Northwestern Medicine scientists have uncovered the mechanism behind why eating late at night is linked to weight gain and diabetes.

The connection between eating time, sleep and obesity is well-known but poorly understood, with research showing that overnutrition can disrupt circadian rhythms and change fat tissue.

New Northwestern research has shown for the first time that energy release may be the molecular mechanism through which our internal clocks control energy balance. From this understanding, the scientists also found that daytime is the ideal time in the light environment of the Earth’s rotation when it is most optimal to dissipate energy as heat. These findings have broad implications from dieting to sleep loss and the way we feed patients who require long-term nutritional assistance.

The paper, “Time-restricted feeding mitigates obesity through adipocyte thermogenesis,” will be published online today, and in print tomorrow (Oct. 21) in the journal Science.

“It is well known, albeit poorly understood, that insults to the body clock are going to be insults to metabolism,” said corresponding study author Dr. Joseph T. Bass, the Charles F. Kettering Professor of Medicine at Northwestern University Feinberg School of Medicine. He also is a Northwestern Medicine endocrinologist.

“When animals consume Western style cafeteria diets — high fat, high carb — the clock gets scrambled,” Bass said. “The clock is sensitive to the time people eat, especially in fat tissue, and that sensitivity is thrown off by high-fat diets. We still don’t understand why that is, but what we do know is that as animals become obese, they start to eat more when they should be asleep. This research shows why that matters.”

Bass is also director of the Center for Diabetes and Metabolism and the chief of endocrinology in the department of medicine at Feinberg. Chelsea Hepler, a postdoctoral fellow in the Bass Lab, was the first author and did many of the biochemistry and genetics experiments that grounded the team’s hypothesis. Rana Gupta, now at Duke University, was also a key collaborator.

Scrambling the internal clock

In the study, mice, who are nocturnal, were fed a high-fat diet either exclusively during their inactive (light) period or during their active (dark) period. Within a week, mice fed during light hours gained more weight compared to those fed in the dark. The team also set the temperature to 30 degrees, where mice expend the least energy, to mitigate the effects of temperature on their findings.

“We thought maybe there’s a component of energy balance where mice are expending more energy eating at specific times,” Hepler said. “That’s why they can eat the same amount of food at different times of the day and be healthier when they eat during active periods versus when they should be sleeping.”

The increase in energy expenditure led the team to look into metabolism of fat tissue to see if the same effect occurred within the endocrine organ. They found that it did, and mice with genetically enhanced thermogenesis — or heat release through fat cells — prevented weight gain and improved health.

Hepler also identified futile creatine cycling, in which creatine (a molecule that helps maintain energy) undergoes storage and release of chemical energy, within fat tissues, implying creatine may be the mechanism underlying heat release.

Intermittent fasting and gastric feeding tubes

The science is underpinned by research done by Bass and colleagues at Northwestern more than 20 years ago that found a relationship between the internal molecular clock and body weight, obesity and metabolism in animals.

The challenge for Bass’s lab, which focuses on using genetic approaches to study physiology, has been figuring out what it all means, and finding the control mechanisms that produce the relationship. This study brings them a step closer.

The findings could inform chronic care, Bass said, especially in cases where patients have gastric feeding tubes. Patients are commonly fed at night while they sleep, when they’re releasing the least amount of energy. Rates of diabetes and obesity tend to be high for these patients, and Bass thinks this could explain why. He also wonders how the research could impact Type II Diabetes treatment. Should meal times be considered when insulin is given, for example?

Hepler will continue to research creatine metabolism. “We need to figure out how, mechanistically, the circadian clock controls creatine metabolism so that we can figure out how to boost it,” she said. “Clocks are doing a lot to metabolic health at the level of fat tissue, and we don’t know how much yet.”

A study of mice found that dietary sugar alters the gut microbiome, setting off a chain of events that leads to metabolic disease, pre-diabetes, and weight gain.

The findings, published today in Cell(link is external and opens in a new window), suggest that diet matters, but an optimal microbiome is equally important for the prevention of metabolic syndrome, diabetes, and obesity. 

Diet alters microbiome

A Western-style high-fat, high-sugar diet can lead to obesity, metabolic syndrome, and diabetes, but how the diet kickstarts unhealthy changes in the body is unknown.

The gut microbiome is indispensable for an animal’s nutrition, so Ivalyo Ivanov, PhD, associate professor of microbiology & immunology at Columbia University Vagelos College of Physicians and Surgeons, and his colleagues investigated the initial effects of the Western-style diet on the microbiome of mice.

After four weeks on the diet, the animals showed characteristics of metabolic syndrome, such as weight gain, insulin resistance, and glucose intolerance. And their microbiomes had changed dramatically, with the amount of segmented filamentous bacteria—common in the gut microbiota of rodents, fish, and chickens—falling sharply and other bacteria increasing in abundance.

Microbiome changes alter Th17 cells

The reduction in filamentous bacteria, the researchers found, was critical to the animals’ health through its effect on Th17 immune cells. The drop in filamentous bacteria reduced the number of Th17 cells in the gut, and further experiments revealed that it’s the Th17 cells that are necessary to prevent metabolic disease, diabetes, and weight gain.

“These immune cells produce molecules that slow down the absorption of ‘bad’ lipids from the intestines and they decrease intestinal inflammation,” Ivanov says. “In other words, they keep the gut healthy and protect the body from absorbing pathogenic lipids.”

Sugar vs. fat

What component of the high-fat, high-sugar diet led to these changes? Ivanov’s team found that sugar was to blame.

“Sugar eliminates the filamentous bacteria, and the protective Th17 cells disappear as a consequence,” says Ivanov. “When we fed mice a sugar-free, high-fat diet, they retain the intestinal Th17 cells and were completely protected from developing obesity and pre-diabetes, even though they ate the same number of calories.”

But eliminating sugar did not help all mice. Among those lacking any filamentous bacteria to begin with, elimination of sugar did not have a beneficial effect, and the animals became obese and developed diabetes.

“This suggests that some popular dietary interventions, such as minimizing sugars, may only work in people who have certain bacterial populations within their microbiota,” Ivanov says.

In those cases, certain probiotics might be helpful. In Ivanov’s mice, supplements of filamentous bacteria led to the recovery of Th17 cells and protection against metabolic syndrome, despite the animals’ consumption of a high-fat diet.

Though people do not have the same filamentous bacteria as mice, Ivanov thinks that other bacteria in people may have the same protective effects.

Providing Th17 cells to the mice also provided protection and may also be therapeutic for people. “Microbiota are important, but the real protection comes from the Th17 cells induced by the bacteria,” Ivanov says.

“Our study emphasizes that a complex interaction between diet, microbiota, and the immune system plays a key role in the development of obesity, metabolic syndrome, type 2 diabetes, and other conditions,” Ivanov says. “It suggests that for optimal health it is important not only to modify your diet but also improve your microbiome or intestinal immune system, for example, by increasing Th17 cell-inducing bacteria.”