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.