New research utilizing time-restricted feeding (TRF) now shows that metabolic homeostasis is maintained as a result of the circadian clock’s control of daily rhythms in feeding and fasting.

Amandine Chaix and colleagues used three different mouse models of altered circadian rhythms: whole-body knockout of Cry1 and Cry2; liver-specific knockout of Bmal1; and liver-specific knockout of Nr1d1 and Nr1d2 (also known as Rev-erbα and Rev-erbβ). The mice were fed a high-fat diet either ad libitum or under TRF (9 or 10 hours during the dark phase); mice in both groups ate the same amount of calories.

The circadian rhythm of the respiratory exchange ratio is disrupted in clocklessmice fed ad libitum, but is restored with time-restricted feeding.

Under ad libitum conditions, the control and mutant mice gained weight and exhibited metabolic abnormalities. Importantly, the mutant mice on TRF were protected from weight gain and metabolic abnormalities. The researchers also conducted extensive transcriptome and metabolome analyses, which showed that TRF reduced the accumulation of lipids in the liver and enhanced cellular defences against metabolic stress.

In addition, the mutant mice on an ad libitum diet were found to have an inflexible respiratory exchange ratio, suggesting that the mice were unable to switch between using carbohydrates and fats for fuel. By contrast, mutant mice on TRF showed normal diurnal patterns in the respiratory exchange ratio.

“Our study shows that TRF protects clock mutant mice from obesity, fatty liver, dyslipidaemia and glucose intolerance without changes in activity or caloric intake,” explains corresponding author Satchidananda Panda. “TRF restores rhythms in feeding and fasting, metabolic pathways and nutrient-sensing pathways.”

TRF protects clock mutant mice from obesity … without changes in activity or caloric intake

The authors note that their study raises many questions that need to be answered. For instance, how the circadian clock regulates feeding rhythms is unclear and the effects of TRF in old animals and over long periods of time are unknown. “Nevertheless, the impact of TRF in delaying onset of metabolic diseases in circadian mutant mice will have significant mechanistic and translational impact,” concludes Panda.