Time-restricted feeding improves insulin resistance and hepatic steatosis in a mouse model of postmenopausal obesity

Abstract

Background Menopause is associated with significant hormonal changes that result in increased total body fat and abdominal fat, amplifying the risk for metabolic syndrome and diseases such as diabetes, cardiovascular disease and cancer in postmenopausal women. Intermittent fasting regimens hold significant health benefit promise for obese humans, however, regimens that include extreme daytime calorie restriction or daytime fasting are generally associated with hunger and irritability, hampering long-term compliance and adoption in the clinical setting. Time-restricted feeding (TRF), a regimen allowing eating only during a specific period in the normal circadian feeding cycle, without calorie restriction, may increase compliance and provide a more clinically viable method for reducing the detrimental metabolic consequences associated with obesity. Methods We tested TRF as an intervention in a mouse model of postmenopausal obesity. Metabolic parameters were measured using Clinical Laboratory Animal Monitoring System (CLAMS) and we carried out glucose tolerance tests. We also stained liver sections with oil red O to examine steatosis and measured gene expression related to gluconeogenesis. Results Preexisting metabolic disease was significantly attenuated during 7 wk of TRF. Despite having access to the same high fat diet (HFD) as ad libitum fed (ALF) mice, TRF mice experienced rapid weight loss followed by a delayed improvement in insulin resistance and a reduced severity of hepatic steatosis by having access to the HFD for only 8 h during their normal nocturnal feeding period. The lower respiratory exchange ratio in the TRF group compared with the ALF group early in the dark phase suggested that fat was the predominant fuel source in the TRF group and correlated with gene expression analyses that suggested a switch from gluconeogenesis to ketogenesis. In addition, TRF mice were more physically active than ALF fed mice. Conclusions Our data support further analysis of TRF as a clinically viable form of intermittent fasting to improve metabolic health due to obesity.

Time-restricted feeding reduces the detrimental effects of a high-fat diet, possibly by modulating the circadian rhythm of hepatic lipid metabolism and gut microbiota

“…FA mice also exhibited signi cant liver steatosis and elevated hepatic levels of TG compared to NA mice, indicating the HFDinduced obesity mice model was well established in the study. And implementation of TRF in mice fed HFD protected against obesity and hepatic lipid accumulation, presented with decreased weight gain, severity of liver steatosis and hepatic TG level compared to FA mice, which was consistent with previous studies in rodent animals [7,43,47,50]. Therefore, it was reasonable to further investigate the underlying mechanism of TRF using the well-established HFD-TRF mice model in the present study.…”

Metabolic Effects of Intermittent Fasting

“…Nearly all studies of rodent fasting regimens, including time-restricted feeding, have been conducted in male mice. We have published a study that recapitulates the overall metabolic benefit of timerestricted feeding as an intervention strategy in an obese, postmenopausal female mouse model (23). Thus, the time-restricted feeding intervention paradigm seems to be translational to both men and women.…”

“…Interestingly, mice whose HFD feeding was restricted to 8 hours during the normal nocturnal eating time consumed equivalent energy, but were protected from obesity, hyperinsulinemia, hepatic steatosis, and inflammation compared with ad libitum HFD-fed mice (47). Time-restricted feeding also is effective as an intervention for diet-induced obesity and associated metabolic dysfunction (17,23).…”

“…Mice on a time-restricted, isocaloric feeding regimen have shown improved muscle coordination toward the end of the feeding period (47). Rodent studies demonstrate that time-restricted feeding regimens increase locomotion (23,47) and improve circadian activity rhythms (47), an indicator of overall rhythmicity. However, data in humans are sparse about whether intermittent fasting regimens impact energy expenditure among free-living adults.…”

Suitability of a 10% fat diet for use in time-restricted feeding experiments with C57BL/6 mice

“…Previous TRF studies have involved access to food for 3-8 h daily [17][18][19][20][21], and we previously provided the purified diets, AIN-76 and AIN-93, to mice and rats daily for 4 h (2 h at both the beginning and end of the dark period). The body masses of these animals were lower than of those that had consumed the same diet ad libitum.…”