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

IF 3.3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Saori Kinoshita, Shinsuke Onuma, Natsuko Yamazaki, Yukinao Shibukawa, Keiichi Ozono, Toshimi Michigami, Masanobu Kawai
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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.

骨细胞中缺乏PTEN会增加脂钙素-2水平,并赋予小鼠对高脂肪饮食诱导的肥胖的抵抗力。
骨细胞已被证明在广泛的代谢过程的调节中发挥关键作用。然而,它们在葡萄糖代谢调节中的作用仍有待确定,尽管越来越多的证据表明成骨细胞在这一调节中起着不可或缺的作用,其中成骨细胞衍生的脂载素-2 (LCN2)已被证明调节葡萄糖代谢。此外,AKT激活可诱导Lcn2表达。这些结果使我们假设AKT在骨细胞中的激活通过调节Lcn2的表达来调节葡萄糖代谢。因此,本研究通过Pten-flox小鼠与Dmp1-Cre小鼠(PtenOcy-/-小鼠)杂交,在骨细胞中删除Pten基因,激活AKT信号。在骨细胞中删除Pten表达导致骨细胞AKT活化,这与脂肪组织质量减少和胰岛素敏感性增强有关。PtenOcy-/-小鼠脂肪组织中Pparg2和脂肪生成相关基因的表达降低。机制上,骨细胞中PTEN的缺乏增加了股骨中Lcn2的表达,这与血清和尿液中Lcn2水平的升高有关。尿LCN2水平与白色脂肪组织质量呈负相关。此外,用重组LCN2处理原代白色脂肪细胞降低了Pparg2和脂肪生成相关基因的表达。这些结果表明,骨细胞中PTEN的缺失增加了Lcn2的表达,Lcn2在脂肪组织中抑制脂肪生成,导致这些小鼠的胰岛素敏感性增强。本研究为AKT激活在骨细胞中通过增加Lcn2表达调节糖代谢的关键作用提供了新的见解。
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来源期刊
Endocrinology
Endocrinology 医学-内分泌学与代谢
CiteScore
8.10
自引率
4.20%
发文量
195
审稿时长
2-3 weeks
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.
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