Time-restricted feeding (TRF) showed a potent effect in preventing obesity and improving metabolicoutcomes in several animal models of obesity. However, there is, as of yet, scarce evidence concerning its effectiveness against obesogenic challenges that more accurately mimic human Western diets, such as the cafeteria diet. Moreover, the mechanism for its efficacy is poorly understood. White adipose browning has been linked to body weight loss. Herein, we tested whether TRF has the potential to induce browning of inguinal white adipose tissue (iWAT) and to attenuate obesity and associated dyslipidemia in a cafeteria-diet-induced obesity model. Male Wistar rats were fed normal laboratory chow (NC) or cafeteria diet (CAF) for 16 weeks and were subdivided into two groups that were subjected to either ad libitum (ad lib, A) or TRF (R) for 8 h per day. Rats under the TRF regimen had a lower body weight gain and adiposity than the diet-matchedad lib rats, despite equivalent levels of food intake and locomotor activity. In addition, TRF improved the deranged lipid profile (total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c)) and atherogenic indices (atherogenic index of plasma (AIP), atherogenic coefficient (AC), coronary risk index (CRI) in CAF-fed rats. Remarkably, TRF resulted in decreased size of adipocytes and induced emergence of multilocular brown-like adipocytes in iWAT of NC- and CAF-fed rats. Protein expression of browning markers, such as uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), were also up-regulated in the iWAToftime-restricted NC- or CAF-fed rats. These findings suggest that a TRF regimen is an effective strategy to improve CAF diet-induced obesity, probably via a mechanismthe involving WAT browning process.

Obesity and diabetes are linked to an increased prevalence of kidney disease. Endoplasmic reticulum stress has recently gained growing importance in the pathogenesis of obesity and diabetes-related kidney disease. Melatonin, is an important anti-obesogenic natural bioactive compound. Previously, our research group showed that the renoprotective effect of melatonin administration was associated with restoring mitochondrial fission/fusion balance and function in a rat model of diabesity-induced kidney injury. This study was carried out to further investigate whether melatonin could suppress renal endoplasmic reticulum (ER) stress response and the downstream unfolded protein response activation under obese and diabetic conditions. Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight (BW)/day) (M–ZDF and M–ZL) or vehicle (C–ZDF and C–ZL) for 17 weeks. Western blot analysis of ER stress-related markers and renal morphology were assessed. Compared to C–ZL rats, higher ER stress response associated with impaired renal morphology was observed in C–ZDF rats. Melatonin supplementation alleviated renal ER stress response in ZDF rats, by decreasing glucose-regulated protein 78 (GRP78), phosphoinositol-requiring enzyme1α (IRE1α), and ATF6 levels but had no effect on phospho–protein kinase RNA–like endoplasmic reticulum kinase (PERK) level. In addition, melatonin supplementation also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins phospho–c–jun amino terminal kinase (JNK), Bax, and cleaved caspase-3, as well as by upregulation of B cell lymphoma (Bcl)-2 protein. These improvements were associated with renal structural recovery. Taken together, our findings revealed that melatonin play a renoprotective role, at least in part, by suppressing ER stress and related pro-apoptotic IRE1α/JNK signaling pathway.

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