Prolonged, isocaloric, time-restricted feeding (TRF) protocols can promote weight loss, improve metabolic dysregulation, and mitigate non-alcoholic fatty liver disease (NAFLD). In addition, 3-day, severe caloric restriction can improve liver metabolism and glucose homeostasis prior to significant weight loss. Thus, we hypothesized that short-term, isocaloric TRF would improve NAFLD and characteristics of metabolic syndrome in diet-induced obese male mice. After 26 weeks of ad libitum access to western diet, mice either continued feeding ad libitum or were provided with access to the same quantity of western diet for 8 h daily, over the course of two weeks. Remarkably, this short-term TRF protocol modestly decreased liver tissue inflammation in the absence of changes in body weight or epidydimal fat mass. There were no changes in hepatic lipid accumulation or other characteristics of NAFLD. We observed no changes in liver lipid metabolism-related gene expression, despite increased plasma free fatty acids and decreased plasma triglycerides in the TRF group. However, liver Grp78 and Txnip expression were decreased with TRF suggesting hepatic endoplasmic reticulum (ER) stress and activation of inflammatory pathways may have been diminished. We conclude that two-week, isocaloric TRF can potentially decrease liver inflammation, without significant weight loss or reductions in hepatic steatosis, in obese mice with NAFLD.

Research into the effects of long-term antioxidant supplementation on the islet microenvironment is limited. This study examined whether long-term N-acetyl-L-cysteine (NAC) supplementation can prevent changes in metabolic outcomes, beta cell function, and pancreatic stellate cell (PaSC) activation in aging mice. Male C57BL/6N mice at 18 weeks were administered 50 mM NAC through their daily drinking water and treated for up to 60 weeks. Aging NAC mice displayed lower body weights and improved glucose tolerance but reduced insulin secretion and insulin signaling compared to control (ND) mice. When some 40-week-old ND and NAC mice were subjected to 8 weeks of a high-fat diet (HFD)-stress challenge, results showed that NAC reduced HFD-induced beta cell oxidative stress and preserved nuclear PDX-1 expression. The findings from this study suggest that while NAC can be beneficial for diet-induced stress during aging, the effects of long-term NAC on the islets of physiologically aging mice are more ambiguous. Further exploration is required to determine the effects of NAC-mediated lowering of beta cell oxidative stress on insulin secretion and signaling pathways. This study highlights the importance of investigating oxidative stress balance in aging islets under normal diet conditions to determine if antioxidative therapies can be utilized without interfering with essential physiological processes.