Adipose tissue is critical for whole body energy homeostasis. Both obesity and lipodystrophy (loss of fat) are associated with diabetes and insulin resistance. Our recent work identified a new mutant mouse, termed teeny, that exhibited growth retardation, lipodystrophy, extreme insulin resistance, severe diabetes with fasting glucose as high as 600-700 mg/dL, and fatty liver.
The teeny phenotype is caused by a null mutation in the Kelch repeat and BTB (POZ) Domain containing 2 (KBTBD2), which has no previously assigned functions. We found that KBTBD2 operates as an E3 ubiquitin ligase to regulate the insulin signaling pathway by targeting degradation of the regulatory subunit of phosphatidylinositol 3-kinase, p85α. Using KBTBD2 conditional knockout mouse models, we found both adipocyte-intrinsic and -extrinsic features of the teeny phenotype.
Although KBTBD2 clearly functions as an important regulator of insulin sensitivity, important questions remain that we are pursuing:
- Why is p85α is selectively degraded by KBTBD2 in different cells and tissues? We hypothesize that KBTBD2 protein might be post-translationally modified to regulate its enzyme activity.
- What is the role of KBTBD2 in growth?
- By what mechanisms do BTB family proteins help maintain body weight?
The role of KBTBD2 in the insulin signaling pathway.