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Epigenetic Obesity In The Fruit Fly

sharma-obesity-drosophila1Regular 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.

Thus,

“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.

@DrSharma
Edmonton, AB

 

 

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Targeting Gut Inflammation Can Reduce Insulin Resistance?

sharma-obesity-adipose-tissue-macrophageWith all of the recent interest in the gut microbiota as a mediator of systemic inflammation and metabolic disease, it was only a matter of time before researchers would begin targeting pro-inflammatory pathways in the gut to change metabolism.

A proof-of-principle, that this is indeed possible, is presented by Helen Luck and colleagues from the University of Toronto in a paper published in Cell Metabolism.

Using mice models, the researchers not only show that a high-fat diet can alter the gut immune system but also that the chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations is reduced in genetically altered mice that lack beta7 integrin-deficient mice (Beta7null), a driver of gut inflammatory response.

Further more, treatment of high-fat-fed normal mice with the local gut anti-inflammatory agent 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters including insulin resistance (although it had no effect on body weight).

These beneficial effects are are associated with reduced gut permeability and endotoxemia as well as decreased visceral adipose tissue inflammation.

Moreover, treatment with ASA also improved antigen-specific tolerance to luminal antigens.

Thus, as the authors conclude,

“…the mucosal immune system affects multiple pathways associated with systemic insulin resistance and represents a novel therapeutic target in this disease.”

Clearly gut inflammation both in relationship to gut microbiota as well as response to dietary factors is likely to be a hot topic in obesity and metabolic research for the foreseeable future.

@DrSharma
Edmonton, AB

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Treating Obesity Seriously Starts By Understanding The Problem

sharma-obesity-doctor-kidThat there are no easy solutions to obesity and managing your weight is challenging at the best of times. But trying to find manage it without understanding even the basics of how your body works to defend its weight is hopeless at best.

A sort paper by Christopher Ochner and colleagues, published in The Lancet Diabetes and Endocrinology, succinctly describes the challenges, and appeals to clinicians (and decision makers) to take this problem seriously (instead of trivialising it as a simple “lifestyle” issue).

“Many clinicians are not adequately aware of the reasons that individuals with obesity struggle to achieve and maintain weight loss, and this poor awareness precludes the provision of effective intervention.”

As readers of these pages are well aware,

“Irrespective of starting weight, caloric restriction triggers several biological adaptations designed to prevent starvation. These adaptations might be potent enough to undermine the long-term effectiveness of lifestyle modification in most individuals with obesity, particularly in an environment that promotes energy overconsumption.”

But is is not just about the body’s defense mechanisms.

“Additional biological adaptations occur with the development of obesity and these function to preserve, or even increase, an individual’s highest sustained lifetime bodyweight. For example, preadipocyte proliferation occurs, increasing fat storage capacity. In addition, habituation to rewarding neural dopamine signalling develops with the chronic overconsumption of palatable foods, leading to a perceived reward deficit and compensatory increases in consumption.”

“…improved lifestyle choices might be sufficient for lasting reductions in bodyweight prior to sustained obesity. Once obesity is established, however, bodyweight seems to become biologically stamped in and defended. Therefore, the mere recommendation to avoid calorically dense foods might be no more effective for the typical patient seeking weight reduction than would be a recommendation to avoid sharp objects for someone bleeding profusely.”

As the authors point out,

“…there is now good evident that these biological adaptations often persist indefinitely, even when a person re-attains a healthy BMI via behaviourally induced weight loss….Thus, we suggest that few individuals ever truly recover from obesity; individuals who formerly had obesity but are able to re-attain a healthy bodyweight via diet and exercise still have ‘obesity in remission’ and are biologically very different from individuals of the same age, sex, and bodyweight who never had obesity.”

To overcome these biological adaptations it is not enough to appeal or rely on will-power alone to sustain long-term weight loss. Rather, treatments need to address these biological adaptations and homeostatic mechanisms, which is exactly what anti-obesity drugs or surgery does.

Thus, the authors have the following advice for clinicians:

“Specifically, clinicians should be proactive in addressing obesity prevention with patients who are overweight and, for those who already have sustained obesity, clinicians should implement a multimodal treatment approach that includes biologically based interventions such as pharmacotherapy and surgery when appropriate.”

“We urge individuals in the medical and scientific community to seek a better understanding of the biological factors that maintain obesity and to approach it as a disease that cannot be reliably prevented or cured with current frontline methods.”

@DrSharma
Edmonton, AB

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Early Bird Registration For Canadian Obesity Summit Ends March 3rd

For all my Canadian readers (and any international readers planning to attend), here just a quick reminder that the deadline for early bird discount registration for the upcoming 4th Canadian Obesity Summit in Toronto, April 28 – May 2, ends March 3rd.

