The Engimatic WNT Signaling and Mesenchymal Stem Cell Adipogenesis : Implications for Metabolic disorders

Abstract

The past decade has witnessed a sudden surge in the obesity prevalence worldwide. Obesity  has been linked to several chronic metabolic disorders including diabetes, hyperlipidemia and atherosclerosis. Due to this there is an immense interest in understanding the intricate aspects of adipogenesis, specifically pertaining to the study of the mechanisms through which various signaling pathways regulate adipocyte differentiation. One such enigmatic signaling  pathway  regulating adipogenesis is the WNT signaling Pathway. The present review focusses on the role of WNT signaling on Adipogenesis and its relationship with the development of metabolic disorders.

Introduction

Obesity is a global health burden, with an estimated prevalence of 3.5 billion adults worldwide Gortmaker et al., 2011Misra and Shrivastava, 2013. The obesity epidemic has been linked to the development of several metabolic complications including metabolic syndrome which is a triad of type II diabetes, hypertension and atherosclerosis Kahn and Flier, 2000. Adipogenesis is a central phenomenon which serves as a key regulator of homeostasis and metabolism. During adipogenesis mesenchymal stem cells precursors differentiate into mature adipocytes Farmer,2006. Several transcription factors including peroxisome proliferator activated receptor gamma PPAR γ, CCAAT/enhancer binding proteins C/EBPα & β are known to coordinately control the adipogenic program Rosen et al., 2000Wu et al., 1999. Recent reports have highlighted the role of extracellular or circulating regulator factors in the regulation of adipogenesis Christodoulides et al., 2009, one such extracellular signaling pathway known to regulate adipogenesis is the WNT signaling pathway. Wingless type MMTV integration site (WNT) signaling pathway consists of several secreted glycoproteins known to regulate several cellular processes Prestwich and Macdougald, 2007. In the current scenario of an obesity epidemic and its interplay with the development of metabolic disorders, there is an urgent need to understand the underlying mechanisms involved in the development of adipocytes i.e from the commitment phase to the differentiation phase, since dysregulated adipogenesis is often known to prelude to the development of metabolic syndrome. The present review focuses on understanding the role of WNT signaling pathway in regulating the mesenchymal stem cell fate, obesity and type II diabetes.

Mesenchymal stem cell: general characteristics and adipocyte lineage commitment

Mesenchymal stem cells (MSC) are multipotent, adherent, fibroblastoid stromal cells capable of differentiating into multiple cell types including adipocytes, oestocytes and chrondocytes Caplan, 1986Piersma et al., 1985. Mesenchymal stem cells where first identified in the bone marrow, however other sources of MSC’s include adipose tissue and skeletal muscle. Bone marrow BMSC expressing various cell surface markers including CD44, CD29, CD73, CD105 and are negative for all hematopoetic markers Chamberlain et al., 2007. The adipogenesis from mesenchymal stem cell precursors involves two distinct phases, the determination phase which involves the commitment of MSC to the adipocyte lineage followed by the terminal differentiation phase characterized by the terminal differentiation of pre-adipocyte into a mature adipocyte Lowe et al., 2011Rosen and Spiegelman, 2014. The mature adipocyte acquires various characteristics including lipid transport and synthesis, secretion of adipose specific proteins and insulin sensitivity.

Several signaling pathways are known to regulate the commitment of mesenchymal stem cell precursor to adipocyte, including Insulin like growth factor signaling, WNT signaling pathway, Sonic Hedgehog pathway Logan and Nusse, 2004, through modulational of various transcription factors including PPARγ and C/EBP family of proteins.

Ppar-γ: the master regulator of adipogenesis

Adipogenic differentiation involves a cascade of events coordinated by several transcription networks, however two key transcription factors crucial for adipogenesis are PPAR γ and C/EBP family members Hamm et al., 2001Mueller et al., 2002.

Peroxisome proliferator activated receptors are members of steroid/thyroid hormone receptor gene superfamily. There are three isoforms of PPAR namely PPAR alpha, gamma and delta Tontonoz and Spiegelman, 2008. PPAR-γ serves as the master regulator of adipogenesis, several studies have demonstrated the requirement of PPAR-γ during both commitment and differentiation phases Schopfer et al., 2005Tzameli et al., 2004. All the three isoforms i.e PPARα, PPARδ and PPARγ are expressed during adipogenesis. Recent genome wide studies have indicated that PPARγ and C/EBP regulate the activity of several genes expressed in mature and developing adipocytes Lefterova et al., 2008Nielsen et al., 2008 including genes involved in insulin sensitivity, lipogenesis and lipolysis. PPARγ mediated pro adipogenic effects are executed upon its ligands mediated activation, one such set of ligands is thiazoliediones (TZD’s), which save as potent agonists for PPARγ Lehmann et al.,1995. Several studies in animal models have reiterated the central role of PPARγ in adipogenic differentiation. Studies using knock out PPAR-γ mice demonstrated a reduced adipocyte differentiation Tzameli et al., 2004. The selective deletion of PPARγ is murine adipose tissue led to the less of both brown and white adipocytes Rosen and Spiegelman, 2014.

