**1. Introduction**

Fibrosis is characteristically defined as the thickening and scarring of tissues from a pathological repair process. While often fibrosis is thought to occur following an injury, in adipose tissue changes in metabolism can trigger an inflammatory cascade that initiates the maladaptive fibrotic repair process. Once initiated, fibrotic changes in adipose tissue have devastating effects for patients. In most cases, adipose tissue fibrosis is undetected, difficult to reverse, and interferes with treatment options for obesity and other comorbidities.

White adipose tissue is responsible for storing and releasing energy in the body by regulating lipogenesis and lipolysis, respectively [1]. Lipogenesis is the process where free fatty acids and glycerol are taken up from the blood stream and stored in adipocytes as triglycerides. Conversely, lipolysis is the process in which triglycerides are catabolized into free fatty acids and glycerol that are released into the blood stream where they are used as an energy source by other organs [2]. An imbalance between these two processes leads to obesity and metabolic diseases, such as type 2 diabetes [3].

Obesity is associated with adipocyte enlargement (hypertrophy) and formation of new adipocytes (hyperplasia) [4]. This increase in adipocyte volume and tissue mass triggers inflammation, further dysregulation in adipose tissue, and eventually adipose tissue fibrosis [5]. Like other fibrotic diseases, adipose tissue fibrosis is the accumulation and increased production of extracellular matrix (ECM) proteins [6,7]. In healthy adipose tissue, the ECM can be remodeled to accommodate normal fluctuations in adipocyte size. However, when adipose tissue becomes fibrotic the stiff ECM cannot be dynamically remodeled.

Historically, obesity has been linked to an overall increase in lipolysis that results in ectopic accumulation of lipids in other tissues and insulin resistance [8,9]. An increase is observed when lipolysis is normalized to overall lean body mass; however, when normalized to lipid content there is a

decrease in basal lipolysis rate per cell [10–12]. Furthermore, starved hypertrophic adipocytes only lose a portion of their stored triglycerides (<50%) without supplemental factors [13]. There is limited literature investigating the e ffect adipose tissue fibrosis has on lipolysis, so most studies assume the same trends as obesity. There are several theories as to why this may not be valid. One being that as adipocytes shrink, stress between the ECM and cells can increase, eventually inhibiting lipolysis, leading to enlarged adipocytes without a mechanism for depleting their lipid stores [7].

With decreased lipolytic function, it is not surprising that fibrotic adipose tissue has been linked to di fficulties losing fat mass [14] and insulin resistance [15]. For example, gastric bypass surgery, which generally causes rapid fat loss and increases in insulin sensitivity, is less e ffective for patients with high degrees of adipose tissue fibrosis [14,16]. Specifically, insulin resistance is linked to higher levels of adipose tissue inflammation and increased ECM deposition [15]. Initially, as insulin sensitivity decreases, adipocytes begin to undergo enhanced lipolysis and release free fatty acids into the environment. These free fatty acids cause further insulin resistance and can lead to inflammation by signaling macrophages and other immune cells to the area [17]. Over time this inflammation increases ECM protein production leading to interstitial fibrosis in adipose tissue. The increased ECM sti ffness prevents the adipocytes from expanding in a healthy manner, causing the tissue to be metabolically dysfunctional, including adipocyte death, decreased lipolysis, and disrupted cell-cell interactions [6,14].

Adipose tissue fibrosis has a complicated and critical role in metabolic dysfunction and obesity. With the growing obesity epidemic, it is important to understand the mechanisms behind the development and progression of adipose tissue fibrosis. Furthermore, targeted therapeutic treatments are required for patients with fibrotic adipose tissue. This article discusses recent research in modeling adipose tissue fibrosis using in vitro (2D and 3D) and in vivo methods with considerations for biomaterial selections. Additionally, this article will outline the importance of adipose tissue in treating other fibrotic diseases and methods used to detect and characterize adipose tissue fibrosis.
