The main characteristic of obesity is an increase in lipid tissue infiltration due to the hypertrophy of existing adipocytes, as well as due to the hyperplasia of adipocytes resulting from de novo adipogenesis from precursor stem cells (Schoettl et al., 2018). Indeed, it was postulated that the ECM, in a spatial as well as temporal manner, regulates adipogenesis (Soukas et al., 2001). In addition to adipocyte deposition, a notable migration of macrophages and vascular cells was correlated to changes in the ECM structure. This remodelling leads to the release of active mediators that can affect immune cells’ recruitment and activation, facilitating the inflammatory state of lipid tissue. Furthermore, the strong upregulation of obese adipose tissue ECM components, including collagens and osteopontin, was suggested to initiate the necrosis of adipocytes, enhance the infiltration of immune cells, leading to tissue inflammation and metabolic dysfunction (Catalan et al., 2012; Ruiz-Ojeda et al., 2019). Thus, the overexpression of endotrophin, resulted from the cleavage of the α-3 chain of collagen VI (Col6a3), facilitates the deposition of fibrotic collagen and initiates adipose tissue inflammation and insulin resistance (Sun et al., 2014). A recent study demonstrated that the expression of MMP14 is strongly upregulated in the adipose tissue of transgenic obese mice. Interestingly, MMP14 proteolytic activity results in the release of endotrophin with concurrent formation of enlarged adipocytes and increase in body weight, altered lipid metabolism and insulin resistance (Li et al., 2020). Furthermore, Springer et al. recently demonstrated a link between alterations in the ECM of obese women and breast cancer. Thus, enhanced adipose tissue interstitial fibrosis facilitates the generation of M2/M1 type macrophages pattern similar to that of tumour-associated macrophages, as well as the generation of associated inflammatory cues (Springer et al., 2019). Under these conditions a paracrine loop consisting of free fatty acids and TNF-α is established among adipocytes and infiltrating macrophages that enhances inflammation-mediated alterations in the adipose tissue (Engin, 2017). Recently, lumican, a small leucine-rich proteoglycan (Nikitovic et al., 2014b), was shown to be overexpressed in ECM of subcutaneous fat of insulin resistant obese individuals. Lumican was demonstrated to alter the organization of collagen I, dysregulate adipogenesis and trigger oxidative stress, facilitating the pathology of obesity-associated insulin resistance (Guzman-Ruiz et al., 2020). A separate study showed that the effect of lumican was diet-dependent and correlated to adipose tissue inflammation. Indeed, the same authors suggest that the ECM protein lumican could pose a convergent point among the ECM, the glucose homeostasis and the metabolic syndrome (Wolff et al., 2019).