WHAT’S NEW?

FOUR LANDMARK STUDIES 

WHAT MAKES MICE FAT? 
Since food consists of fat, protein and carbs, it has proven difficult to pinpoint exactly what aspect of the typical diet leads to weight gain. Part of the problem is that it is very difficult to do studies on humans where what they eat is controlled for long enough periods to work out what are the most important factors, however studies on animals that are similar to us can help point us in the right direction.

Scientists from the University of Aberdeen and the Chinese Academy of Sciences have undertaken the largest study of its kind looking at what components of diet – fat, carbohydrates or protein – caused mice to gain weight. The study was published in the journal Cell Metabolism and includes 29 different diets that vary in their fat, carbohydrate (in particular sugars) and protein contents.

The mice were fed these diets for three months, which is equivalent to nine years in humans. In total over 100,000 measurements were made of body weight changes and their body fat was measured using a micro MRI machine.

Professor John Speakman, who led the study, said: “The result of this enormous study was unequivocal – the only thing that made the mice get fat was eating more fat in their diets. “Carbohydrates including up to 30% of calories coming from sugar had no effect. Combining sugar with fat had no more impact than fat alone. There was no evidence that low protein (down to 5%) stimulated greater intake, suggesting there is no protein target. These effects of dietary fat seemed to be because uniquely fat in the diet stimulated the reward centres in the brain, stimulating greater intake. A clear limitation of this study is that it is based on mice rather than humans. However, mice have lots of similarities to humans in their physiology and metabolism, and we are never going to do studies where the diets of humans are controlled in the same way for such long periods. So the evidence it provides is a good clue to what the effects of different diets are likely to be in humans.

Read more: 

• Fat Consumption is the Only Cause of Weight Gain
• Dietary Fat, but Not Protein or Carbohydrate, Regulates Energy Intake and Causes Adiposity in Mice 

HOW SLEEP LOSS MAY CONTRIBUTE TO WEIGHT GAIN
Epidemiological studies have shown that the risk for obesity and type 2 diabetes is elevated in those who suffer from chronic sleep loss or who carry out shift work. Other studies have shown an association between disrupted sleep and adverse weight gain, in which fat accumulation is increased at the same time as the muscle mass is reduced – a combination that in and of itself has been associated with numerous adverse health consequences.

In a new study, researchers at Uppsala University now demonstrate that one night of sleep loss has a tissue-specific impact on the regulation of gene expression and metabolism in humans. This may explain how shift work and chronic sleep loss impairs our metabolism and adversely affects our body composition.

The researchers studied 15 healthy normal-weight individuals who participated in two in-lab sessions in which activity and meal patterns were highly standardised. In randomised order, the participants slept a normal night of sleep (over eight hours) during one session, and were instead kept awake the entire night during the other session. The morning after each night-time intervention, small tissue samples (biopsies) were taken from the participants’ subcutaneous fat (fat under the skin) and skeletal muscle. These two tissues often exhibit disrupted metabolism in conditions such as obesity and diabetes. At the same time in the morning, blood samples were also taken to enable a comparison across tissue compartments of a number of metabolites. These metabolites comprise sugar molecules, as well as different fats and amino acids (building blocks of proteins).

The tissue samples revealed that the sleep loss condition resulted in a tissue-specific change in DNA methylation, one mechanism that regulates gene expression. DNA methylation is a so-called epigenetic modification that is involved in regulating how the genes of each cell in the body are turned on or off, and is impacted by both hereditary as well as environmental factors, such as physical activity.

“Our new findings indicate that sleep loss causes tissue-specific changes to the degree of DNA methylation in genes spread throughout the human genome. Our parallel analysis of both muscle and adipose [fat] tissue further enabled us to reveal that DNA methylation is not regulated similarly in these tissues in response to acute sleep loss,” says Jonathan Cedernaes who led the study. “It will be interesting to investigate to what extent one or more nights of recovery sleep can normalise the metabolic changes that we observe at the tissue level as a result of sleep loss. Diet and exercise are factors that can also alter DNA methylation, and these factors can thus possibly be used to counteract adverse metabolic effects of sleep loss,” he says.

