A tale with a Twist: a developmental gene with potential relevance for metabolic dysfunction and inflammation in adipose tissue

Abstract

The Twist proteins (Twist-1 and -2) are highly conserved developmental proteins with key roles for the transcriptional regulation in mesenchymal cell lineages. They belong to the super-family of bHLH proteins and exhibit bi-functional roles as both activators and repressors of gene transcription. The Twist proteins are expressed at low levels in adult tissues but may become abundantly re-expressed in cells undergoing malignant transformation. This observation prompted extensive research on the roles of Twist proteins in cancer progression and metastasis. Very recent studies indicate a novel role for Twist-1 as a potential regulator of adipose tissue (AT) remodeling and inflammation. Several studies suggested that developmental genes are important determinants of obesity, fat distribution and remodeling capacity of different adipose depots. Twist-1 is abundantly and selectively expressed in the adult AT and its constitutive expression is significantly higher in subcutaneous (SAT) vs. visceral (VAT) fat in both mice and humans. Moreover, Twist1 expression is strongly correlated with BMI and insulin resistance in humans. However, the functional roles and transcriptional downstream targets of Twist1 in AT are largely unexplored. The purpose of this review is to highlight the major findings related to Twist1 expression in different fat depots and cellular components of AT and to discuss the potential mechanisms suggesting a role for Twist1 in AT metabolism, inflammation and remodeling.

Keywords: IL12; T cells; Twist1; human obesity; inflammation; type 2 diabetes; visceral fat.

Figure 1

Molecular structure of the human Twist protein. Twist1 has the typical modular structure of the basic helix-loop-helix (bHLH) transcription factor family. At the N-terminus region 2 nuclear localization signals (NLS) are located at positions 37–40 and 73–77, respectively. The protein–protein interactions are delineated with black bars on top; PCAF = p300/CBP associated factor; CPB = cAMP response element binding protein; binding of the partner proteins in this region inhibits recruitment of the histone remodeling proteins HDAC (histone de-acetylase) and HAT (histone acetyl transferase). Twist1 can form heterodimers with other bHLH transcription factors that subsequently bind to the consensus E-box sequences in target genes. Some of the binding partners are the universal E-box proteins E12 and E47; also, Myo D involved in muscle differentiation; Id family of proteins can sequester the E-box transcription factors and therefore prevent formation of the dimers with Twist1. In the C-terminal region, the functional Twist box domain can bind Runx 2 or 3 (runt transcription factors). A number of functional Ser/Thr residues allow post-translational modification of Twist1 (illustrated on the bottom).

Figure 2

(A) Twist1 transcriptional effects in white (Thisse et al., 1987) and brown (Thisse et al., 1988) adipocytes. 1. In white human adipocytes Twist1 participates in basic transcription of TNFα and IL6, possibly by direct binding to their Ebox consensus sequences; however, increased formation of TNFα, up-regulates Twist which in turn will bind to p65 and prevent trans-activation of the TNFα and IL6 genes by the active NFkB complex; also, Twist increase expression attenuates the effect of TNFα on MCP-1 production; by participating in this negative feedback loop, Twist1 may limit inflammation in white adipocytes; Twis-1 also has metabolic effects by direct binding to PGC1α (PPARγ co-activator 1) which in turn increases fatty acid oxidation. 2. In mouse brown adipocytes Twist1 is up-regulated by PPARδ ; Twist1 binding to PGC1α promotes recruitment of HDAC5 at the promoter of the target genes UCP1 (uncoupling protein 1) and CPT1 (carnitine palmitolyl transferase 1) which results in reduced brown fat energy dissipation. (B) Pathways modulated by Twist1 leading to potentially improved insulin resistance in obesity. Excess nutrient excess and obesity leads to adipocyte inflammation, immune cell recruitment in adipose tissue and hypertrophic and hyperplastic remodeling of AT. Inflamed adipocytes secrete pro-inflammatory cytokines (TNFα, IL6, etc.) which via NFkB and STAT3 lead to formation of chemokines including MCP1 (macrophage attractant protein 1) that further exacerbate tissue inflammation. Twist1 is activated by TNFα and acts via a negative regulatory loop at the level of NKkB to limit formation of pro-inflammatory cytokines and chemokines; the macrophages infiltrating adipose tissue in obesity are a rich source of IL12 which induces Th1 polarization of T cells and via STAT4 and Tbet induces formation of IFNγ ; Twist1 is also up-regulated by IL12/STAT4; Twist may bind to Runx3 and prevent the latter to interact with Tbet therefore reducing IFNγ transcription; by limiting the pro-inflammatory effects of IL12, Twist1 further prevents local inflammation; active expansion of adipose tissue in obesity may not be matched by adequate angiogenesis; local hypoxia activates HIF1α and HIF2α (hypoxia-inducible factors) which can directly bind and up-regulate Twist1 expression; Twist1 in turn may promote formation of VEGFA that induces angiogenesis and restores the adequate oxygen and nutrient demand of the adipose tissue leading to “healthy” remodeling. Collectively, these pathways modulated by Twist1 may lead to prevention of insulin resistance in obesity.