Ectopic and visceral fat deposition in aging, obesity, and idiopathic pulmonary fibrosis: an interconnected role

Abstract

Idiopathic pulmonary fibrosis (IPF) is considered an age-related disease. Age-related changes, along with other factors such as obesity, hormonal imbalances, and various metabolic disorders, lead to ectopic fat deposition (EFD). This accumulation of fat outside of its normal storage sites is associated with detrimental effects such as lipotoxicity, oxidative stress, inflammation, and insulin resistance. This narrative review provides an overview of the connection between ectopic and visceral fat deposition in aging, obesity, and IPF. It also elucidates the mechanism by which ectopic fat deposition in the airways and lungs, pericardium, skeletal muscles, and pancreas contributes to lung injury and fibrosis in patients with IPF, directly or indirectly. Moreover, the review discusses the impact of EFD on the severity of the disease, quality of life, presence of comorbidities, and overall prognosis in IPF patients. The review provides detailed information on recent research regarding representative lipid-lowering drugs, hypoglycemic drugs, and lipid-targeting drugs in animal experiments and clinical studies. This may offer new therapeutic directions for patients with IPF.

Keywords: Aging; Ectopic fat deposition; Idiopathic pulmonary fibrosis; Inflammation; Visceral adipose tissue.

Fig. 1

Alterations in aging adipose tissue and the involvement of fat deposition in the occurrence and development of IPF. 1) During the aging process, excessive expansion of adipose tissue leads to hypoxia. This stimulates adipocytes and ATMs to secrete inflammatory chemokines, resulting in immune cell infiltration in aging adipose tissue. 2) Fibrosis in dysfunctional adipose tissue leads to lipotoxicity and an increased leptin/adiponectin ratio. This activates highly proinflammatory M1-type macrophages (M1 ATMs) through molecules such as leptin, PAI-1, FFA, and inflammatory cytokines, thereby exacerbating the inflammatory response. 3) Lipotoxicity and inflammation in aging adipose tissue leads to endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, autophagy and necrosis of AT2 cells. Subsequently, in the alveoli, cell debris, recruited immune cells, and foam cells (macrophages engulfing lipid droplets) participate in the inflammatory cascade response, resulting in fibroblast-to-myofibroblast (MYF) transformation and epithelial-mesenchymal transition (EMT). 4) Adipose factors such as Ang II, PAI-1, and S1P can also promote fibroblast-to-MYF transformation. 5) Lipotoxicity and inflammation not only promote the differentiation of LIFs into MYFs but also affect the supply of pulmonary surfactant precursors to AT2 cells. The figure was created using BioRender (www.biorender.com). Abbreviations: adipose tissue macrophages (ATMs), plasminogen activator inhibitor-1 (PAI-1), free fatty acids (FFA), alveolar epithelial type II cells (AT2), myofibroblast (MYF), epithelial-mesenchymal transition (EMT), Angiotensin II (Ang II), sphingosine-1-phosphate (S1P), lipofibroblasts (LIFs)

Fig. 2

Alterations in adipose tissue distribution in aging individuals contribute to the development of IPF. The left part illustrates the distribution of white adipose tissue and brown adipose tissue in the healthy human body. The right part shows a list of comorbidities associated with an excessive accumulation of ectopic fat and visceral adipose tissue in elderly individuals. The figure was created using BioRender (www.biorender.com). Abbreviations: alveolar epithelial type II cells (AT2), chronic obstructive pulmonary disease (COPD), insulin resistance (IR), lipofibroblast (LIF), myofibroblast (MYF), obstructive sleep apnea syndrome (OSAS), pulmonary arterial hypertension (PAH), surfactant protein A (SPA)