Transgenic Conversion of Omega‐6 to Omega‐3 Fatty Acids via <i>fat‐1</i> Reduces Obesity‐Related Intervertebral Disc Degeneration

ABSTRACT Introduction Low back pain is a leading cause of disability, largely due to intervertebral disc (IVD) degeneration. Obesity is a risk factor for IVD degeneration and promotes the release of pro‐inflammatory cytokines from adipocytes, leading to inflammation and triggering catabolic degenerative pathways. Western diets high in omega‐6 fatty acids (n‐6 FAs) exacerbate inflammation and obesity, increasing the risk for musculoskeletal diseases. Conversely, omega‐3 (n‐3) FA enriched diets may mitigate these adverse effects. The nonmammalian fat‐1 gene converts n‐6 to n‐3 FAs, thereby reducing n‐6:n‐3 ratios and systemic inflammation. This study aims to elucidate the role of n‐6:n‐3 FA ratios in IVD degeneration by comparing wildtype (WT) and fat‐1 transgenic mice fed n‐6 enriched HFD (n‐6 HFD). Methods Male and female WT and fat‐1 transgenic mice were fed control or n‐6‐HFD. Body composition (weight, adiposity) and disc height index (DHI) were assessed at 16 weeks of age using microCT imaging. Chronic effects were evaluated at 60 weeks of age via serum cytokines (inflammatory panel), bone parameters (microCT), DHI, and histological grading of H&amp;E staining. Results At 16 weeks, HFD increased adiposity, while fat‐1 mice exhibited reduced weight gain. In vivo microCT revealed lower DHI in HFD‐fed animals but higher DHI in fat‐1 groups, with sex and lumbar level differences. At 60 weeks, inflammatory cytokines (IL‐6, IL‐17A) were elevated in the serum of WT HFD mice compared to fat‐1 HFD mice. Histopathological staining revealed increased fibrosis, cell loss, and matrix disorganization in the IVDs of HFD‐fed WT mice. However, IVDs of fat‐1 mice were protected from the degenerative effects of HFD. Conclusions Lowering the n‐6:n‐3 FA ratio via endogenous fat‐1 activity modulates systemic inflammatory profiles in a sex‐dependent manner and protects against obesity‐driven IVD degeneration. These findings highlight the potential of dietary interventions or fat‐1 gene therapy for treating obesity‐associated IVD pathology.