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Irisin, a novel adipomyokine, has been proposed to be a therapeutic agent against obesity‐related metabolic disease. Royal Jelly (RJ) and tocotrienol‐rich fraction (TRF) are suggested to promote obesity and its related problems through potential mutual mechanistic pathways. This investigation intended to evaluate the glycemic and inflammation‐promoting effects of RJ, TRF, and their combinations to evaluate their synergic effects through irisin action in obese rats induced by a high‐fat diet (HFD) that underwent a calorie restriction diet (CRD). Fifty HFD‐fed obese rats received the following interventions: RJ, TRF, or RJ + TRF in combination with a CRD for eight consecutive weeks. After the investigation, body weight, fasting blood sugar (FBS), irisin, insulin, C‐reactive protein (CRP), interleukin‐6 (IL‐6), interleukin‐1 beta (IL‐1β), leptin, adiponectin, and insulin resistance (IR) were assessed. After 8 weeks of treatment, significant weight reduction was noticed in rats that received RJ and RJ + TRF related to the CRD rats (p <.001), although this reduction was not considerable in TRF‐treated rats. RJ and RJ + TRF supplementation markedly elevated irisin concentrations in CRD rats (p <.05), but TRF did not. Glycemic indices, inflammatory indices including IL‐1β and CRP levels, and leptin concentrations were significantly decreased after RJ, TRF, and their combinations were added to CRD (p <.05). According to the mediational analysis results, irisin mediated the promoting effects of RJ on glycemic hemostasis. Based on the results of this investigation, RJ and TRF are novel nutrients that have the potential to improve obesity‐related disorders. This research suggests that RJ exerts its beneficial glycemic regulatory effects through irisin. [ABSTRACT FROM AUTHOR]