Regular readers are well aware of the considerable evidence now supporting the notion that inter-generational transmission of obesity risk through epigenetic modification may well be a key factor in the recent global rise in obesity rates (over the past 100 years or so).
Now a brief review article by Susan Ozanne from the University of Cambridge, UK, published in the New England Journal of Medicine, describes how researchers have now identified a clear and conserved epigenetic signature that is associated with obesity across species (from the fruit fly all the way to humans).
The article discusses how the transmission of susceptibility to obesity can occur as a consequence of “developmental programming,” whereby environmental factors (e.g. a high-fat diet) encountered at the point of conception and during fetal and neonatal life can permanently influences the structure, function, and metabolism of key organs in the offsprin, thus leading to an increased risk of diseases such as obesity later in life.
There is now evidence that such intergenerational transmission of disease can occur through environmental manipulation of both the maternal and paternal lines – thus, this is not something that is just a matter of maternal environment.
Thus, as Ozanne points out,
“Epigenetic mechanisms that influence gene expression have been proposed to mediate the effects of both maternal and paternal dietary manipulation on disease susceptibility in the offspring (these mechanisms include alterations in DNA methylation, histone modifications, and the expression of microRNAs).”
Work in the fruit fly has linked the effect of paternal sugar-feeding on the chromatin structure at a specific region of the X chromosome and transcriptome analysis of embryos generated from fathers fed a high-sugar diet, revealed dysregulation of transcripts encoding two proteins (one of them is called Su(var)) known to change chromatin structure and gene regulation.
Subsequent analyses of microarray data sets from humans and mice likewise revealed a depletion of the Su(var) proteins in three data sets from humans and in two data sets from mice.
“This finding is consistent with the possibility that the depletion of the Su(var) pathway may be brought about by an environmental insult to the genome that is associated with obesity.”
Not only do these studies provide important insights into just how generational transmission of obesity may work but it may also lead to the development of early tests to determine the susceptibility of individuals to the future development of conditions like obesity or diabetes based on epigenetic signatures.
All of this may be far more relevant for clinical practice than most readers may think – indeed, a focus on maternal (and now paternal?) health as a target to reduce the risk of childhood (and adult) obesity is already underway.
This issue will certainly be a “hot topic” at the Canadian Obesity Summit in Toronto later this month.
However, whether or not Canadian hospitals are ready to look after these patients with in the right setting with the right equipment and whether healthcare providers are aware of and sensitive to the special needs of these patients is not clear.
This is why, Mary Forhan and her team at the University of Alberta is currently conducting a qualitative and quantitative assessment of exactly what problems patients with severe obesity face in healthcare settings.
The study, funded by Alberta Innovates Health Solution (AIHS) will look at the special challenges that these patients present in a range for settings – acute care, cancer, cardiology and rehabilitation.
A substudy will also examine the issues faced by kids and adolescent with severe obesity in healthcare settings.
Together, this project should lead to a better understanding on how healthcare systems better prepare themselves to deliver compassionate and professional care to adults and children living with severe obesity in Alberta. The learnings will likely also inform healthcare systems elsewhere.
For more on this study visit the AIHS website.
If you are someone living with severe obesity, who has experienced issues in your healthcare that could have been prevented or addressed with appropriate equipment and/or training, I’d love to hear your story.
Conflict: I am a co-investigator on this project.
The recently released Canadian Practice Guidelines on the prevention and management of overweight and obesity in children and youth released by the Canadian Task Force on Preventive Health Care (CMAJ 2015), rightly recommended that surgery not be routinely offered to children or youth who are overweight or obese.
Nevertheless, there is increasing evidence that some of these kids, especially those with severe obesity, may well require rather drastic treatments that go well beyond the current clinical practice of doing almost nothing.
Just how ill kids can be before they are generally considered potential candidates for bariatric surgery is evident from a study by Marc Michalsky and colleagues, who just published the baseline characteristics of participants in the Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Study, a prospective cohort study following patients undergoing bariatric surgery at five adolescent weight-loss surgery centers in the United States (JAMA Pediatrics).
While the mean age of participants was 17 with a median body mass index of 50, the prevalence of cardiovascular risk factors was remarkable: fasting hyperinsulinemia (74%), elevated hsCRP (75%), dyslipidemia (50%), elevated blood pressure (49%), impaired fasting glucose levels (26%), and diabetes mellitus (14%).
Not reported in this paper are the many non-cardiovascular problems raging from psychiatric issues to sleep apnea and muskuloskeletal problems, that often dramatically affect the life of these kids.
While surgery certainly appears rather drastic, the fact that these kids are undergoing surgery is merely an indicator of the fact that we don’t have effective medical treatments for this patient population, which would likely require a combination of behavioural interventions and polypharmacy to achieve anything close to the current weight-loss success of bariatric surgery.
That this cannot be the ultimate answer to obesity management (whether for kids or adults), is evident from the rising number of kids and adults presenting with ever-higher BMI’s and related comorbidity – not all of these can or will want surgery.
Thus, while current anti-obesity medications cannot compete with the magnitude of weight-loss generally seen with surgery, medications together with behavioural interventions may well play a role in helping prevent progressive weight gain in earlier stages of the disease.
Unfortunately, I am not aware of any studies that have explored the use of medications in kids to stabilize weight in order to avoid surgery. This would, in my opinion, be a very worthwhile use of such medications.
Regular readers will be well of the very real social and health impact of weight bias and discrimination.
Now, Sara Kirk of Dalhousie University, Halifax, NS, invites you to join her free Massive Open Online Course (MOOC), on weight bias and stigma in obesity, which will be starting on April 20th 2015 (just a week before the Canadian Obesity Summit in Toronto).
The course builds on Kirk’s extensive research in this area and the dramatic presentation that was created from her findings.
Participants will be able to explore some of the personal and professional biases that surround weight management and that impact patient care and experience.
This will hopefully give health professionals better insight into how to approach individuals experiencing obesity in a respectful and non-judgmental manner and provide strategies to build positive and supportive relationships between health care providers and patients.
While targeted at health care providers, the course should also be of interest to anyone interested in learning more about what weight bias is and how it can impact health and relationships.
Participants who complete the course requirements can apply for a citation of completion (for a nominal fee).
On the last day of the 8th Annual Obesity Symposium here in Norderstedt, Germany, Marco Bueter from the University of Zurich presented a fascinating series of studies (just published in Circulation), demonstrating the “weight-independent” benefits of gastric bypass surgery on endothelial function (using an animal model).
Besides showing that 8 days after bypass surgery rats with diet-induced obesity had higher plasma levels of bile acids and GLP-1, that were associated with improved endothelium-dependent relaxation, not seen in sham-operated weight matched controls, but also that these effects could be prevented by blocking GLP-1 receptors with exendin 9-39.
In contrast, similar effects to those seen on vascular function in bypass rats were seen in sham-operated rats treated for 8 days with the GLP-1 analogue, liraglutide, or as the authors describe it,
“liraglutide restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB”
Together these studies suggest that GLP-1 may well play an important causal role in the improved vascular function seen in patients undergoing gastric bypass surgery.
These findings are all the more interesting as liraglutide has now been approved for obesity treatment in the USA, Canada and Europe.
While these data are certainly not enough to describe liraglutide as “surgery in a pen”, they are indeed promising in terms of potential benefits of this treatment that may well be weight independent.
All the more reason to anticipate the outcome of the ongoing LEADER trial, which is currently evaluating the effect of liraglutide treatment on cardiovascular outcomes in patients with type 2 diabetes.
Disclaimer: I have served as a paid consultant and speaker for Novo Nordisk, the maker of liraglutide.