Obesity is one of the main clinical characteristics associated with the heterogeneous genetic disorder Bardet-Biedl syndrome (BBS). Leucine zipper transcription factor like 1 (LZTFL1) is a member of the BBS gene family. Our work showed that Lztfl1knockout (LZKO) mice display the obesity phenotype as early as three months of age. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into various cell types, including adipocytes. To understand the role of LZTFL1 in adipogenesis, we analyzed MSCs isolated from LZKO mouse compact bones (CB-MSCs). Compared to wildtype (WT), LZKO CB-MSCs had elongated primary cilia with tapered tips and increased levels of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor that favors adipogenesis, and nuclear glucocorticoid receptor (GR), a transcription factor involved in Pparγ activation. Also, LZKO CB-MSCs had a lower level of total β-catenin, a core factor of the antiadipogenic canonical Wnt/b-catenin signaling pathway involved in limiting the nuclear localization of GR. Interaction between caveolin1 (CAV1) and LRP6, the main receptor for canonical Wnt signaling, is known to be critical for Wnt pathway activation and β-catenin stabilization. Compared to WT cells, LZKO cells had elevated total, cell-surface, and lipid-raft-associated LRP6 and reduced CAV1, strongly indicating alterations in the components of the Wnt-signaling pathway. We show that in the absence of LZTFL1, adipogenesis-restraining Wnt/β-catenin signaling is inhibited and adipogenesis-favorable factors are stimulated in CB-MSCs, leading to enhanced adipogenesis. Evidence provided here could help in understanding the mechanism and molecular basis of obesity in LZTFL1-defective patients.

中文翻译：

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LZTFL1 耗竭小鼠间充质干细胞中异常的 Wnt/β-catenin 信号传导导致脂肪生成增加，对肥胖有影响。


肥胖是与异质性遗传病 Bardet-Biedl 综合征 （BBS） 相关的主要临床特征之一。亮氨酸拉链转录因子样 1 （LZTFL1） 是 BBS 基因家族的成员。我们的研究表明，Lztfl1knockout （LZKO） 小鼠早在 3 个月大时就表现出肥胖表型。间充质干细胞 （MSC） 是多能干细胞，可以分化成各种细胞类型，包括脂肪细胞。为了了解 LZTFL1 在脂肪生成中的作用，我们分析了从 LZKO 小鼠紧凑骨 （CB-MSC） 中分离的 MSC。与野生型 （WT） 相比，LZKO CB-MSCs 具有细长的初级纤毛，尖端逐渐变细，过氧化物酶体增殖物激活受体γ （PPARγ） 水平升高，PPARγ 是一种有利于脂肪生成的关键转录因子，核糖皮质激素受体 （GR） 是一种参与 Pparγ 激活的转录因子。此外，LZKO CB-MSC 的总 β-catenin 水平较低，这是抗脂肪生成经典 Wnt/b-catenin 信号通路的核心因子，参与限制 GR 的核定位。已知 caveolin1 （CAV1） 和 LRP6（经典 Wnt 信号传导的主要受体）之间的相互作用对 Wnt 通路激活和 β-catenin 稳定至关重要。与 WT 细胞相比，LZKO 细胞的总、细胞表面和脂筏相关 LRP6 升高，CAV1 降低，强烈表明 Wnt 信号通路成分的改变。我们表明，在没有 LZTFL1 的情况下，抑制脂肪生成抑制 Wnt/β-catenin 信号传导，并在 CB-MSC 中刺激脂肪生成有利因子，导致脂肪生成增强。此处提供的证据可能有助于了解 LZTFL1 缺陷患者肥胖的机制和分子基础。