3. SAT in immuno-metabolic diseases
Obesity is associated with a state of low-grade inflammation in SAT. This poses a heightened risk for the development of various health conditions, including type 2 diabetes (T2D), autoimmune and autoinflammatory diseases, cardiovascular disease, and cancer (5, 80-88). The systemic low-grade inflammation associated with obesity contributes to insulin resistance in skeletal muscle and liver (89, 90). Additionally, AT macrophages and innate lymphoid cells type 1 (ILCs1) promote AT fibrosis by inducing ECM deposition, which contributes to insulin resistance and T2D (91, 92). Inhibition of AT fibrosis may be a mechanism to improve glucose intolerance (93).
The inflammatory state linked to obesity stems from multiple mechanisms. In individuals with obesity, the expansion of adipocytes leads to increased release of adipokines like leptin and resistin, alongside decreased levels of the anti-inflammatory adiponectin (94, 95). This directly promotes a phenotypic shift of adipose tissue-resident immune cells toward a pro-inflammatory state (96-98). Investigations into lymphocyte responses in obesity highlight a skewed polarization of SAT-resident helper T cells in obese individuals towards a pro-inflammatory Th1 phenotype (99-101) (Fig 5). SAT adipocytes of obese patients also express all 10 Toll-like receptors (TLRs), with TLR-4 exhibiting the highest expression (102, 103). TLR4 activation triggers the NF-κB signaling pathway in adipocytes and monocytes/macrophages, subsequently leading to the release of monocyte chemoattractant protein-1 (MCP-1) and pro-inflammatory cytokines such as interleukin β (IL1β), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) (104, 105). Elevated MCP-1 levels further prompt the infiltration of monocytes into SAT, where they differentiate into pro-inflammatory (M1) macrophages (Fig 5) (106, 107). Increased levels of TNF-α have significant effects in induction of lipolysis, the breakdown of fat stored in adipose tissue. TNF-induced lipolysis is a complex process involving the activation of inflammatory pathways, lipolytic enzyme activity and release of free fatty acids (FFAs) (108, 109). Elevated levels of FFAs released during lipolysis can impair insulin signaling in peripheral tissues such as muscle and liver, contributing to insulin resistance and metabolic dysfunction (110). Understanding these mechanisms is important for elucidating the role of TNF in metabolic disorders and inflammatory conditions associated with dysregulated lipid metabolism.
Excessive caloric intake in obesity also leads to increased reactive oxygen specious (ROS) production in adipocytes, causing mitochondrial dysfunction (111). Abnormal mitochondrial function in adipocytes leads to lipid accumulation, ultimately contributing to metabolic syndrome (112). Therefore, mitigating excessive ROS production and chronic inflammation in SAT of obese individuals present a novel approach to address obesity-related immunometabolic disorders.