دورية أكاديمية
Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice.
العنوان: | Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice. |
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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 |
تدمد: | 1091-6490 |
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DOI: | 10.1073/pnas.1614467113 |