Are Obesity-Related Insulin Resistance and Type 2 Diabetes Autoimmune Diseases?

Proposed pathways, centered in the VAT, to autoimmune responses during obesity. Intrinsic inflammatory changes cooperate with obesity-associated dysbiosis in the gut to initiate self- or microbe-specific adaptive immune responses in the VAT, generating a feed-forward inflammatory loop that worsens insulin signaling. Long-term caloric excess causes hypertrophy and ER stress in white adipocytes, leading to the release of adipokines and chemoattractants that help activate and/or recruit innate cells, such as macrophages, and adaptive immune cells, such as B and T cells, to the VAT. Obesity-associated dysbiosis contributes to increased gut permeability, facilitating leakage of microbial products and oral antigens across the gut epithelium. Together with lipid excess and dying adipocytes, these serve as potential sources of antigens and costimulatory signals for the activation of VAT B and T cells, a process that can potentially take place in the draining lymph nodes or locally in the VAT. Activated B and T cells, in turn, contribute to VAT inflammation through the secretion of inflammatory cytokines and antibodies or through cross talk with other immune cells. DAMPs, danger-associated molecular patterns. PAMPs, pathogen-associated molecular patterns.