title: Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity.
abstract: The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity.
authors.affiliation: Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
authors.forename: Elisabeth K
authors.initials: EK
authors.lastname: Malle
authors.affiliation: Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Zammit
authors.affiliation: Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
authors.forename: Stacey N
authors.initials: SN
authors.lastname: Walters
authors.affiliation: School of Chemistry, University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: Yen Chin
authors.initials: YC
authors.lastname: Koay
authors.affiliation: Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia St Vincent's Clinical School, University of New South Wales, Sydney NSW 2010, Australia.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
authors.forename: Bernice M
authors.initials: BM
authors.lastname: Tan
authors.affiliation: Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Villanueva
authors.affiliation: Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia St Vincent's Clinical School, University of New South Wales, Sydney NSW 2010, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy VIC 3065, Australia.
authors.forename: Tom
authors.initials: T
authors.lastname: Loudovaris
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, England, UK.
authors.forename: James
authors.initials: J
authors.lastname: Cantley
authors.affiliation: School of Chemistry, University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: Shelli R
authors.initials: SR
authors.lastname: McAlpine
authors.affiliation: Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hesselson
authors.affiliation: Transplantation Immunology Group, Immunology Division, Cancer Bioinformatics, Cancer Division, B Cell Biology, Immunology Division, and Beta Cell Regeneration, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia s.grey@garvan.org.au.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D017931:DNA Primers; D007328:Insulin; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase