Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues

Abstract

White adipose tissue (WAT) has key metabolic and endocrine functions and plays a role in regulating energy homeostasis and insulin sensitivity. WAT is characterised by its capacity to adapt and expand in response to surplus energy through processes of adipocyte hypertrophy and/or recruitment and proliferation of precursor cells in combination with vascular and extracellular matrix remodelling. However, in the context of sustained obesity, WAT undergoes fibro-inflammation, which compromises its functionality, contributing to increased risk of type 2 diabetes and cardiovascular diseases. Conversely, brown adipose tissue (BAT) and browning of WAT represent potential therapeutic approaches, since dysfunctional white adipocyte-induced lipid overspill can be halted by BAT/browning-mediated oxidative anti-lipotoxic effects. Better understanding of the cellular and molecular pathophysiological mechanisms regulating adipocyte size, number and depot-dependent expansion has become a focus of interest over recent decades. Here, we summarise the mechanisms contributing to adipose tissue (AT) plasticity and function including characteristics and cellular complexity of the various adipose depots and we discuss recent insights into AT origins, identification of adipose precursors, pathophysiological regulation of adipogenesis and its relation to WAT/BAT expandability in obesity and its associated comorbidities.

Keywords: Adipogenesis; Adipose tissue; Development; Fibrosis; Inflammation; Obesity; Plasticity; Review; Tissue remodelling; Type 2 diabetes.

Fig. 1

BAT/WAT adipogenesis and associated tissue remodelling. (a) Adipogenesis consists of a two-step process involving, successively, mesenchymal precursors, committed pre-adipocytes, growth-arrested pre-adipocytes, mitotic clonal expansion, terminal differentiation and mature adipocytes. The first step of white adipocyte differentiation is the generation of pre-adipocytes from mesenchymal precursors (MSCs) MYF5⁻ (grey arrow) or MYF5⁺ (brown arrows), driven by BMP4. By promoting dissociation of the WISP2–ZNF423 complex, BMP4 allows nuclear entry of ZNF423 and PPARγ induction. Repression of ZNF521, which negatively regulates ZNF423 by repressing EBF1, also constitutes an early event in induction of white adipogenesis. The second step of adipogenesis is the differentiation of pre-adipocytes into mature adipocytes (green arrow), a process that involves the activation of transcription factors C/EBPβ and C/EBPδ, first during mitotic clonal expansion of pre-adipocytes and subsequently induction of C/EBPα and PPARγ2, which maintains the terminal differentiation of the adipocyte. Finally, SREBP1 is considered to be the third key transcription factor for adipogenesis, inducing expression of adipocyte-specific genes such as FABP4, adiponectin, GLUT4 (also known as SLC2A4), and LPL. C/EBPζ, a dominant inhibitor of C/EBPα and β, is induced in late adipocyte differentiation and has been proposed as an inhibitor of adipogenesis. Both canonical and non-canonical Wnt signalling pathways negatively regulate adipogenesis. β-Catenin mediates canonical Wnt signalling by activating cyclin D1, conversely with inhibition of PPARγ and C/EBPα, causing a further decrease in adipogenesis. Similar to WAT, commitment of brown pre-adipocytes from MYF5⁺ MSCs (brown arrows) and differentiation into brown adipocytes (orange arrow) involves transcriptional control by C/EBPs and PPARγ2 while some transcription factors, such as FOXC2, PGC1α and PDRM16, are specific to brown cell fate leading to brown-specific thermogenic markers such as UCP-1. Recent evidence suggests that both brown and white adipocytes may derive from endothelial precursors (red arrows). (b) Angiogenesis is driven by angiogenic factors produced by adipocytes and vascular cells. VEGF-A is considered the main pro-angiogenic factor of AT. VEGF-A binds to VEGF receptors 1 and 2 to drive the migration of so-called ‘tip cells’, the ECs at the tip of a new capillary. Other growth factors such as ANGPTL4 and FGF-2 drive the migration and proliferation of stalk cells, the endothelial cells between the tip cells and the existing vessel that drive elongation. The new vessel is stabilised by the production of ECM components, forming the basement membrane, and the recruitment of pericytes. (c) Pre-adipocytes are surrounded by a fibrous ECM enriched in collagen I, collagen III and fibronectin replaced by the basement membrane, a specialised ECM surrounding mature adipocytes composed of collagen IV, collagen XVIII, entactin and laminin. ECM remodelling during adipogenesis involves degradation of pre-adipocyte ECM by proteases (MMPs, ADAMT and cathepsins). This liberates growth factors and matricellular proteins that are important for the synthesis of the new mature adipocyte basement membrane. ADAMT, a disintegrin and MMP with thrombospondin motifs; ANGPTL4, angiopoietin-like 4; EBF1, early B-cell factor 1; LPL, lipoprotein lipase

Fig. 2

SAT and VAT pathological remodelling in obesity and potential strategies. (a) WAT undergoes cellular and structural remodelling in obesity, characterised by the following: (1) adipocyte hypertrophy associated with production of inflammatory factors (VAT > SAT); (2) accumulation of immune cells such as macrophages organised around dead adipocytes (VAT > SAT); (3) decreased capillary density associated with EC dysfunction (i.e. activation, inflammation and senescence) (VAT > SAT); (4) activation of fibroblasts and APs (SAT > VAT) leading to fibrosis deposition and decreased tissue plasticity (SAT > VAT). (b) Differential strategies between WAT and BAT depots to prevent obesity-related disorders, targeting tissue plasticity/remodelling and response to sympathetic tone, to promote healthy SAT expansion and browning, conversely with limited VAT expansion and lipotoxic action, and BAT activation and recruitment of APs