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

ABSTRACT: 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 p85?, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85? ubiquitination and proteasome-mediated degradation. In the absence of KBTBD2, p85? accumulated to 30-fold greater levels than in wild-type adipocytes, and excessive p110-free p85? blocked the binding of p85?-p110 heterodimers to IRS1, interrupting the insulin signal. Both transplantation of wild-type adipose tissue and homozygous germ line inactivation of the p85?-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 p85? abundance.

SUBMITTER: Zhang Z 

PROVIDER: S-EPMC5081616 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature