Browsing by Author "Jones, Ben"

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    Expanded LUXendin Color Palette for GLP1R Detection and Visualization In Vitro and In Vivo
    (American Chemical Society, 2022-04-04) Ast, Julia; Novak, Alissa N.; Podewin, Tom; Fine, Nicholas H.F.; Jones, Ben; Tomas, Alejandra; Birke, Ramona; Roßmann, Kilian; Eichhorst, Jenny; Lehmann, Martin; Linnemann, Amelia K.; Hodson, David J.; Broichhagen, Johannes; Pediatrics, School of Medicine
    The glucagon-like peptide-1 receptor (GLP1R) is expressed in peripheral tissues and the brain, where it exerts pleiotropic actions on metabolic and inflammatory processes. Detection and visualization of GLP1R remains challenging, partly due to a lack of validated reagents. Previously, we generated LUXendins, antagonistic red and far-red fluorescent probes for specific labeling of GLP1R in live and fixed cells/tissues. We now extend this concept to the green and near-infrared color ranges by synthesizing and testing LUXendin492, LUXendin551, LUXendin615, and LUXendin762. All four probes brightly and specifically label GLP1R in cells and pancreatic islets. Further, LUXendin551 acts as a chemical beta cell reporter in preclinical rodent models, while LUXendin762 allows noninvasive imaging, highlighting differentially accessible GLP1R populations. We thus expand the color palette of LUXendins to seven different spectra, opening up a range of experiments using wide-field microscopy available in most labs through super-resolution imaging and whole animal imaging. With this, we expect that LUXendins will continue to generate novel and specific insights into GLP1R biology.
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    Mitofusins Mfn1 and Mfn2 Are Required to Preserve Glucose- but Not Incretin-Stimulated β-Cell Connectivity and Insulin Secretion
    (American Diabetes Association, 2022) Georgiadou, Eleni; Muralidharan, Charanya; Martinez, Michelle; Chabosseau, Pauline; Akalestou, Elina; Tomas, Alejandra; Wern, Fiona Yong Su; Stylianides, Theodoros; Wretlind, Asger; Legido-Quigley, Cristina; Jones, Ben; Lopez-Noriega, Livia; Xu, Yanwen; Gu, Guoqiang; Alsabeeh, Nour; Cruciani-Guglielmacci, Céline; Magnan, Christophe; Ibberson, Mark; Leclerc, Isabelle; Ali, Yusuf; Soleimanpour, Scott A.; Linnemann, Amelia K.; Rodriguez, Tristan A.; Rutter, Guy A.; Biochemistry and Molecular Biology, School of Medicine
    Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic β-cells. Whether mitofusin gene expression, and hence, mitochondrial network integrity, is important for glucose or incretin signaling has not previously been explored. Here, we generated mice with β-cell-selective, adult-restricted deletion knock-out (dKO) of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2-dKO mice displayed elevated fed and fasted glycemia and a more than fivefold decrease in plasma insulin. Mitochondrial length, glucose-induced polarization, ATP synthesis, and cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2-dKO mice, and glucagon-like peptide 1 or glucose-dependent insulinotropic peptide receptor agonists largely corrected defective glucose-stimulated insulin secretion through enhanced EPAC-dependent signaling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps-based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the β-cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in β-cells, the potential contributions of altered mitochondrial dynamics to diabetes development, and the impact of incretins on this process.