Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion

OBJECTIVE: IL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presently unclear. A conditional mouse model with reduced brain IL-6Ra expression was used to explore how blunted central IL-6 signaling alters metabolic status in lean and obese mice. METHODS: Transgenic mice with reduced levels of central IL-6 receptor alpha (IL-6Ra) (IL-6Ra KD mice) and Nestin Cre controls (Cre(+/-) mice) were fed standard chow or high-fat diet for 20 weeks. Obese and lean mouse cohorts underwent metabolic phenotyping with various measures of energy and glucose homeostasis determined. Glucose-stimulated insulin secretion was assessed in vivo and ex vivo in both mouse groups. RESULTS: IL-6Ra KD mice exhibited altered body fat mass, liver steatosis, plasma insulin, IL-6 and NEFA levels versus Cre(+/-) mice in a diet-dependent manner. IL-6Ra KD mice had increased food intake, higher RER, decreased energy expenditure with diminished cold tolerance compared to Cre(+/-) controls. Standard chow-fed IL-6Ra KD mice displayed reduced plasma insulin and glucose-stimulated insulin secretion with impaired glucose disposal and unchanged insulin sensitivity. Isolated pancreatic islets from standard chow-fed IL-6Ra KD mice showed comparable morphology and glucose-stimulated insulin secretion to Cre(+/-) controls. The diminished in vivo insulin secretion exhibited by IL-6Ra KD mice was recovered by blockade of autonomic ganglia. CONCLUSIONS: This study shows that central IL-6Ra signaling contributes to glucose and energy control mechanisms by regulating food intake, energy expenditure, fuel flexibility and insulin secretion. A plausible mechanism linking central IL-6Ra signaling and pancreatic insulin secretion is through the modulation of autonomic output activity. Thus, brain IL-6 signaling may contribute to the central adaptive mechanisms engaged in response to metabolic stress

Formation and Reactivity with (BuCN)-Bu-t of a Thorium Phosphinidiide through a Combined Experimental and Computational Analysis

International audienceAn investigation of the formation of a thorium phosphinidiide reveals that changing from a 2,4,6-(Pr3C6H2)-Pr-i (Tipp)-substituted phosphido ligand to a 2,4,6-Me3C6H2 (Mes) ligand forms a similar product, [(C5Me5)(2)Th](2)(P-2,6-CH2C6H2-4-CH3), but via a different sequence of bond activations. The resulting phosphinidiide was reacted with 1 and 2 equiv of (BuCN)-Bu-t, leading to mono(ketimide), [(C5Me5)(2)Th](2)[mu(2)-P-(2-CH2-6-(N=C(Bu-t)(CH2))-4-Me-C6H2)], and bis(ketimide), [(C5Me5)(2)Th](2)[mu(2)-P-(2-CH2-6-(N=C(Bu-t)(CH2))-4-Me-C6H2)], complexes, respectively, through insertion into the thorium- carbon bonds. An analysis of the Th-P-Th moiety showed a correlation of decreased Th-P-Th bond angle and upheld P-31 NMR chemical shift with decreasing Th-P covalent bond character

Functionalization of Carbon Monoxide and tert-Butyl Nitrile by Intramolecular Proton Transfer in a Bis(Phosphido) Thorium Complex

International audienceWe report intramolecular proton transfer reactions to functionalize carbon monoxide and tert-butyl nitrile from a bis(phosphido) thorium complex. The reaction of (C5Me5)(2)Th[PH(Mes)](2), Mes = 2,4,6-Me3C6H2, with 1 atm of CO yields (C5Me5)(2)Th(kappa(2)-(O,O)-OCH(2)PMes-C(O)PMes), in which one CO molecule is inserted into each thorium-phosphorus bond. Concomitant transfer of two protons, formerly coordinated to phosphorus, are now bound to one of the carbon atoms from one of the inserted CO molecules. DFT calculations were employed to determine the lowest energy pathway. With tert-butyl nitrile, (BuCN)-Bu-t, only one nitrile inserts into a thorium-phosphorus bond, but the proton is transferred to nitrogen with one phosphido remaining unperturbed affording (C5Me5)(2)Th[PH(Mes)][kappa(2)-(P,N)-N(H)C(CMe3)P(Mes)]. Surprisingly, reaction of this compound with KN(SiMe3)(2) removes the proton bound to nitrogen, not phosphorus

Synthesis and Utility of Neptunium(III) Hydrocarbyl Complex.

To extend organoactinide chemistry beyond uranium, reported here is the first structurally characterized transuranic hydrocarbyl complex, Np[η4 -Me2 NC(H)C6 H5 ]3 (1), from reaction of NpCl4 (DME)2 with four equivalents of K[Me2 NC(H)C6 H5 ]. Unlike the UIII species, the neptunium analogue can be used to access other NpIII complexes. The reaction of 1 with three equivalents of HE2 C(2,6-Mes2 -C6 H3 ) (E=O, S) yields [(2,6-Mes2 -C6 H3 )CE2 ]3 Np(THF)2 , maintaining the trivalent oxidation state

Synthesis and Utility of Neptunium(III) Hydrocarbyl Complex

To extend organoactinide chemistry beyond uranium, reported here is the first structurally characterized transuranic hydrocarbyl complex, Np[η4 -Me2 NC(H)C6 H5 ]3 (1), from reaction of NpCl4 (DME)2 with four equivalents of K[Me2 NC(H)C6 H5 ]. Unlike the UIII species, the neptunium analogue can be used to access other NpIII complexes. The reaction of 1 with three equivalents of HE2 C(2,6-Mes2 -C6 H3 ) (E=O, S) yields [(2,6-Mes2 -C6 H3 )CE2 ]3 Np(THF)2 , maintaining the trivalent oxidation state

Isolation of a [Fe(CO)(4)](2-)-Bridged Diuranium Complex Obtained via Reduction of Fe(CO)(5) with Uranium(III)

International audienceTreatment of the U(III) complex, [(C5Me5)(2)U(OMes)(THF)], Mes = 2,4,6-Me3C6H2, with Fe(CO)(5) forms [{(C5Me5)(2)(MesO)U}(2)(mu(2)-(OC)(2)Fe(CO)(2))] with the bridging, tetrahedral Fe(CO)(4) moiety. This complex has been studied using H-1 NMR, IR vibrational, UV-vis electronic absorption, and zero-field Fe-57 Mossbauer spectroscopy as well as single-crystal X-ray diffraction analysis, magnetic measurements, and DFT calculations