Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis

Article Article scientifique Article Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis eng 2022-07-15 2022-07-15 author Ursino Gloria 909891 author Ramadori Giorgio 0000-0003-0194-3257 790895 author Hoefler Anna 0000-0002-7126-2935 925330 author Odouard Soline 909222 author Sousa Teixeira Pryscila 935446 author Visentin Florian 708660 author Veyrat-Durebex Christelle 0000-0001-5301-6493 629027 author Lucibello Giulia 0000-0002-5543-1719 953475 author Firnkes Raquel 895218 author Ricci Serena 889456 author Vianna Claudia R. author Jia Lin 0000-0002-7653-7395 author Dirlewanger Mijam 629834 author Klee Philippe 0000-0003-4799-6602 500735 author Elmquist Joel K. author Roth Johannes 0000-0001-7035-8348 author Vogl Thomas 0000-0001-9669-7479 author Schwitzgebel Luscher Valérie 0000-0002-8015-950X 133261 author Jornayvaz François 0000-0001-9425-3137 641037 author Boland Andreas 0000-0003-1218-6714 912539 author Coppari Roberto 0000-0003-1288-6948 780442 4107 10.1038/s41467-022-31803-5 35840613 2041-1723 PMC9287425 https://www.nature.com/articles/s41467-022-31803-5 <p>Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.</p> Dewey 612 Dewey 616 Dewey 618 Dewey 570 Swiss National Science Foundation Structural studies of cytokine-mediated signal transduction 310030_185235 CH Project funding European Commission Compositions for use in the treatment of insulin deficiency conditions 899766 LifeWithoutInsulin EU H2020 European Commission Metabolic actions of brain leptin receptors signaling in type 1 diabetes 614847 LIFEWITHOUTINSULIN EU FP7 Swiss National Science Foundation To elucidate the pathways promoting survival in insulin deficiency 310030_184767 CH Project funding 134 Département de physiologie cellulaire et métabolisme 21C 58 Département de pédiatrie, gynécologie et obstétrique 223 56 Département de médecine 221 7daed2ee-1311-4824-9df9-2e51260a966a Département de biologie moléculaire et cellulaire 16484 false 578 La biologie du métabolisme dans la santé et la maladie 921 144 Diabète et métabolisme 178 1263 MASLD/MASH et résistance à l'insuline 997 Nature communications 13 1 5d65706b-656d-45d4-b721-2a6dced39240 Article (Published version) Public Article-scientifique-from-unpaywall.pdf 2451139 application/pdf CC BY-4.0 bfc97193-a9ef-445d-9921-97f722b3255e Supplemental data Public 41467_2022_31803_MOESM1_ESM(1).pdf 1751152 application/pdf CC BY-4.0 5631161b-d1b9-457f-b11a-32095fa2dfd8 Supplemental data Public Copie de 41467_2022_31803_MOESM3_ES.xlsx 16313140 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet CC BY-4.0 openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique Faculté de médecine / Section de médecine clinique / Département de médecine Faculté des sciences / Section de biologie / Département de biologie moléculaire et cellulaire

Title	Published in	Year	Views	Downloads

Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis	Nature communications	2022	387	133
S100A9 extends lifespan in insulin deficiency	Nature Communications	2019	465	282

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