Adipocyte-specific Nrf2 deletion negates nitro-oleic acid benefits on glucose tolerance in diet-induced obesity

Obesity is commonly linked with white adipose tissue (WAT) dysfunction, setting off inflammation and oxidative stress, both key contributors to the cardiometabolic complications associated with obesity. To improve metabolic and cardiovascular health, countering these inflammatory and oxidative signaling processes is crucial. Offering potential in this context, the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by nitro-fatty acids (NO₂-FA) promote diverse anti-inflammatory signaling and counteract oxidative stress. Additionally, we previously highlighted that nitro-oleic acid (NO₂-OA) preferentially accumulates in WAT and provides protection against already established high fat diet (HFD)-mediated impaired glucose tolerance. The precise mechanism accounting for these protective effects remained largely unexplored until now. Herein, we reveal that protective effects of improved glucose tolerance by NO₂-OA is absent when Nrf2 is specifically ablated in adipocytes (ANKO mice). NO₂-OA treatment did not alter body weight between ANKO and littermate controls (Nrf2^fl/fl) mice on both the HFD and low-fat diet (LFD). As expected, at day 76 (before NO₂-OA treatment) and notably at day 125 (daily treatment of 15 mg/kg NO₂-OA for 48 days), both HFD-fed Nrf2^fl/fl and ANKO mice exhibited increased fat mass and reduced lean mass compared to LFD controls. However, throughout the NO₂-OA treatment, no distinction was observed between Nrf2^fl/fl and ANKO in the HFD-fed mice as well as in the Nrf2^fl/fl mice fed a LFD. Glucose tolerance tests revealed impaired glucose tolerance in HFD-fed Nrf2^fl/fl and ANKO compared to LFD-fed Nrf2^fl/fl mice. Notably, NO₂-OA treatment improved glucose tolerance in HFD-fed Nrf2^fl/fl but did not yield the same improvement in ANKO mice at days 15, 30, and 55 of treatment. Unraveling the pathways linked to NO₂-OA's protective effects in obesity-mediated impairment in glucose tolerance is pivotal within the realm of precision medicine, crucially propelling future applications and refining novel drug-based strategies.