Read more: 

• Acute sleep loss results in tissue-specific alterations in genome-wide DNA methylation state and metabolic fuel utilization in humans 
• For more information, please contact: Jonathan Cedernaes, M.D., Ph.D. at the Neuroscience Department, Uppsala University. jonathan.cedernaes@neuro.uu.se 

AN INSIDE LOOK AT PROBIOTICS 
Every day, millions of people take probiotics – preparations containing live bacteria that are meant to fortify their immune systems, prevent disease or repair the adverse effects of antibiotics. Yet the benefits of probiotics have not really been medically proven. It is not even clear if probiotic bacteria really colonize the digestive tract or, if they do, what effects these have on humans and their microbiomes – the native bacteria in their guts. In two back-to-back reports published in Cell, researchers at the Weizmann Institute of Science show – in both mice and in humans – that a probiotic preparation of 11 strains of the most widely used probiotic families may sometimes be less-than-beneficial for the user and their microbiome.

To explore how probiotics truly affect us would turn out to be an “inside job”: For the first study, 25 human volunteers underwent upper endoscopy and colonoscopy to sample their baseline microbiome composition and function in different gut regions. Fifteen of those volunteers were then divided into two groups: The first were administered the 11-strain probiotic preparation, and the second were given placebo pills. Three weeks into the four-week treatment, all participants underwent a second upper endoscopy and colonoscopy to assess their response to the probiotics or placebo, and they were then followed for an additional two months.

The researchers discovered that probiotics’ gut colonization was highly individual. However, they fell into two main groups: The “persisters” guts hosted the probiotic microbes while the microbiomes of “resisters” expelled them. The team found they could predict whether a person would be a persister or resister just by examining their baseline microbiome and host gene expression profile. Persisters, they noted, exhibited changes to their native microbiome and gut gene expression profile, while resisters did not have such changes.

“Our results suggest that probiotics should not be universally given to the public as a ‘one size fits all’ supplement,” says Dr Eran Elinav. “Instead, they could be tailored to each individual and their particular needs. Our findings even suggest how such personalization might be carried out.” Dr Eran Segal continues: “These results add to our previous ones on diet that had revealed a similar individual response to foods, and which have highlighted the role of the gut microbiome in driving very specific clinical differences between people.”

In the second study, the researchers addressed a related question that is of equal importance to the general public, who are often told to take probiotics to counter the effects of antibiotics: Do probiotics colonize the gut following antibiotic treatment, and how does this impact the human host and their microbiome? The researchers administered wide-spectrum antibiotics to 21 human volunteers, who then underwent an upper endoscopy and colonoscopy to observe the changes to both the gut and its microbiome following the antibiotic treatment. Next, the volunteers were randomly assigned to one of three groups. The first was a “watch and wait” group, letting their microbiome recover on its own. The second group was administered the 11-strain probiotic preparation over a four-week period. The third group was treated with an autologous fecal microbiome transplant (aFMT), made up of their own bacteria that had been collected before giving them the antibiotic.

Probiotics, after the antibiotic had cleared the path, could easily colonize the human gut – more so than in the previous study in which antibiotics had not been given. To the team’s surprise, the probiotics’ gut colonization prevented both the host gut’s gene expression and their microbiome from returning to their normal pre-antibiotic configurations for months afterward. In contrast, autologous FMT resulted in the native gut microbiome recolonizing and the gut gene expression profile returning to normal within days. “These results,” says Elinav, “reveal a new and potentially alarming adverse side effect of probiotic use with antibiotics that might even bring long-term consequences. In contrast, personalized treatment – replenishing the gut with one’s own microbes – was associated with a full reversal of the drugs’ effects.”

Since probiotics are among the world’s most traded over-the-counter supplements, these results may have immediate, broad implications. “Contrary to the current dogma that probiotics are harmless and benefit everyone,” says Segal, “we suggest that probiotics preparations should be tailored to individuals, or that such treatments such as autologous FMT may be indicated in some cases.”

Read more: 

• Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features 
• Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT 

PREVENTING DIABETES 
The PREVIEW diabetes prevention learning module provides an up-to-date, evidence-based and easy-to-use interactive summary of healthy eating, physical activity and psychology for the prevention of type 2 diabetes and is freely available here.