A Wrong Fate Decision in Adipose Stem Cells upon Obesity

Abstract

Progress has been made in identifying stem cell aging as a pathological manifestation of a variety of diseases, including obesity. Adipose stem cells (ASCs) play a core role in adipocyte turnover, which maintains tissue homeostasis. Given aberrant lineage determination as a feature of stem cell aging, failure in adipogenesis is a culprit of adipose hypertrophy, resulting in adiposopathy and related complications. In this review, we elucidate how ASC fails in entering adipogenic lineage, with a specific focus on extracellular signaling pathways, epigenetic drift, metabolic reprogramming, and mechanical stretch. Nonetheless, such detrimental alternations can be reversed by guiding ASCs towards adipogenesis. Considering the pathological role of ASC aging in obesity, targeting adipogenesis as an anti-obesity treatment will be a key area of future research, and a strategy to rejuvenate tissue stem cell will be capable of alleviating metabolic syndrome.

Keywords: adipogenesis; fate determination; hypertrophic obesity; inflammation; stem cell aging.

Figure 1

Schematic summary of cell cycle regulation in ASCs. The mammalian cell cycle is the process composed of four phases: growth 1 (G₁), DNA synthesis (S), growth 2 (G₂), as well as mitosis (M). Similar to other adult stem cells, it is often that ASC enters the quiescent state (G₀) when there are no mitogenic stimuli. To ensure the cellular quality, the cell cycle progression is controlled by three major checkpoints, including G₁/S checkpoint, the G₂/M checkpoint, and metaphase checkpoint (as indicated by red-colored bar). Mechanistically, these checkpoints are governed by the activity of cyclin and its partner cyclin-dependent kinase. For instance, the complex composed of E-type cyclin (Cyclin E) with cyclin-dependent kinase 2 (CDK2) inactivates the retinoblastoma protein (Rb) via phosphorylation (P), and in turn relieves the inhibitory effect on E2F transcription factor. As such, this enables ASC to undergo gene profile reprogramming for entering S phase. By contrast, the cell cycle progression can be arrested by CDK inhibitors via blocking the binding between cyclin and corresponding CDK.

Figure 2

Schematic diagram on BMP, Wnt, and Hh signalling. The mechanism of lineage commitment in ASCs is extensively studied in relation to BMP, Wnt, and Hh signaling. It should be noted that, while BMP signaling pathway is pro-adipogenic and promotes the expression of PPARγ and C/EBP, the TGFβ, Wnt, and Hh signaling pathways are anti-adipogenic (as marked with red cross). As observed in both rodents and obese patients, dysregulation in these pathways restricts the AT expandability and hence promotes the adipocyte hypertrophy. Nevertheless, this also offers a variety of potential therapeutic targets against obesity, by which restoring the adipogenic capacity can maintain the metabolic health and adipocyte turnover.