Fibrosis in adipose tissue is a major driver of obesity-related metabolic dysregulation. It is characterized by an overaccumulation of extracellular matrix (ECM) during unhealthy expansion of adipose tissue in response to over nutrition. In obese adipose-depots, hypoxia stimulates multiple pro-fibrotic signaling pathways in different cell populations, thereby inducing the overproduction of the ECM components, including collagens, noncollagenous proteins, and additional enzymatic components of ECM synthesis. As a consequence, local fibrosis develops. The result of fibrosis-induced mechanical stress not only triggers cell necrosis and inflammation locally in adipose tissue but also leads to system-wide lipotoxicity and insulin resistance. A better understanding of the mechanisms underlying the obesity-induced fibrosis will help design therapeutic approaches to reduce or reverse the pathological changes associated with obese adipose tissue. Here, we aim to summarize the major advances in the field, which include newly identified fibrotic factors, cell populations that contribute to the fibrosis in adipose tissue, as well as novel mechanisms underlying the development of fibrosis. We further discuss the potential therapeutic strategies to target fibrosis in adipose tissue for the treatment of obesity-linked metabolic diseases and cancer. © 2023 American Physiological Society. Compr Physiol 13:4387-4407, 2023.
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