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Transgenerational Transmission of Metabolic Disease

sharma-obesity-dna_molecule9If  anyone ever tells you that the current obesity epidemic can have nothing to do with genetics because “genes don’t change in a couple of generations”, it is completely fair to let them know that they probably do not know what they are talking about.

Indeed, there is now overwhelming evidence showing that a variety of health problems, particularly related to metabolic diseases including obesity, can well be transmitted from generation to generation as a result of epigenetic modifications that persist in subsequent generations, even if these are no longer exposed to the “trigger” environment.

Anyone who is interested in learning about how much we know about these intergenerational mechanisms, will probably want to read a recent review article on this subject by Rachel Stegemann and David Buchner, published in Seminars in Cell & Developmental Biology.

In this papers the authors review examples of transgenerational inheritance of metabolic disease in both humans and model organisms and how these can be triggered by both genetic and environmental stimuli.ors

As the authors note,

“A diverse assortment of initial triggers can induce transgenerational inheritance including high-fat or high-sugar diets, low-protein diets, various toxins, and ancestral genetic variants. Although the mechanistic basis underlying the transgenerational inheritance of disease risk remains largely unknown, putative molecules mediating transmission include small RNAs, histone modifications, and DNA methylation.”

They also discuss example of therapeutically targeting the epigenome (e.g. through dietary modification or exercise) to prevent the transgenerational transmission of metabolic disease.

These findings have substantial implications for our attempts to prevent or even reverse the development of obesity in future generations.

@DrSharma
Vancouver, BC

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Does Food Availability Have Much To Do With Obesity?

sharma-obesity-variety1Before you respond “of course” – you may wish to take a look at the systematic review by Laura Cobb and colleagues from Johns Hopkins University, published in OBESITY.

The authors looked at 71 Canadian and US studies that examined the relationship between obesity and retail food environments and concluded that,

“Despite the large number of studies, we found limited evidence for associations between local food environments and obesity. “

To be fair, the researchers also concluded that much of the research in this area lacks high-quality studies, that would lead to a more robust understanding  of this issue.

In fact, the authors had to slice and dice the data to tease out “positive” findings that included a possible relationship between fast food outlets and obesity in low-income children or an inverse trend for obesity with the availability of supermarkets (a supposed surrogate measure for availability of fresh produce).

Of course, not finding a robust relationship between the food environment and obesity should not be all that surprising, given the many factors that can potentially play a role in obesity rates.

(Readers may recall that there used to be similar enthusiasm between the role of the built environment (e.g. walkability) for rising obesity rates, till the research on this issue turned out to be rather inconclusive. )

None of this should be interpreted to mean that the food or built environments have nothing to do with obesity – however, we must remember that these type of studies virtually never prove causality and that the factors that determine food and built environments are in fact almost as complicated as the factors that determine individual body weights, so finding a robust relationship between the two would be rather surprising.

Allow me to predict that with the increasing trend of fast food outlets offering healthier (or rather less-unhealthy) choices and supermarkets offering ample amounts of “fast food” and a vast array of unhealthy packaged foods, any relationship between retail food environments and obesity (even if it does exist), will be even harder to prove that ever before (outliers are no better than anecdotal evidence and should generally be ignored).

Changing food environments to provide better access to affordable healthier foods should be a “no-brainer” for policy makers, irrespective of whether or not the current environment has anything to do with obesity or not (the same could be said for walkability of neighbourhoods and the prevention of urban sprawl).

@DrSharma
Edmonton, AB

 

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Dose-Response Relationship Between Obesity And Breast Cancer

sharma-obesity-bc-ribbon1-150x1501With all the concern about the impact of obesity on metabolic and cardiovascular health, it is often forgotten that after smoking, obesity is the single most important risk factor for many common cancers, including of course breast cancer.

The importance of this relationship is again documented by Marian Neuhouser and colleagues in a paper published in JAMA Oncology.

The study examines the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up (about 13 years) in the Women’s Health Initiative (WHI) clinical trials, involving over 67,000 postmenopausal women ages 50 to 79 years at 40 US clinical centers..

Overall, 3388 invasive breast cancers were observed over the follow-up period with women who were overweight or obese having increased risk that was related to their degree of excess weight.

