Roux-en-Y gastric bypass (RYGB) is highly effective in reversing obesity and associated diabetes. Recent observations in humans suggest a contributing role of increased circulating bile acids in mediating such effects. Here we use a diet-induced obesity (DIO) mouse model and compare metabolic remission when bile flow is diverted through a gallbladder anastomosis to jejunum, ileum or duodenum (sham control). We find that only bile diversion to the ileum results in physiologic changes similar to RYGB, including sustained improvements in weight, glucose tolerance and hepatic steatosis despite differential effects on hepatic gene expression. Circulating free fatty acids and triglycerides decrease while bile acids increase, particularly conjugated tauro-β-muricholic acid, an FXR antagonist. Activity of the hepatic FXR/FGF15 signalling axis is reduced and associated with altered gut microbiota. Thus bile diversion, independent of surgical rearrangement of the gastrointestinal tract, imparts significant weight loss accompanied by improved glucose and lipid homeostasis that are hallmarks of RYGB.

o-Xylylene has been prepared by irradiation of 1,4-dihydrophthalazine and five other precursors in glassy solutions at -196°. 1,4-Dihydrophthalazine is thermally unstable ( / * = 15.4 ± 1 kcal, 5 = = -7 • 2.5 eu). o-Xylylene appears to be a ground state singlet. It is stable indefinitely in rigid media but dimerizes fast as soon as the medium is softened. Irradiation converts it to benzocyclobutene. It shows characteristic absorption and fluorescence. The emitting state as well as the ground state are most likely planar. The triplet has not been detected. The spectral data are well accounted for by semiempirical 7r-electron calculations, which also predict the existence of a low-lying partly doubly excited state. Cl wave functions of the low-lying states of the three isomeric xylylenes are analyzed in terms of both delocalized and localized frontier orbitals as well as natural orbital occupation numbers to bring out the characteristic features of a biradicaloid species, and approximate relations to classical resonance formulas are established. Biradicalsare an important class of reaction intermediates. First, they are suspected to play a central role in numerous thermal reactions, particularly cycloadditions and isomerizations.3 Second, in photochemical reactions, the geometry possessed by the reacting species at the time of return from the excited to the ground state undoubtedly is of importance in determining the nature of final products. Such geometries are likely to correspond to minima in the excited state potential energy hypersurface and to crossings, or avoided crossings, between it and the ground state surface, and many of them probably are of "biradicaloid" nature.48 We use the adjective biradicaloid for those molecular geometries at which a simple MO picture of the species shows two approximately4*3 nonbonding molecular orbitals containing a total of two electrons in the ground state, irrespectively of the nature of their distribution in the ground state.5 Examples are squareplanar geometry of cyclobutadiene and open-chain geometry of tetramethylene, CH2CH2CH2CH2, both most likely corresponding to minima in the lowest triplet state but quite possibly not in the lowest singlet state. Most commonly, only tetramethylene would be considered a biradical, but our usage of the term biradicaloid geometry is meant to encompass both cases.Clearly, experimental data on the nature of the elec-(l) Presented in part at the 165th National Meeting of the American Chemical Society, Dallas, Texas, April 9, 1973. Support by the National Sicence Foundation (GP-26557) is gratefully acknowledged.(2) Alfred P.

Activation of cyclic nucleotide-dependent signaling pathways leads to phosphorylation of the small heat shock-related protein, HSP20, on serine 16, and relaxation of vascular smooth muscle. In this study, we used an enhanced protein transduction domain (PTD) sequence to deliver HSP20 phosphopeptide analogs into porcine coronary artery. The transduction of phosphoHSP20 analogs led to dose-dependent relaxation of coronary artery smooth muscle. Peptides containing the protein transduction domain coupled to a random orientation of the same amino acids did not. Direct fluorescence microscopy of arterial rings incubated with fluorescein isothiocyanate (FITC)-PTD or FITC-PTD-HSP20 peptides showed a diffuse peptide uptake. Mass spectrometric immunoassays (MSIAs) of smooth muscle homogenates were used to determine whether the phosphopeptide analogs affected the phosphorylation of endogenous HSP20. Treatment with the phosphodiesterase inhibitor papaverine led to a mass shift of 80 Da. However, there was no mass shift of HSP20 in muscles treated with phosphoHSP20 analogs. This suggests that the PTD-phosphoHSP20 peptide alone is sufficient to inhibit force maintenance and likely has a direct effect on the target of phosphorylated HSP20. These results suggest that transduction of phosphopeptide analogs of HSP20 directly alters physiological responses of intact muscles. The data also support a direct role for phosphorylated HSP20 in mediating vasorelaxation.

N-Acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) (EC 3.1.4.4) catalyzes the final step in the biosynthesis of N-acyl-ethanolamides. Reduced NAPE-PLD expression and activity may contribute to obesity and inflammation, but a lack of effective NAPE-PLD inhibitors has been a major obstacle to elucidating the role of NAPE-PLD and N-acyl-ethanolamide biosynthesis in these processes. The endogenous bile acid lithocholic acid (LCA) inhibits NAPE-PLD activity (with an IC50 of 68 μm), but LCA is also a highly potent ligand for TGR5 (EC50 0.52 μm). Recently, the first selective small-molecule inhibitor of NAPE-PLD, ARN19874, has been reported (having an IC50 of 34 μm). To identify more potent inhibitors of NAPE-PLD, here we used a quenched fluorescent NAPE analog, PED-A1, as a substrate for recombinant mouse Nape-pld to screen a panel of bile acids and a library of experimental compounds (the Spectrum Collection). Muricholic acids and several other bile acids inhibited Nape-pld with potency similar to that of LCA. We identified 14 potent Nape-pld inhibitors in the Spectrum Collection, with the two most potent (IC50 = ∼2 μm) being symmetrically substituted dichlorophenes, i.e. hexachlorophene and bithionol. Structure–activity relationship assays using additional substituted dichlorophenes identified key moieties needed for Nape-pld inhibition. Both hexachlorophene and bithionol exhibited significant selectivity for Nape-pld compared with nontarget lipase activities such as Streptomyces chromofuscus PLD or serum lipase. Both also effectively inhibited NAPE-PLD activity in cultured HEK293 cells. We conclude that symmetrically substituted dichlorophenes potently inhibit NAPE-PLD in cultured cells and have significant selectivity for NAPE-PLD versus other tissue-associated lipases.

Bile acids (BAs) are a family of hydroxylated steroids secreted by the liver that aid in the breakdown and absorption of dietary fats. BAs also function as nutrient and inflammatory signaling molecules, acting through cognate receptors, to coordinate host metabolism. Commensal bacteria in the gastrointestinal tract are functional modifiers of the BA pool, affecting composition and abundance. Deconjugation of host BAs creates a molecular network that inextricably links gut microtia with their host. In this review we highlight the roles of BAs in mediating this mutualistic relationship with a focus on those events that impact host physiology and metabolism.

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