{"title":"Lack of PTEN in Osteocytes Increases Lipocalin-2 Level and Confers Resistance to High-Fat Diet-Induced Obesity in Mice.","authors":"Saori Kinoshita, Shinsuke Onuma, Natsuko Yamazaki, Yukinao Shibukawa, Keiichi Ozono, Toshimi Michigami, Masanobu Kawai","doi":"10.1210/endocr/bqaf026","DOIUrl":null,"url":null,"abstract":"<p><p>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 (PtenOcy-/- 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 PtenOcy-/- 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.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Endocrinology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1210/endocr/bqaf026","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
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 (PtenOcy-/- 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 PtenOcy-/- 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.
期刊介绍:
The mission of Endocrinology is to be the authoritative source of emerging hormone science and to disseminate that new knowledge to scientists, clinicians, and the public in a way that will enable "hormone science to health." Endocrinology welcomes the submission of original research investigating endocrine systems and diseases at all levels of biological organization, incorporating molecular mechanistic studies, such as hormone-receptor interactions, in all areas of endocrinology, as well as cross-disciplinary and integrative studies. The editors of Endocrinology encourage the submission of research in emerging areas not traditionally recognized as endocrinology or metabolism in addition to the following traditionally recognized fields: Adrenal; Bone Health and Osteoporosis; Cardiovascular Endocrinology; Diabetes; Endocrine-Disrupting Chemicals; Endocrine Neoplasia and Cancer; Growth; Neuroendocrinology; Nuclear Receptors and Their Ligands; Obesity; Reproductive Endocrinology; Signaling Pathways; and Thyroid.