Wnt/β-Catenin Signaling and Obesity

Figures

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  FIGURE 1. A simplified representation of precise modulation of canonic Wnt/β-catenin signaling. Wnt proteins combine with low-density lipoprotein receptor-related protein (LRP) 5 or 6 coreceptor and Frizzled (FZD) seven transmembrane domain receptors as Wnt-FZD-LRP5/6 complex; the cytoplasmic part of FZD interacts with Disheveled (DVL), and tightly regulates the activity of the β-catenin cytoplasmic pool by inhibiting its phosphorylation. Then β-catenin enters the nucleus, and turns on transcription via binding to members of the lymphoid enhancer factor (TCF/LEF) family of transcription factors. ZNRF3/RNF43 is a negative feedback regulator of Wnt/β-catenin signaling. With a lack of R-spondin proteins (RSPOs), ZNRF3/RNF43 is recruited by DVL to Wnt-FZD-LRP5/6 complex to mediate their degradation (left panel). When RSPOs are present, they simultaneously combine with the extracellular regions of both ZNRF3/RNF43 and LGR4/5/6, leading to autoubiquitination, endocytosis, and membrane clearance of ZNRF3/RNF43. Therefore, RSPOs sensitizes cells to Wnt/β-catenin signaling by inhibiting ZNRF3/RNF43, resulting in increased Wnt-FZD-LRP5/6 complex availability at the cell surface (right panel).…

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  FIGURE 2. Wnt/β-catenin signaling in adipose precursors and pre-mature/mature adipocytes. When Wnt/β-catenin signaling is activated, β-catenin enters the nucleus and it turns on transcription via binding to TCF/LEF family of transcription factors. β-catenin–TCF/LEF complex is needed to recruit transcriptional co-activator to be functional, including the CREB-binding protein (CBP) or its closely associated homolog E1A associated protein p300, B cell lymphoma 9 (BCL-9), the co-activator Pygopus (PYGO), etc. Wnt/β-catenin signaling activation in adipose precursor cells leads β-catenin to combine with co-activators CBP, resulting in precursor proliferation and potency maintenance; in pre-mature/mature adipocytes, β-catenin combines with co-activator p300, resulting in the initiation of differentiation.

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  FIGURE 3. Wnt/β-catenin signaling participates in HFD-induced depot-specific hypertrophy and hyperplasia. In response to HFD stimulation, vWAT (including eWAT) adipocyte precursors are first activated by Wnt/β-catenin signaling, leading to their rapid and transient burst of proliferation “overproliferation.” Then adipocyte precursors stop “overproliferation”, remain quiescent, and wait for another signal to reactivate. Meanwhile, the PDGFRα pathway is activated, inhibits “overproliferated” adipocyte precursor adipogenesis (possibly) via suppressing Wnt/β-catenin signaling, then triggers hypertrophy of existing mature adipocytes. Hypertrophied adipocytes may secrete some adipokines to promote the subsequent lipid filling of these activated APs. However, in sWAT (including iWAT), HFD stimulation activates Wnt/β-catenin signaling to promote SWAT mature adipocytes hypertrophy. As hypertrophied adipocytes reach their maximal size and secrete adipokines or emit other signals, adipocyte precursors are then induced to “overproliferation” and new adipocytes will form to meet the demand of increasing lipid storage.

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  FIGURE 4. Wnt/β-catenin signaling regulates the development of depot-specific beige adipocytes. In response to cold or β3 adrenergic receptor agonists, both sWAT and vWAT adipocyte progenitors (in adipose cells, APs consist of adipocyte progenitors and preadipocytes) are induced to asymmetric division possibly via the activation of Wnt/β-catenin signaling. However, the division percentage between preadipocytes and adipocyte progenitors is different in sWAT and vWAT. Most likely, the percentage of vWAT adipocyte progenitors dividing into progenitors is far more than that of preadipocytes. There is the possibility that mature white adipocytes may directly transform into beige adipocytes via transdifferentiation in vivo. In addition, there are dormant beige adipocytes (unilocular and UCP1-) that can be activated to multilocular and UCP1+ beige adipocytes. Activated beige adipocytes of sWAT can be converted into white-type adipocytes when warmed up, and these white-type adipocytes have the capacity to reconvert into beige adipocytes when re-exposed to cold stimulation.