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Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6418-E6426. Epub 2016 Oct 5.

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

Author information

1
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
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.
3
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; Bruce.Beutler@UTSouthwestern.edu.

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 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.

KEYWORDS:

Kbtbd2; diabetes; insulin resistance; p85α; ubiquitination

PMID:
27708159
PMCID:
PMC5081616
DOI:
10.1073/pnas.1614467113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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