The “Big Bang” in obese fat: Events initiatingobesity-induced adipose tissue inflammation

Obesity is associated with the accumulation of pro-inflammatory cells in visceral adiposetissue (VAT), which is an important underlying cause of insulin resistance and progres-sion to diabetes mellitus type 2 (DM2). Although the role of pro-inflammatory cytokinesin disease development is established, the initiating events leading to immune cell acti-vation remain elusive. Lean adipose tissue is predominantly populated with regulatorycells, such as eosinophils and type 2 innate lymphocytes. These cells maintain tissuehomeostasis through the excretion of type 2 cytokines, such as IL-4, IL-5, and IL-13,which keep adipose tissue macrophages (ATMs) in an anti-inflammatory, M2-like state.Diet-induced obesity is associated with the loss of tissue homeostasis and developmentof type 1 inflammatory responses in VAT, characterized by IFN-γ. A key event is a shiftof ATMs toward an M1 phenotype. Recent studies show that obesity-induced adipocytehypertrophy results in upregulated surface expression of stress markers. Adipose stressis detected by local sentinels, such as NK cells and CD8+T cells, which produce IFN-γ,driving M1 ATM polarization. A rapid accumulation of pro-inflammatory cells in VATfollows, leading to inflammation. In this review, we provide an overview of events lead-ing to adipose tissue inflammation, with a special focus on adipose homeostasis and theobesity-induced loss of homeostasis which marks the initiation of VAT inflammation