To anyone who has been at a previous Canadian Summit, attending is certainly a “no-brainer” – for anyone, who hasn’t been, check out these workshops that are only part of the 5-day scientific program – there are also countless plenary sessions and poster presentations – check out the full program here.

Workshops:

Public Engagement Workshop (By Invitation Only)

Pre-Summit Prep Course – Overview of Obesity Management ($50)

Achieving Patient‐Centeredness in Obesity Management within Primary Care Settings

Obesity in young people with physical disabilities

CON-SNP Leadership Workshop: Strengthening CON-SNP from the ground up (Invitation only)

Exploring the Interactions Between Physical Well-Being and Obesity

Healthy Food Retail: Local public‐private partnerships to improve availability of healthy food in retail settings

How Can I Prepare My Patient for Bariatric Surgery? Practical tips from orientation to operating room

Intergenerational Determinants of Obesity: From programming to parenting

Neighbourhood Walkability and its Relationship with Walking: Does measurement matter?

The EPODE Canadian Obesity Forum: Game Changer

Achieving and Maintaining Healthy Weight with Every Step

Adolescent Bariatric Surgery – Now or Later? Teen and provider perspectives

Preventive Care 2020: A workshop to design the ideal experience to engage patients with obesity in preventive healthcare

Promoting Healthy Maternal Weights in Pregnancy and Postpartum

Rewriting the Script on Weight Management: Interprofessional workshop

SciCom-muniCON: Science Communication-Sharing and exchanging knowledge from a variety of vantage points

The Canadian Task Force on Preventive Health Care’s guidelines on obesity prevention and management in adults and children in primary care

Paediatric Obesity Treatment Workshop (Invitation only)

Balanced View: Addressing weight bias and stigma in healthcare

Drugs, Drinking and Disordered Eating: Managing challenging cases in bariatric surgery

From Mindless to Mindful Waiting: Tools to help the bariatric patient succeed

Getting Down to Basics in Designing Effective Programs to Promote Health and Weight Loss

Improving Body Image in Our Patients: A key component of weight management

Meal Replacements in Obesity Management: A psychosocial and behavioural intervention and/or weight loss tool

Type 2 Diabetes in Children and Adolescents: A translational view

Weight Bias: What do we know and where can we go from here?

Energy Balance in the Weight- Reduced Obese Individual: A biological reality that favours weight regain

Innovative and Collaborative Models of Care for Obesity Treatment in the Early Years

Transition of Care in Obesity Management : Bridging the gap between pediatric and adult healthcare services

Neuromuscular Meeting workshop – Please note: Separate registration is required for this event at no charge

To register – click here.

@DrSharma
Edmonton, AB

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Anti-Inflammatory Effects Of A Healthy Nordic Diet

Nordic Diet Food Pyramid

Nordic Diet Food Pyramid

During my current visit to speak at the Icelandic Medical Association Annual Conference and meet with policy makers, my hosts are doing a wonderful job of introducing me to their “Nordic” fare consisting largely of fish, rye bread and other local produce.

Reason enough to post on this recent article by Marjukka Kolehmainen and her team of Scandinavian colleagues, published in the American Journal of Clinical Nutrition, which examines the effects of a Nordic diet on the expression of inflammatory markers in adipose tissue of individuals with the metabolic syndrome.

Participants in this 18-24 week study were randomised to either a Nordic or control diet in the SYSDIET study, whereby participants for this “substudy” were selected from centres in Kuopio, Lund and Oulo. Importantly, subjects chosen for this analysis were relatively weight stable, having lost or gained less than 5% of their body weight during the course of the study.

In accordance with recommendations for a healthy Nordic diet, subjects in the intervention group were counselled to increase their consumption of whole-grain products, berries, fruits and vegetables, rapeseed oil, have three fish meals per week, and chose low-fat dairy products, while avoiding sugar-sweetened products. In contrast, the control group was advised to consume low-fiber cereal products and dairy fat–based spreads while limiting their fish intake to that generally consumed by the average Nordic population.

Gene expression studies were performed in biopsies from subcutaneous fat tissue and showed differential expression of about 130 genes between the two dietary groups – most of which were related to pathways involved in immune and inflammatory response, including genes involved in leukocyte trafficking and macrophage recruitment (e.g., interferon regulatory factor 1, CD97), adaptive immune response (interleukin32, interleukin 6 receptor), and reactive oxygen species (neutrophil cytosolic factor 1).

Together, the analyses showed a significant reduction in many of these markers consistent with an “anti-inflammatory” effect of the Nordic diet.

As the authors point out, these beneficial effects were seen with very little or no weight loss, suggesting that they are indeed attributable to the changes in dietary intake.

These findings may well have implications for us here in Canada, where eating a “Nordic” diet with local ingredients, may well be a far better alternative than trying to emulate a “Mediterranean” diet, the green house impact of which would be anything but healthy.

@DrSharma
Reykjavik, Iceland

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