Lack of PTEN in Osteocytes Increases Lipocalin-2 Level and Confers Resistance to High-Fat Diet–Induced Obesity in Mice

Saori Kinoshita, Shinsuke Onuma, Natsuko Yamazaki, Yukinao Shibukawa, Keiichi Ozono, Toshimi Michigami, Masanobu Kawai
Endocrinology, Volume 166, Issue 3, March 2025, bqaf026
https://doi.org/10.1210/endocr/bqaf026

Abstract

Osteocytes have been shown to play critical roles in the regulation of a wide range of metabolic processes. However, their role in the regulation of glucose metabolism remains to be determined despite accumulating evidence of the integral role of osteoblasts in this regulation, in which osteoblast-derived lipocalin-2 (LCN2) has been shown to regulate glucose metabolism. Additionally, Lcn2 expression is induced by AKT activation. These results led us to hypothesize that AKT activation in osteocytes regulates glucose metabolism by modulating Lcn2 expression. Therefore, in this study, the Pten gene was deleted in osteocytes to activate AKT signaling by crossing Pten-flox mice with Dmp1-Cre mice (Pten_Ocy^−∕− mice). Deleting Pten expression in osteocytes resulted in osteocytic AKT activation, which was associated with decreased adipose tissue mass and enhanced insulin sensitivity. Expression of Pparg2 and lipogenesis-associated genes were decreased in the adipose tissue of Pten_Ocy^−∕− mice. Mechanistically, the lack of Phosphatase and Tensin Homolog Deleted from Chromosome 10 (PTEN) in osteocytes increased Lcn2 expression in the femur, which was associated with increased serum and urine LCN2 levels. The urinary LCN2 level was negatively associated with white adipose tissue mass. Additionally, the treatment of primary white adipocytes with recombinant LCN2 reduced the expression of Pparg2 and lipogenesis-related genes. These results suggest that the absence of PTEN in osteocytes increases the expression of Lcn2, which acts in the adipose tissue to suppress lipogenesis, resulting in enhanced insulin sensitivity in these mice. This study provides novel insights into the critical role of AKT activation in osteocytes in regulating glucose metabolism by increasing Lcn2 expression.

You may also like...