Short-term time-restricted feeding during the resting phase is sufficient to induce leptin resistance that contributes to development of obesity and metabolic disorders in mice

ABSTRACT Feeding at unusual times of the day is thought to be associated with obesity and metabolic disorders in both experimental animals and humans. We previously reported that time-imposed feeding during the sleep phase (daytime feeding, DF) induces obesity and metabolic disorders compared with mice fed only during the active phase (nighttime feeding, NF). The present study aimed to determine whether leptin resistance is caused by DF, and whether it is involved in the underlying mechanisms of DF-induced obesity in mice, since leptin plays an essential role in regulating energy expenditure and adiposity in addition to food intake. We compared leptin sensitivity by evaluating the effects of exogenous injected leptin on food intake and body weight in wild-type C57BL/6J mice under NF and DF. The mice were fed with a high-fat high-sucrose diet throughout the study. To determine whether leptin resistance is a cause or a result of DF-induced obesity with metabolic disorders, we restricted the feeding times of leptin resistant db/db mice. We also examined leptin sensitivity in leptin deficient ob/ob mice under NF and DF to elucidate the underlying mechanisms of DF-induced leptin resistance. C57BL/6J mice under DF gained more weight and adiposity compared with mice under NF, and developed hyperleptinemia and hypothermia. We found that six days of DF abolished exogenous leptin-induced hypophagia and reduction in body weight in mice. We also found that the leptin injection significantly suppressed the mRNA expression of lipogenic genes in the liver of NF, but not in DF mice, suggesting that short-term DF was sufficient to induce metabolic leptin resistance. The DF-induced increases in body weight gain, food efficiency, adipose tissue mass, lipogenic gene expression in metabolic tissues, and hepatic lipid accumulation were abolished in db/db mice, suggesting that the leptin resistance is a cause of DF-induced metabolic disorders. DF resulted in deep hypothermia in db/db, as well as in wild-type mice, suggesting that a decrease in energy expenditure was not the main cause of DF-induced obesity. Exogenous leptin reduced the body weight of ob/ob mice under both NF and DF, and the effect was significantly higher in DF- than in NF-ob/ob mice. Therefore, the development of DF-induced leptin resistance requires endogenous leptin, and central leptin sensitivity fluctuates in a circadian manner. The present findings suggest that leptin resistance is responsible for DF-induced obesity and metabolic disorders, and that the circadian fluctuation of central leptin sensitivity might be involved in leptin resistance induced by DF, although further studies are needed to elucidate the mechanisms of metabolic disorders that depend on the time of feeding. Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; ANOVA, analysis of variance; DF, daytime feeding; FFA, free fatty acid; HOMA-IR, homeostasis model assessment of insulin resistance; NEAT, non-exercise activity thermogenesis; NF, nighttime feeding; PI3, phosphatidylinositol 3; RF, restricted feeding; RW, running-wheel; SCN, suprachiasmatic nucleus; SEM, standard error of the mean; STAT3, signal transducer and activator of transcription 3; T-Cho, total cholesterol; TG, triglyceride; WAT, white adipose tissues.