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

Zhao Zhang, Emre Turer, Xiaohong Li, Xiaoming Zhan, Mihwa Choi, Miao Tang, Amanda Press, Steven R. Smith, Adeline Divoux, Eva Marie Y Moresco, Bruce Beutler

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E6418-E6426
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number42
DOIs
StatePublished - Oct 18 2016

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Insulin Resistance
Insulin
Diet
Clustered Regularly Interspaced Short Palindromic Repeats
Cullin Proteins
Ethylnitrosourea
Lipodystrophy
Mutation
Ubiquitin-Protein Ligases
Ubiquitination
Liver
Proteasome Endopeptidase Complex
Leptin
Adipocytes
Germ Cells
Genes
Adipose Tissue
Phosphotransferases
Transplantation
Alleles

Keywords

  • Diabetes
  • Insulin resistance
  • Kbtbd2
  • p85α
  • Ubiquitination

ASJC Scopus subject areas

  • General

Cite this

Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice. / Zhang, Zhao; Turer, Emre; Li, Xiaohong; Zhan, Xiaoming; Choi, Mihwa; Tang, Miao; Press, Amanda; Smith, Steven R.; Divoux, Adeline; Moresco, Eva Marie Y; Beutler, Bruce.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 42, 18.10.2016, p. E6418-E6426.

Research output: Contribution to journalArticle

Zhang, Zhao ; Turer, Emre ; Li, Xiaohong ; Zhan, Xiaoming ; Choi, Mihwa ; Tang, Miao ; Press, Amanda ; Smith, Steven R. ; Divoux, Adeline ; Moresco, Eva Marie Y ; Beutler, Bruce. / Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 42. pp. E6418-E6426.
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