Emerging evidence indicates that several obesity-related disorders etiologically resulted from imbalanced inflammatory markers (6, 7). Furthermore, the available evidence demonstrates the role of hypothalamic ER stress in the pathogenesis of HFD-induced obesity in the animal model. It is revealed that hypothalamic ER stress causes adipose tissue dysfunction and consequently more inflammatory cytokine secretion (11, 27).
In the current experiment, we realized 8-weeks CRD reduced GRP78 in the hypothalamus and both WAT and BAT of obese rats but not significantly. The magnitude of the CRD effect on ER stress reduction in a previous study was remarkable than in our investigation, possibly because of far greater weight loss relative to our study (40% vs 9.14%) (9). Also, the high-fat percentage of CRD consumed in our study may have reduced the effect of calorie restriction on ER stress improvement. We also measured systemic inflammation by assaying TNF-α and MCP1 which diminished with CRD compared to HFD. Furthermore, the expression of TNF-α and MCP1 in WAT decreased significantly. Obtained results indicated that CRD could diminish the inflammatory markers in adipocytes but the composition of diet along with calorie restriction is an important determinant in ER stress. Regarding some reports about the anti-inflammatory effect of RJ in obesity (17, 18), we added RJ to CRD. Our findings showed that RJ treatment through CRD reduced the expression of GRP78 and suppressed both WAT and hypothalamic ER stress. Moreover, RJ exerted a suppressive effect on inflammatory parameters in adipose tissue and serum so caused a noticeable reduction in inflammation compared to the CRD alone. Our data is inconsistent with previous studies evaluated anti-inflammatory effects of RJ but to the best of our knowledge, no study has examined the anti-inflammatory effects of RJ from ER stress modulating view. Significant weight loss in the RJ group in our study compared to the CRD group could be a contributing factor in ER stress decrement. In the recent investigation, RJ could not reduce the ER stress dramatically in BAT. It is suggested that obesity-related ER stress is more evident in WAT than in BAT (28). Perhaps, during higher ER stress, RJ exerts more significant effects.
TRF, neither in adipose tissue nor in the hypothalamus, significantly decreased the mRNA levels of GRP78 more than CRD did in obese rats. However, the serum concentration of TNF-α and MCP1 significantly diminished in the TRF group relative to the CRD group. Our results are in line with previous reports of the anti-inflammatory effect of TRF but do not confirm some previous studies about the inhibitory effect of γT3 on ER stress (16, 29). These studies evaluated the effect of pure γT3 on hepatic ER stress which possibly exerts stronger effects than TRF does. The inhibitory effects of α-tocopherol against T3 and their possible interaction cannot be ignored (30).
Contreras et al. showed that ER stress suppression in the hypothalamus triggered WAT remodeling and BAT activation via inducing the sympathetic nervous system (SNS) (11). Besides, we recently revealed that RJ administration activated BAT and also caused WAT remodeling through sympathetic activation (31). Therefore, we suggest that RJ has a critical role in the modulation of hypothalamic ER stress and leads to SNS activation, which in turn activates WAT browning and decreases ER stress in WAT and attenuates obesity-induced inflammation.
RJ + TRF group demonstrated anti-inflammatory effects similar to RJ-fed rats. regarding the minor effect of TRF in ER stress suppression, it is therefore likely that the RJ is responsible for ER stress modulation in the RJ + TRF group.
Overall, the current study implies that RJ along with CRD protects against HFD-induced ER stress in the hypothalamus and WAT. We suggest that ER stress modulation seems to be a possible mechanism by which RJ exerts some of its anti-inflammatory properties then improve adipose tissue dysfunction and inflammatory condition in obesity more than CRD alone. Hence, RJ could be considered as a therapeutic approach to diminish some obesity-related disorders.