Fibrosis and adipose tissue dysfunction

Abstract

Fibrosis is increasingly appreciated as a major player in adipose tissue dysfunction. In rapidly expanding adipose tissue, pervasive hypoxia leads to an induction of HIF1α that in turn leads to a potent profibrotic transcriptional program. The pathophysiological impact of adipose tissue fibrosis is likely to play an equally important role on systemic metabolic alterations as fibrotic conditions play in the liver, heart, and kidney. Here, we discuss recent advances in our understanding of the genesis, modulation, and systemic impact of excessive extracellular matrix (ECM) accumulation in adipose tissue of both rodents and humans and the ensuing impact on metabolic dysfunction.

Figure 1. Proposed models for the sequential steps leading to adipose tissue fibrosis and metabolic dysfunction

Obese fat pad expansion quickly leads to a hypoxic state. As a result, HIF1α is induced. (1). A whole set of “fibrotic response” genes, including collagens and their biosynthetic enzymes, such as LOX, are dramatically up-regulated under these conditions. This regulation results in the abnormal development of ECM, leading to local fibrosis, which triggers necrosis of adipocytes. The dead adipocytes then attract classically activated pro-inflammatory M1 macrophages which ultimately lead to inflammation and metabolic dysfunction. (2). Other models suggest that HIF1α may also directly induce pro-inflammatory factors, such as IL6 and MIF, which in turn causes M1 macrophage infiltration. The preadipocytes, macrophages and the interactions between these cell types ultimately produce fibrotic components, which finally lead cause pathological expansion of fat pads.

Figure 2. Higher levels of fibrosis in obese versus lean subjects in both subcutaneous and visceral AT

Morbidly obese subjects with more fibrosis in their subcutaneous adipose tissue lose less fat mass at 3, 6 and 12 months post bypass, suggesting that fibrosis could be used as a good and independent predictor of weight loss after surgical interventions. Arrows indicate pericellular fibrosis. Data are represented as mean +/− SEM.