دورية أكاديمية
أعرض في EDS

Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice.

التفاصيل البيبلوغرافية
العنوان: Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice.
المؤلفون: Zhang Z; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Turer E; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Li X; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Zhan X; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Choi M; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Tang M; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Press A; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Smith SR; Translational Research institute for Metabolism and Diabetes, Florida Hospital, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827; Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827., Divoux A; Translational Research institute for Metabolism and Diabetes, Florida Hospital, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827; Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827., Moresco EM; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390., Beutler B; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; Bruce.Beutler@UTSouthwestern.edu.
المصدر: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Oct 18; Vol. 113 (42), pp. E6418-E6426. Date of Electronic Publication: 2016 Oct 05.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : National Academy of Sciences
مواضيع طبية MeSH: Genetic Predisposition to Disease* , Insulin Resistance*/genetics, Diabetes Mellitus/*etiology , Diabetes Mellitus/*metabolism , Diet/*adverse effects, Adipocytes/metabolism ; Adipose Tissue/metabolism ; Adipose Tissue/transplantation ; Animals ; Blood Glucose ; Class Ia Phosphatidylinositol 3-Kinase/genetics ; Class Ia Phosphatidylinositol 3-Kinase/metabolism ; Cullin Proteins/metabolism ; Disease Models, Animal ; Fatty Liver/etiology ; Fatty Liver/metabolism ; Fatty Liver/pathology ; Gene Expression Regulation ; Genetic Association Studies ; Genotype ; Insulin/blood ; Lipodystrophy/etiology ; Lipodystrophy/metabolism ; Lipodystrophy/pathology ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mutation ; Obesity/etiology ; Obesity/pathology ; Phenotype ; Protein Binding ; Protein Transport ; Signal Transduction ; Ubiquitination
مستخلص: We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation. In the absence of KBTBD2, p85α accumulated to 30-fold greater levels than in wild-type adipocytes, and excessive p110-free p85α blocked the binding of p85α-p110 heterodimers to IRS1, interrupting the insulin signal. Both transplantation of wild-type adipose tissue and homozygous germ line inactivation of the p85α-encoding gene Pik3r1 rescued diabetes and hepatic steatosis phenotypes of Kbtbd2 -/- mice. Kbtbd2 was down-regulated in diet-induced obese insulin-resistant mice in a leptin-dependent manner. KBTBD2 is an essential regulator of the insulin-signaling pathway, modulating insulin sensitivity by limiting p85α abundance.
Competing Interests: The authors declare no conflict of interest.
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معلومات مُعتمدة: T32 DK007745 United States DK NIDDK NIH HHS; U19 AI100627 United States AI NIAID NIH HHS; P01 AI070167 United States AI NIAID NIH HHS; P30 DK057521 United States DK NIDDK NIH HHS; K08 DK107886 United States DK NIDDK NIH HHS; K99 DK115766 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: Kbtbd2; diabetes; insulin resistance; p85α; ubiquitination
المشرفين على المادة: 0 (Blood Glucose)
0 (Cul3 protein, mouse)
0 (Cullin Proteins)
0 (Insulin)
EC 2.7.1.137 (Class Ia Phosphatidylinositol 3-Kinase)
تواريخ الأحداث: Date Created: 20161007 Date Completed: 20180130 Latest Revision: 20200516
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC5081616
DOI: 10.1073/pnas.1614467113
PMID: 27708159
قاعدة البيانات: MEDLINE
الوصف
تدمد:1091-6490
DOI:10.1073/pnas.1614467113