Wnt signalling and the control of cellular metabolism

Abstract

At the cellular level, the biological processes of cell proliferation, growth arrest, differentiation and apoptosis are all tightly coupled to appropriate alterations in metabolic status. In the case of cell proliferation, this requires redirecting metabolic pathways to provide the fuel and basic components for new cells. Ultimately, the successful co-ordination of cell-specific biology with cellular metabolism underscores multicellular processes as diverse as embryonic development, adult tissue remodelling and cancer cell biology. The Wnt signalling network has been implicated in all of these areas. While each of the Wnt-dependent signalling pathways are being individually delineated in a range of experimental systems, our understanding of how they integrate and regulate cellular metabolism is still in its infancy. In the present review we reassess the roles of Wnt signalling in functionally linking cellular metabolism to tissue development and function.

Figures

Figure 1. β-Catenin-dependent Wnt signalling

Panels show unstimulated (A), Wnt-stimulated induction of β-catenin/TCF target gene expression (B), and commonly reported mechanisms of feedback inhibition (C). Wnt/β-catenin signalling is inhibited by induction of (1) Dkk1 which sequesters LRP5/6 co-receptors; (2) sFRPs which sequester Wnt ligands; (3) Dapper1 (Dact1) which binds dishevelled proteins; and (4) selective components of the ubiquitin-degradation machinery such as β-TrCP. An animated version of this Figure is available at http://www.BiochemJ.org/bj/427/0001/bj4270001add.htm.

Figure 2. β-catenin-independent Wnt signalling

(A) Fzd/LRP-mediated regulation of mTORC1. (B) LRP-independent, but Fzd-mediated signals. (C) Fzd-independent signalling via ROR2 or Ryk receptors.

Figure 3. Wnt signalling and Wnt target genes link to cellular metabolic pathways

Activation of Wnt signals can be directly and indirectly linked to increasing flux through glycolysis, the tricarboxylic acid cycle and glutaminolysis. Collectively this promotes lactate production and utilization of glucose and glutamine as a carbon source for biosynthetic processes.

Figure 4. Putative role of Wnt signalling networks in paracrine regulation of titrated adipogenesis

(A) Paracrine regulation of adipogenesis by Wnt10b. Co-culture experiments demonstrate that Wnt10b-expressing cells do not differentiate, but can also inhibit the adipogenic potential of neighbouring preadipocytes. Co-cultures of preadipocytes expressing either empty vector (EV), Wnt10b or GFP (green fluorescent protein) only were induced to differentiate into adipocytes. Similar results were observed when Wnt10b-expressing preadipocytes were replaced by preadipocytes in which Dact1 was knocked down [98]. Images were generated using Cell-IQ from Chipman Technologies. (B) The paracrine Wnt signalling network mediates cross-talk between preadipocytes and maturing adipocytes. This network is also nutritionally regulated and may regulate titrated adipocyte recruitment in vivo [98].

Figure 5. Adipose tissue expansion during the development of obesity and diabetes is accompanied by dynamic alterations in Wnt/β-catenin signalling components

As adipose tissue expands, activators of Wnt/β-catenin signalling are decreased while inhibitors increase. However, this reciprocal regulation appears to be uncoupled in dysfunctional obese insulin-resistant adipose tissue, probably due to increased pro-inflammatory cytokine activity. BMI, body mass index; HFD, high-fat diet.