# The Vicious Cycle of Obesity and Low Back Pain: A Comprehensive Review
## 6 The Biochemical Impact of Obesity on the Spine
### The Adipokine Cascade  
Adipokines are bioactive signalling molecules secreted by adipose tissue that regulate immune responses, inflammation, and tissue remodelling. In obesity, adipose tissue enters a chronic low-grade inflammatory state, characterized by elevated levels of pro-inflammatory adipokines, such as leptin, resistin, and LCN2, and decreased levels of anti-inflammatory molecules like adiponectin [137] (Table 2). This imbalance perpetuates systemic inflammation and metabolic dysfunction, contributing to the pathogenesis of IDD. Dysregulated adipokine signalling promotes ECM degradation, oxidative stress, and apoptosis in IVD cells, primarily via Toll-like receptor (TLR)-mediated pathways [138; 139]. In particular, pro-inflammatory adipokines like leptin as well as immune mediators secreted by vertebral MAT have been shown to exacerbate IDD [140]. Leptin and resistin, both elevated in obesity, enhance ECM breakdown, upregulate inflammatory cytokines, and induce IVD cell apoptosis [136; 141]. Conversely, adiponectin, typically anti-inflammatory, is reduced in obesity. However, its role in IDD appears to be context-dependent, with evidence suggesting it may still activate inflammatory signalling under certain conditions [142]. Additional adipokines, such as LCN2 and visfatin, further drive degeneration, i.e., LCN2 activates NF-\(\kappa\)B and increases MMP9 activity, while visfatin promotes IL-6 production and mediates IL-1\(\beta\)-induced apoptosis in NP cells [143; 144; 138]. Together, these alterations in adipokine secretion (Table 2) foster a pro-inflammatory, catabolic microenvironment within the disc (as well as other spinal tissues), accelerating degeneration and reinforcing the mechanistic link between obesity and IDD. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Adipokine** & **Type** & **Function** & **Effect on IDD** & **Refs.** \\ \hline CCL2 & Chemokine & Regulates immune cell migration. Involved in neuroinflammation. & Increases macrophage infiltration, enhances NF-\(\kappa\)B activation, and contributes to IDD. & [145; 146; 147; 148; 149] \\ CXCL5 & Chemokine & Pro-inflammatory mediator and attractant for granulocytes. & Elevated in LBP and IDD models and & \\  & & & & \\  & & & \\  & & & & \\  & & & \\  & & & & \\  & & & & \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Overview of obesity-related dysregulated adipokines and their association with IDD. Adipokines also influence pain pathways, potentially amplifying pain perception in obesity-related LBP. Leptin and resistin, for instance, can promote IL-1 synthesis, sensitizing nociceptors and enhancing central pain processing [183; 184]. Leptin, along with its receptor (LepR), is expressed in dorsal root ganglion neurons and contributes to neuropathic pain by upregulating N-methyl-D-aspartate receptor (NMDAR) subunits, increasing neuronal nitric oxide synthase, and intensifying pain signalling. These effects link systemic inflammation  
\begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Adipokine** & **Type** & **Function** & **Effect on IDD** & **Refs. ** \\ \hline Chemerin & Cytokine & Links innate and adaptive immunity. Interacts with CMKLRI to regulate inflammation. & Activates NF-kB via CMKLRI and TLR4. & [157] \\  & & Signaling pathway mediator in chronic low-grade inflammatory diseases, including obesity, diabetes mellitus, and cardiovascular diseases. Potential target of TGF-B, contributing to capillary formation. & Increases inflammation, induces IL-1, IL-17. & \\ TNF-\(\alpha\) & Cytokine & Autimmune diseases and inflammatory responses. Strongly promotes interleukins and MMP production. & Increases inflammation, induces IL-1, IL-17. & Increases ECM degrading metalloproteinases leading to IDD. \\  & & & Interleukins are a diverse family of cytokines regulating immune responses. IL-1 and IL-6 & IL-1 triggers inflammatory cascades that drive inflammatory and share functional overlap with ILR signalling.