Aberrant Wnt/β-catenin signaling in the mesenchymal stem cells of LZTFL1-depleted mice leads to increased adipogenesis, with implications for obesity

Abstract

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 3 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 Pparg 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.

Keywords: LZTFL1; Wnt signaling; adipogenesis; caveolin; cell surface protein; cilia; glucocorticoid receptor; mesenchymal stem cells (MSCs); obesity; peroxisome proliferator-activated receptor γ (PPARγ).