FPU student grant awarded to one of the authors (Ref.: AP2009-4409).Mestre, S.; Sales, S.; Palacios, M.; Lorente, M.; Mallol, G.; Pérez-Herranz, V. (2013). Low-cost inorganic cation exchange membrane for electrodialysis: optimum processing temperature for the cation exchanger. Desalination and Water Treatment. 51(16-18):3317-3324. https://doi.org/10.1080/19443994.2012.749177S331733245116-18Strathmann, H. (2010). Electromembrane Processes: Basic Aspects and Applications. Comprehensive Membrane Science and Engineering, 391-429. doi:10.1016/b978-0-08-093250-7.00048-7Drioli, E., & Fontananova, E. (s. f.). Integrated Membrane Processes. Membrane Operations, 265-283. doi:10.1002/9783527626779.ch12Strathmann, H. (s. f.). Fundamentals in Electromembrane Separation Processes. Membrane Operations, 83-119. doi:10.1002/9783527626779.ch5Alberti, G., Casciola, M., Costantino, U., & Levi, G. (1978). Inorganic ion exchange membranes consisting of microcrystals of zirconium phosphate supported by Kynar®. Journal of Membrane Science, 3(2), 179-190. doi:10.1016/s0376-7388(00)83021-5Semiat, R., & Hasson, D. (s. f.). Seawater and Brackish-Water Desalination with Membrane Operations. Membrane Operations, 221-243. doi:10.1002/9783527626779.ch10Bregman, J. ., & Braman, R. . (1965). Inorganic ion exchange membranes. Journal of Colloid Science, 20(9), 913-922. doi:10.1016/0095-8522(65)90064-4Bishop, H. K., Bittles, J. A., & Guter, G. A. (1969). Investigation of inorganic ion exchange membranes for electrodialysis. Desalination, 6(3), 369-380. doi:10.1016/s0011-9164(00)80226-xRajan, K. S., Boies, D. B., Casolo, A. J., & Bregman, J. . (1966). Inorganic ion-exchange membranes and their application to electrodialysis. Desalination, 1(3), 231-246. doi:10.1016/s0011-9164(00)80255-6INAMUDDIN, KHAN, S., SIDDIQUI, W., & KHAN, A. (2007). Synthesis, characterization and ion-exchange properties of a new and novel ‘organic–inorganic’ hybrid cation-exchanger: Nylon-6,6, Zr(IV) phosphate. Talanta, 71(2), 841-847. doi:10.1016/j.talanta.2006.05.042HELEN, M., VISWANATHAN, B., & MURTHY, S. (2007). Synthesis and characterization of composite membranes based on α-zirconium phosphate and silicotungstic acid. Journal of Membrane Science, 292(1-2), 98-105. doi:10.1016/j.memsci.2007.01.018Yu.S. Dzyaz’ko, V.N. Belyakov, N.V. Stefanyak, S.L. Vasilyuk, Anion-exchange properties of composite ceramic membranes containing hydrated zirconium dioxide, Russ. J. Appl. Chem. 79 (2006) 769–773.Linkov, V. ., & Belyakov, V. . (2001). Novel ceramic membranes for electrodialysis. Separation and Purification Technology, 25(1-3), 57-63. doi:10.1016/s1383-5866(01)00090-9Linkov, V. M., Dzyaz’ko, Y. S., Belyakov, V. N., & Atamanyuk, V. Y. (2007). Inorganic composite membranes for electrodialytic desaltination. Russian Journal of Applied Chemistry, 80(4), 576-581. doi:10.1134/s1070427207040118El-Sourougy, M. R., Zaki, E. E., & Aly, H. F. (1997). Transport characteristics of ceramic supported zirconium phosphate membrane. Journal of Membrane Science, 126(1), 107-113. doi:10.1016/s0376-7388(96)00273-6Sánchez, E., Mestre, S., Pérez-Herranz, V., & García-Gabaldón, M. (2005). Síntesis de membranas cerámicas para la regeneración de baños de cromado agotados. Boletín de la Sociedad Española de Cerámica y Vidrio, 44(6), 409-414. doi:10.3989/cyv.2005.v44.i6.340Sánchez, E., Mestre, S., Pérez-Herranz, V., Reyes, H., & Añó, E. (2006). Membrane electrochemical reactor for continuous regeneration of spent chromium plating baths. 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Measurement of the branching ratio Γ(Λb⁰ → ψ(2S)Λ0)/Γ(Λb⁰ → J/ψΛ0) with the ATLAS detector

An observation of the $\Lambda_b^0 \rightarrow \psi(2S) \Lambda^0$ decay and a comparison of its branching fraction with that of the $\Lambda_b^0 \rightarrow J/\psi \Lambda^0$ decay has been made with the ATLAS detector in proton--proton collisions at $\sqrt{s}=8\,$TeV at the LHC using an integrated luminosity of $20.6\,$fb$^{-1}$. The $J/\psi$ and $\psi(2S)$ mesons are reconstructed in their decays to a muon pair, while the $\Lambda^0\rightarrow p\pi^-$ decay is exploited for the $\Lambda^0$ baryon reconstruction. The $\Lambda_b^0$ baryons are reconstructed with transverse momentum $p_{\rm T}>10\,$GeV and pseudorapidity $|\eta|<2.1$. The measured branching ratio of the $\Lambda_b^0 \rightarrow \psi(2S) \Lambda^0$ and $\Lambda_b^0 \rightarrow J/\psi \Lambda^0$ decays is $\Gamma(\Lambda_b^0 \rightarrow \psi(2S)\Lambda^0)/\Gamma(\Lambda_b^0 \rightarrow J/\psi\Lambda^0) = 0.501\pm 0.033 ({\rm stat})\pm 0.019({\rm syst})$, lower than the expectation from the covariant quark model.Comment: 12 pages plus author list (28 pages total), 5 figures, 1 table, published on Physics Letters B 751 (2015) 63-80. All figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/BPHY-2013-08