Challenges and opportunities in obesity: the role of adipocytes during tissue fibrosis

Abstract

Obesity is a chronic disease that affects the energy balance of the whole body. In addition to increasing fat mass, tissue fibrosis occurred in white adipose tissue in obese condition. Fibrosis is the over-activation of fibroblasts leading to excessive accumulation of extracellular matrix, which could be caused by various factors, including the status of adipocytes. The morphology of adipocytes responds rapidly and dynamically to nutrient fluctuations. Adaptive hypertrophy of normal adipocytes protects peripheral organs from damage from lipotoxicity. However, the biological behavior of hypertrophic adipocytes in chronic obesity is abnormally altered. Adipocytes lead to fibrotic remodeling of the extracellular matrix by inducing unresolved chronic inflammation, persistent hypoxia, and increasing myofibroblast numbers. Moreover, adipocyte-induced fibrosis not only restricts the flexible expansion and contraction of adipose tissue but also initiates the development of various diseases through cellular autonomic and paracrine effects. Regarding anti-fibrotic therapy, dysregulated intracellular signaling and epigenetic changes represent potential candidate targets. Thus, modulation of adipocytes may provide potential therapeutic avenues for reversing pathological fibrosis in adipose tissue and achieving the anti-obesity purpose.

Keywords: AMT; adipocytes; fibroblasts; fibrosis; obesity.

Figure 1

Mechanisms of adipocytes in adipose tissue fibrosis. Dysfunctional adipocytes secrete proinflammatory cytokines and free fatty acids, which activate immune inflammatory cells and amplify the inflammatory cascade. In addition, imbalanced adipokines and hypoxia-inducible factors further promote the development of adipose tissue fibrosis. In this condition, mature adipocytes and adipose stem cells transdifferentiate into myofibroblasts. Activated myofibroblasts aggregate and a large amount of extracellular matrix is deposited in adipose tissue.

Figure 2

Schematic diagram illustrating the cellular mechanism of adipocyte-mesenchymal transition (AMT) in adipose tissue remodeling under the challenge of obesity. In response to a high-fat diet, alongside the classical fibroblast activation pathway, highly plastic adipocytes can also undergo transdifferentiation into myofibroblasts. By downregulating key adipogenic gene markers including PPAR-γ, both mature adipocytes and adipose stem cells initiate the fibrosis pathway as the predominant mechanism, leading to morphological alterations and gene reprogramming that drive their differentiation towards a myofibroblast phenotype.

Figure 3

Crosstalk between adipose tissue and other organs. In the state of obesity, adipocytes undergo transdifferentiation into myofibroblasts via the release of various fibrophilic cytokines, thereby promoting local fibrosis of the adipose tissue. The presence of fibrotic adipose tissue not only significantly restricts the hypertrophy and proliferative adaptability of adipocytes themselves but also exerts a detrimental influence on neighboring tissues and organs through direct infiltration. Consequently, there is an increased risk and severity associated with non-alcoholic liver cirrhosis, cardiovascular disease, osteoarthritis, cancer, and scleroderma.