| First Author | Zhang Z | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 42 | Pages | E6418-E6426 |
| PubMed ID | 27708159 | Mgi Jnum | J:236520 |
| Mgi Id | MGI:5806303 | Doi | 10.1073/pnas.1614467113 |
| Citation | Zhang Z, et al. (2016) Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice. Proc Natl Acad Sci U S A 113(42):E6418-E6426 |
| abstractText | 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 p85alpha, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85alpha ubiquitination and proteasome-mediated degradation. In the absence of KBTBD2, p85alpha accumulated to 30-fold greater levels than in wild-type adipocytes, and excessive p110-free p85alpha blocked the binding of p85alpha-p110 heterodimers to IRS1, interrupting the insulin signal. Both transplantation of wild-type adipose tissue and homozygous germ line inactivation of the p85alpha-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 p85alpha abundance. |