Compared to normal weight women, individuals with Class II and III obesity had a 60% greater risk for invasive breast cancer with an almost 2-fold greater risk for estrogen receptor–positive and progesterone receptor–positive breast cancers.

Class II and III obesity was also associated with a 2-fold greater risk for larger tumor size, positive lymph nodes and deaths.

Furthermore, risk was increased in women with a baseline BMI of less than 25.0 who gained more than 5% of body weight over the follow-up period.

Given this importance of obesity for breast cancer, one can only wonder just how much of the Cancer research funding raised by the Pink Ribbon campaign and other Cancer charities, finds its way into research on obesity treatment and prevention – can’t say I know of any cancer funding that has knocked on the doors of my fellow obesity researchers.

@DrSharma
Edmonton, AB

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An Update On Non-Alcoholic Fatty Liver Disease

Fatty Liver

Fatty Liver

Of all of the common complications of obesity, fatty liver disease is perhaps the most insidious. Often starting without clinical symptoms and little more than a mild increase in liver enzymes, it can progress to inflammation, fibrosis, cirrhosis and ultimate liver failure. It can also markedly increase the risk for hepatocellular cancer even in patients who do not progress to cirrhosis.

Now, a paper by Mary Rinella from Northwestern University, Chicago, published in JAMA provides a comprehensive overview of what we know and do not know about early detection and management of this condition.

The findings are based on a review of 16 randomized clinical trials, 44 cohort or case-control studies, 6 population-based studies, and 7 meta-analyses.

Overall between 75 million and 100 million individuals in the US are estimated to have nonalcoholic fatty liver disease with 66% of individuals older than 50 years with diabetes or obesity having nonalcoholic steatohepatitis with advanced fibrosis.

Although the diagnosis and staging of fatty liver disease requires a liver biopsy, biomarkers (e.g. cytokeratin 18) may eventually help in the detection of advanced fibrosis.

In addition, non-invasive imaging techniques including vibration-controlled transient elastography, ultrasound with acoustic radiation force impulse or even magnetic resonance elastography are fairly accurate in the detection of hepatic fibrosis and are the most reliable modalities for the diagnosis of advanced fibrosis (cirrhosis or precirrhosis).

 

Currently, weight loss is the only proven treatment for fatty liver disease. Pharmacotherapy including treatment with vitamin E, pioglitazone, and obeticholic acid may also provide some benefit (none of these treatments currently are approved for this indication by the UD FDA). Futhermore, the potential benefits of existing and emerging anti-obesity treatments on the incidence and progression of fatty liver remains to be established.

As Rinella points out,

“It is important that primary care physicians, endocrinologists, and other specialists be aware of the scope and long-term effects of the disease.”

Clearly, screening for fatty liver disease needs to be part of every routine work up of individuals presenting with excess weight.

@DrSharma
Edmonton, AB

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Does Childhood Obesity Prevention Only Work In Rich Kids?

sharma-obesity-pima-indian-kidsRecent publications suggest that the increase in childhood obesity seen in the US over the past several decades may finally be leveling off – an observation happily interpreted as a sign that not all is lost and that preventive measures may be working.

However, as a paper by Ashlesha Datar and Paul Chung, just published in JAMA pediatrics, these findings may be misleading in that they hide the increasing disparities in the prevalence of childhood obesity across ethnic and social groups.

The authors analysed data from the Early Childhood Longitudinal Study kindergarten class (ECLS-K), consisting of two separate nationally representative cohorts recruited as kindergarteners during the 1998 to 1999 and 2010 to 2011 school years, which includes approximately 17,000 and 15,560 kindergarteners, respectively.

Between 1998 and 2010, with a nearly 20% overall increase in obesity prevalence, obesity decreased nonsignificantly for the highest quintile of socioeconomic class, increased nonsignificantly for the second-highest quintile, and increased significantly for the lowest three quintiles. The greatest increase was seen in non-Hispanic black kids.

Thus, the authors point out that not only have childhood obesity rates substantially increased during the time periods of this study, but also that this increase was accompanied by a substantial increase in socioeconomic disparities as obesity decreased in children with higher socioeconomic backgrounds but increased among children with lower socioeconomic backgrounds.

Perhaps our childhood prevention measures are not reaching the kids who need them the most?

@DrSharma
Edmonton, AB

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