Mice with faulty circadian clocks are prone to obesity and diabetes. So are mice fed a diet high in fat. Remarkably, animals that have both of these obesity-driving conditions can stay lean and metabolically healthy by simply limiting the time of day when they eat. In a study published today (August 30) in Cell Metabolism, researchers report that restricting feeding times to mice’s active hours can overcome both defective clock genes and an unhealthy diet, a finding that may have an impact in the clinic.
The work corroborates previous research showing how powerful restricted feeding can be to improve clock function, says Kristin Eckel-Mahan, a circadian biologist at the University of Texas Health Science Center at Houston who did not participate in the study. Over the last 20 years, biologists have found circadian clocks keeping physiologic time in almost every organ. They have also shown that mice with disrupted clocks often develop metabolic diseases, such as obesity, and that circadian clock proteins physically bind to the promoters of many metabolic regulators and instruct them when to turn on and off.
For Satchidananda Panda of the Salk Institute, these lines of evidence came together in 2009, when his group published a study showing that in mice without the clock component Cryptochrome, feeding and fasting could drive the expression of some, but not all, of the metabolic regulators throughout the body. Other groups have also confirmed that even in the absence of the clock it is still possible to drive some genetic rhythms. In this latest study, he and colleagues wanted to look more closely at how the cycling of clock and metabolic transcripts induced by time-restricted feeding, rather than normal genetic rhythms, influences the health of mice.
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The researchers used three different strains of mice: a whole-body knockout of Cryptochrome and two strains that were each missing one of two clock-related genes from the liver, where disruption of the clock can also lead to metabolic dysfunction. When the mice had round-the-clock access to a diet high in fat, which can lead to metabolic dysfunction even in wildtype mice, they gained weight, had high cholesterol, and became glucose intolerant and insulin resistant. But mice that could eat the high fat diet for only 10 hours of their active phase had none of these symptoms; instead, they had higher endurance on a treadmill than the other rodents.
“Even if you don’t have the internal navigator, if you get guidance from outside, then you can still maintain homeostasis,” says Panda. The work “also points out redundancies in the system. There is an internal timing cue, but if this timing cue is weak, then you can give the system timing from outside and in that way, the external timing . . . takes over.”
The authors “did a very nice job of incorporating several different clock mutant models . . . side-by-side and really demonstrating the beneficial effects of this restricted feeding paradigm,” says Eckel-Mahan.
The beneficial effects of time-restricted feeding are likely related to the way the gut clock communicates with the liver and then to muscles and fat, Paolo Sassone-Corsi, a circadian biologist at the University of California, Irvine, who did not participate in the study, tells The Scientist. “The future is really understanding how these clocks connect to each other,” he says. “The other aspect that to me is critical here is the relevance to humans.”
Panda says the work has translational potential, both for people with mutations in clock genes that genome-wide studies have linked to metabolic diseases and for older people, whose circadian clocks don’t work as well as they age, which could contribute to an increased risk of age-related problems such as diabetes and cardiovascular disease. “The question is: can we adopt time-restricted eating in old age to reduce the risk for these diseases?” he says. “Almost all of us in our old age are clock-mutant humans. Maybe the good lifestyle will override the effect of the dampened clock.”
A. Chaix et al., “Time-restricted feeding prevents obesity and metabolic syndrome in mice lacking a circadian clock,” Cell Metab, doi:10.1016/j.cmet.2018.08.004, 2018.