This is once again demonstrated in a fascinating series of experiments by Stefano Guidotti and colleagues from the University of Groningen, The Netherlands, in a paper published in Physiology and Behaviour.
The researchers performed their experiments in mice that were selectively bred over 50 generations to voluntarily spend hours in running wheels. Interestingly, the female “runner” mice remain resistant to becoming obese as adults when exposed to a high-fat diet even when they don’t have access to a running wheel.
Thus, these mice are resistant to developing obesity whether they run or just sit around.
What the researchers now show is that this “resistance” to gaining excess weight (bred over generations) can be fully cancelled out simply by exposing the mice to a high-fat diet for a couple of days shortly after birth.
With this exposure, these mice (and even their offspring) are suddenly no longer resistant to weight gain later in life and in fact gain as much weight on high-calories diets as normal mice.
Even more interestingly, the short term perinatal exposure to the high-energy diet does not cancel out their love for running. When given a wheel, they continue running just as much as before but even this no longer prevents them from gaining weight.
Thus it appears that exposure to a high-energy diet during the perinatal period can have profound effects on the risk of developing adult obesity even in animals bred to be obesity resistant – and, the love for running, does not appear to protect against weight gain.
Or, as the authors put it,
“..resistance to high-energy diet-induce obesity in adult female mice from lines selectively bred over ~ 50 generations for increased wheel running behavior was blocked by additional perinatal high-energy diet exposure in only one cycle of breeding. An explanation for this effect is that potential allelic variants underlying the trait of diet-induced obesity proneness were not eliminated but rather silenced by the selection protocol, and switched on again by perinatal high-energy diet exposure by epigenetic mechanisms”
Moreover, this effect of perinatal high-energy diet exposure and its “reversal effect” on obesity resistance can be passed on to the next generation.
Reason enough to wonder just how much the rather dramatic changes in perinatal feeding of infants over the last few decades may be contributing to the obesity epidemic.
Shortly after a meal, there is a spike in the cerebrospinal fluid concentration of nutrients with direct access to various nutrient-sensitive sites in the brain.
Now a paper by Olof Lagerlöf and colleagues, published in SCIENCE, shows that in mice, the glycosylation enzyme O-GlcNAc transferase (OGT), present in a wide range of neurons involved in energy regulation and feeding behaviours, may play an important role in the satiety response.
Genetic and molecular manipulation of this enzyme in adult mice resulted in marked effects on feeding and weight gain.
Reducing the activity of the enzyme resulted in animals eating much larger meals (but not more often) with substantial gain in fat (but not lean) mass.
In contrast, increasing the activity of this enzyme resulted in reduced food intake during eating episodes.
Not only does it make sense that a molecule known to play a role as a nutrient-sensor would play a role in the central regulation of food intake, but the authors are optimistic that this enzyme may be a target for finding new anti-obesity medications.
This, however, does not mean that genetic risk is not modifiable.
Thus, a paper by Carlos Celis-Morales and colleagues, published in OBESITY, suggests that physical activity may attenuate some of the weight gain attributable to the FTO gene, one of the more common obesity risk alleles.
Their study includes data from 1,280 participants in the European Food4Me trial.
Overall, the FTO (rs9939609) genotype was associated with a higher body weight of about 1 Kg per risk allele, 0.5 Kg/m2 higher BMI, and 1.1 cm greater waist circumference.
While these “effects” were higher among inactive individuals (BMI by 1.06 kg/m2 per allele and waist circumference by 2.7 cm per allele), they were lower in individuals with moderate to high physical activity (BMI by 0.16 kg/me and Waist circumference by 0.5 cm).
Thus, it appears that increased physical activity may attenuate (but not fully prevent) the effect of FTO genotype on BMI and WC.
Exactly how clinically relevant these findings are and whether they would have any effect at all on public health messages or individual counselling, where increased physical activity is likely to be recommended irrespective of any “genetic markers” (or at least should be) is pretty doubtful.
Currently, we have yet to await any practical consequences of genotyping individuals for obesity “risk” alleles.
One of the coming features of the Canadian Obesity Network’s patient engagement strategy is a new series of public webinars on topics relevant to obesity by Canadian experts.
I will have the honour of giving the inaugural talk in this series on Tuesday, Feb 23, 2016, 12.00 pm (Eastern) on the topic of “why obesity is a chronic disease”.
The webinar is free but seats are limited, so registration for this event is recommended.
You can also join the discussion on Facebook.
In case you miss it, the talk will be posted on the CON website after the event.
Join me in looking forward to this and forthcoming webinars in this series.
Now a study by Silje Steinbeckk and colleagues from Norway, published in JAMA Pediatrics, suggests that while genetic factors are important, these may not act through an effect on appetite or eating behaviour.
The longitudinal study was conducted in a representative birth cohort at the Trondheim Early Secure Study, enrolled at age 4 years during 2007 to 2008, with follow-ups at ages 6 and 8 years. Analyses included 652 children with genotype, adiposity, and appetite data.
While there was clear effect of genetic risk (measured as a composite score of 32 genetic variants) on increase in body weight and fat mass), there was no clear relationship to appetite traits measured at age 6 years with the Children’s Eating Behavior Questionnaire.
Thus, the authors conclude that while genetic risk for obesity is associated with accelerated childhood weight gain, appetite traits may not be the most promising target for preventing excessive weight gain.
So if not through appetite, how do these genes increase the risk for weight gain. Obviously there are a number of possibilities ranging from subtle effects on energy metabolism, adipocyte differentiation or other factors that may not directly be related to eating behaviour.
Another possibility may well be that the instrument used to assess appetite traits may simply not be sensitive and reliable enough to capture subtle changes in ingestive behaviour.
Thus, while there is no doubt that genetic risk may well be a key determinant of childhood obesity, exactly how this effect is mediated remains unclear.