Novel Secreted Adipokine WNT1-inducible

WNT1-inducible signaling pathway protein 2 (WISP2) is expressed primarily in mesenchymal stem cells, fibroblasts, and adipogenic precursor cells. It is both a secreted and cytosolic protein, the latter regulating the adipogenic commitment of precursor cells and the induction of PPARγ by BMP4.

To examine the effect of secreted protein, we expressed a full-length and a truncated non-secreted WISP2 in NIH3T3 fibroblasts. Secreted, but not truncated, WISP2 activated the canonical WNT pathway with increased levels of β-catenin, its nuclear-directed phosphorylation, and LRP5/6 phosphorylation. It also inhibited Pparg activation and the effect of secreted WISP2 was reversed by the WNT antagonist DICKKOPF-1.

Differentiated 3T3-L1 adipose cells were also target cells in which extracellular WISP2 activated the canonical WNT pathway, inhibited Pparg and associated adipose genes, and, similar to WNT3a, promoted partial cell dedifferentiation and induction of a phenotype. of myofibroblasts with activation of fibrosis markers. .

Thus, WISP2 exerts dual actions on mesenchymal precursor cells; Secreted WISP2 activates canonical WNT and maintains cells in an undifferentiated state, while cytosolic WISP2 regulates adipogenic commitment.

The increase in the incidence and prevalence of type 2 diabetes over the past 20 years is primarily due to the global obesity epidemic. Subcutaneous adipose tissue, the largest adipose depot in man, has a limited ability to expand. When the limited extensibility of subcutaneous fat to store and dispose of excess dietary energy becomes insufficient, it will lead to fat accumulation in various ectopic depots, including the liver, with the induction of lipotoxicity and the well-known metabolic complications of the obesity. 1, 2, 3).

The expansion of subcutaneous adipose tissue by excess energy can be achieved in two different ways; either by expansion of existing adipocytes (hypertrophy) or by recruitment of new cells (hyperplasia). Fat cell enlargement (hypertrophic obesity), rather than recruitment of new cells (hyperplastic obesity), is associated with dysregulated adipose tissue, inflammation, increased fibrosis, and local and systemic insulin resistance

Hypertrophic obesity in man is also associated with a decreased ability to recruit new adipogenic precursor cells into the adipogenic lineage. The process of commitment of multipotent mesenchymal stem cells to the adipose lineage has not been well understood, whereas adipogenic differentiation is under the control of peroxisome proliferator-activated receptor γ (PPARγ) 2 and CCAAT-binding protein/ (C/EBPα) enhancer (7).

A key pathway that regulates early precursor cell commitment and adipogenesis is the wingless canonical-type murine mammary tumor virus (MMTV) integration site (WNT) family.

This extracellular pathway regulates cell proliferation, cell survival, and cell fate. Canonical WNT signaling and activation maintain precursor cell proliferation, prevent their entry into adipogenesis, and must be inhibited to activate Pparg and C/ebpa (8, 9, 10).

Canonical WNT ligands bind Frizzled (FZD) and low-density lipoprotein (LRP) receptor-related proteins with inhibition of the downstream degradation complex for β-catenin and stabilization of this molecule.

Nuclear β-catenin binds to transcription factors of the T-cell-specific transcription factor/lymphoid enhancer-binding factor (Tcf/Lef) families with activation of several WNT target genes (9, 11).

In a recent extensive study of the ability of human adipogenic precursor cells to undergo differentiation, we provided evidence for a decreased ability of early precursor cells in the subcutaneous adipose tissue of hypertrophically obese individuals to initiate adipogenesis (6).

Importantly, this was not due to a lack of adipogenic precursor cells but to a failure to inhibit canonical WNT activation in these cells and to activate the expression of important secreted WNT antagonists, in particular, DICKKOPF-1.

In further support of this concept, we found that WNT1-inducible signaling pathway protein 2 (WISP2), frequently used as a marker of canonical WNT activation (12), is increased in subcutaneous adipose tissue precursor cells and positively associated with insulin resistance. and amount of ectopic fat accumulation (13).

We also found that WISP2 is a secreted protein, highly expressed in mesenchymal stem cells, fibroblasts, and preadipocytes, and adipogenic differentiation was associated with a marked reduction in Wisp2 expression, while differentiation was inhibited by extracellular WISP2.

WISP2 was also recently identified in a proteomic analysis of the human adipose tissue secretome (14) and thus can be considered a novel secreted adipokine. However, the general regulation of Wisp2 expression is unclear, although canonical WNT ligands can increase it (12, 13).