Wnt and adipogenesis

Wingless type MMTV integration site (WNTS) are a family of several glycoproteins which are known to play an essential role in several cellular processes including cell fate determination, proliferation and differentiation Clevers, 2006. WNT’s exert their effect through canonical (β- catenin dependent) and noncanonical (β catenin independent pathways of signaling Li et al., 2006Xavier et al., 2014.

The canonical WNT pathway binds to transmembrane frizzled (Frz) receptors, low density lipoprotein receptor related protein 5 or 6 (Lrp 5/6) and intracellular protein of disheveled (DSH) family, which upon activation results in inhibition of another intracellular complex comprising of axin glycogen synthase kinase 3 (GSK3)-β and adenomatous polyposis cote (APC). This results in hypo phosphorylation of β catenin and its translocation into the nucleus where it binds to T cell specific transcription factor (TCF) in order to activate WNT target genes Bennett et al., 2002Jones and Jomary,2002. The non-canonical WNT signaling pathway functions in a β catenin independent manner. The WNT and FZD homologues act through heteromeric GTP binding protein and trigger intracellular calcium release, activating calcineurin and other calcium/ calmodulin dependant kinases Semenov et al., 2007.

Several studies have highlighted the key role of WNT signaling in regulating adipogenesis. WNT’s are a key decider in decision of Mesenchymal stem cell precursor’s cell fate i.e whether it would commit to oestogenic or adipogenic lineage. Several reports indicate that WNT signaling pathway regulates the mesenchymal stem cell fate by suppressing adipogenesis through the prevention of induction of master regulators PPARγ and C/EBP transcription factors during preadipocyte differentiation Kang et al., 2007. The endogenous factor WNT10b has been shown to stabilize free cytosolic β catenin, thereby inhibiting adipogenesis Ross et al., 2000. The expression of WNT 10b is highest during pre-adipocytes and rapidly decreases upon induction of adipocyte differentiation Ross et al., 2000. A recent study demonstrated the role of WNT6, WNT10a in addition to WNT10b in inhibiting adipogenesis Cawthorn et al.,2012. A study by Krishnan et al., 2006 reported that the over expression of WNT10b blocks adipogenesis however adding of WNT 10b anti-sera to 3T3-L1 preadipocyte cell lines resulted in promotion of adipogenesis Krishnan et al., 2006.

Wnt signaling and metabolic disorders

Obesity is major contributing factor which preludes to the onset of several chronic metabolic disorders including type 2 diabetes. Therefore it is imperative to understand the intricacies involved in the regulation of adipogenesis including the signaling pathways which are know to regulate this phenomenon. WNT signaling is a crucial regulator of adipocyte differentiation Welters and Kulkarni, 2008. The importance of WNT signaling pathway in regulation of adipogenesis has come to the forefront as several studies have elucidated that a dysregulation in WNT signaling often preludes to metabolic pathology. Several studies have demonstrated the expression of various components of the WNT signaling pathway members in endocrine cells including human islets and rodent β cell lines Heller et al., 2003Hermann et al., 2007. Many components of WNT pathway have been shown to be involved in β cell proliferation, cholesterol metabolism and glucose induced insulin secretion Fujino et al., 2003Rulifson et al., 2007.

Polymorphisms in LRP5 and WNT10b have shown to be associated with obesity in the European population Christodoulides et al., 2006Guo et al., 2006. Genome wide association studies have identified TCF7L2 as a type diabetes susceptibility gene Jin,2008. Furthermore, the key effector of the WNT signaling pathway bipartite transcription factor T cell factor 2 (TCF7L2) polymorphisms have been linked to susceptibility to type 2 diabetes by a number of studies of different ethnicities Florez,2007Weedon, 2007.

Conclusion

Extensive and exhaustive research elucidating the role of WNT signaling pathway as a modulator of adipogenesis has generated tremendous interest in the understanding interplay between the WNT signaling cascade components and the triad of diabetes, hyperlipidemia and atherosclerosis. Future studies directed to understand the underlying mechanisms through which WNT signaling regulates adipogenesis and the interplay between the various signaling pathways during adipogenesis would pay the way for future WNT directed therapeutics for metabolic disorders.

Abbreviations

MSC- Mesenchymal Stem cell, PPAR gamma: Peroxisome proliferator activated receptor.