Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including cancer, and is increasingly recognized as a growing cause of preventable cancer risk. Chronic inflammation, a well-known mediator of cancer, is a central characteristic of obesity, leading to many of its complications, and obesity-induced inflammation confers additional cancer risk beyond obesity itself. Multiple mechanisms facilitate this strong association between cancer and obesity. Adipose tissue is an important endocrine organ, secreting several hormones, including leptin and adiponectin, and chemokines that can regulate tumor behavior, inflammation, and the tumor microenvironment. Excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of proinflammatory factors. Cells from adipose tissue, such as cancer-associated adipocytes and adipose-derived stem cells, enter the cancer microenvironment to enhance protumoral effects. Dysregulated metabolism that stems from obesity, including insulin resistance, hyperglycemia, and dyslipidemia, can further impact tumor growth and development. This review describes how adipose tissue becomes inflamed in obesity, summarizes ways these mechanisms impact cancer development, and discusses their role in four adipose-associated cancers that demonstrate elevated incidence or mortality in obesity.

Adipose-resident T-cells (ARTs) regulate metabolic and inflammatory responses in obesity, but ART activation signals are poorly understood. Here, we describe class II major histocompatibility complex (MHCII) as an important component of high-fat diet (HFD)-induced obesity. Microarray analysis of primary adipocytes revealed that multiple genes involved in MHCII antigen processing and presentation increased in obese women. In mice, adipocyte MHCII increased within two weeks HFD, paralleling increases in pro-inflammatory and decreases in anti-inflammatory ART markers, and preceding adipose tissue macrophage (ATM) accumulation and pro-inflammatory M1 polarization. Mouse 3T3-L1 and primary adipocytes activated T-cells in an antigen-specific, contact-dependent manner, indicating adipocyte MHCII is functional. HFD-fed MHCII−/− mice developed less adipose inflammation and insulin resistance than wild-type mice, despite developing similar adiposity. These investigations uncover a mechanism whereby a HFD-induced adipocyte/ART dialogue involving MHCII instigates adipose inflammation and, together with ATM MHCII, escalates its progression.