FGF10 and Lipofibroblasts in Lung Homeostasis and Disease: Insights Gained From the Adipocytes

Abstract

Adipocytes not only function as energy depots but also secrete numerous adipokines that regulate multiple metabolic processes, including lipid homeostasis. Dysregulation of lipid homeostasis, which often leads to adipocyte hypertrophy and/or ectopic lipid deposition in non-adipocyte cells such as muscle and liver, is linked to the development of insulin resistance. Similarly, an altered secretion profile of adipokines or imbalance between calorie intake and energy expenditure is associated with obesity, among other related metabolic disorders. In lungs, lipid-laden adipocyte-like cells known as lipofibroblasts share numerous developmental and functional similarities with adipocytes, and similarly influence alveolar lipid homeostasis by facilitating pulmonary surfactant production. Unsurprisingly, disruption in alveolar lipid homeostasis may propagate several chronic inflammatory disorders of the lung. Given the numerous similarities between the two cell types, dissecting the molecular mechanisms underlying adipocyte development and function will offer valuable insights that may be applied to, at least, some aspects of lipofibroblast biology in normal and diseased lungs. FGF10, a major ligand for FGFR2b, is a multifunctional growth factor that is indispensable for several biological processes, including development of various organs and tissues such as the lung and WAT. Moreover, accumulating evidence strongly implicates FGF10 in several key aspects of adipogenesis as well as lipofibroblast formation and maintenance, and as a potential player in adipocyte metabolism. This review summarizes our current understanding of the role of FGF10 in adipocytes, while attempting to derive insights on the existing literature and extrapolate the knowledge to pulmonary lipofibroblasts.

Adipose Tissue Inflammation and Pulmonary Dysfunction in Obesity

“…Recently, visceral depots of fat have also been found in the lungs, where lipids are stored in lipid-laden adipocyte-like cells known as 'lipofibroblasts'. These cells have a key role in regulating alveolar lipid homeostasis and pulmonary surfactant production, facilitating oxygen absorption [33].…”

“…As in VAT adipocytes, ectopic lipid accumulation can also occur in lung lipofibroblasts in obesity, altering their function. When alveolar lipid homeostasis is disrupted in morbid obesity, dysfunctional lipofibroblasts could transdifferentiate into myofibroblasts, which produce excess extracellular matrix that can lead to pulmonary fibrosis [33].…”

Potential Impact of Diabetes and Obesity on Alveolar Type 2 (AT2)-Lipofibroblast (LIF) Interactions After COVID-19 Infection

“…As LIFs share commonalities with adipocytes (for example, their high lipid droplet content, their dependence on Fgf10 signaling for their formation), it is possible that LIFs also represent cellular targets for COVID-19. In this situation, both the AT2 stem cells and their niche would be impacted, resulting in irreversible lung damage and lethality ( Figure 2 ; Lv et al, 2021 ).…”

Kub3 Deficiency Causes Aberrant Late Embryonic Lung Development in Mice by the FGF Signaling Pathway

“…The FGF family comprises at least 22 members, among which, Fgf10—a ligand expressed and released by the adjacent lung mesenchyme—specifically binds and activates Fgfr2b in the epithelium [ 11 , 12 , 13 , 14 ]. Fgf10–Fgfr2b signaling has been shown to be essential for lung bud formation and controlling the branching morphogenesis of the lung [ 4 , 11 , 15 , 16 ].…”

“…The FGF family comprises at least 22 members, among which, Fgf10—a ligand expressed and released by the adjacent lung mesenchyme—specifically binds and activates Fgfr2b in the epithelium [ 11 , 12 , 13 , 14 ]. Fgf10–Fgfr2b signaling has been shown to be essential for lung bud formation and controlling the branching morphogenesis of the lung [ 4 , 11 , 15 , 16 ]. The importance of Fgf10 in lung development has been illustrated by the phenotypes of Fgf10 knockout mice, which die shortly after birth due to the complete absence of lungs [ 5 , 8 , 10 , 17 ].…”