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Limbic Effects On Physical Activity And Obesity

sharma-obesity-running-mouseThe amygdala is a part of the so-called limbic system that performs a primary role in the processing of memory, decision-making, and emotional reactions. The amygdala has also been implicated in a variety of mental health problems including anxiety, binge drinking and post-traumatic stress syndrome.

A study by Xu and colleagues, published in the Journal of Clinical Investigation now shows that in mice, activity of the estrogen receptor–α (ERα) in the medial amygdala may have a profound influence on the development of obesity – an effect, which appears to me largely mediated through effects on physical activity.

Building on previous work showing that ERα activity in the brain prevents obesity in both males and female rats, the researchers used a series of complex experiments to demonstrate that specific deletion of the ERα gene from SIM1 neurons, which are highly expressed in the medial amygdala, cause a marked decrease in physical activity and weight gain in both male and female mice fed with regular chow, without any increase in food intake. In addition, this deletion caused increased susceptibility to diet-induced obesity in males but not in females.

Deletion of the ERα receptor also blunted the body weight-lowering effects of a glucagon-like peptide-1-estrogen (GLP-1-estrogen) conjugate.

In contrast, over-expression or stimulation of SIM1 neurons increased physical activity in mice and protected them from diet-induced obesity.

These findings point to a novel mechanism of neuronal control of physical activity, which in turn appears to have important effects on the susceptibility to weight gain.

@DrSharma
Edmonton, AB

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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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Do Genetics Explain Variability in Weight-Loss Response to Liraglutide?

sharma-obesity-dna_molecule9As with any medication (for anything!) not everyone responds the same.

Now a small study by Mojca Jensterle and colleagues from Ljubljana, published in the European Journal of Clinical Pharmacology, reports that genetic variability in the GLP-1 receptor gene may predict the variability to the human GLP-1 analogue liraglutide, now approved for obesity treatment in the US, Canada and Europe.

In their study, Jensterle and colleagues examine the realationship between two common alleles (variants) of the GLP-1 receptor in 57 women with obesity and polycystic ovary syndrome.

All women were treated with liraglutide 1.2 mg QD s.c (well under the 3.0 mg QD dose approved for obesity treatment) for 12 weeks.

Twenty of the participants were classified as strong responders (>5% weight loss), who lost about 7.4 Kg, whereas 37 were considered poor responders losing only 2.2 Kg.

Carriers of at least one rs10305420 allele were about 70% less likely to be a high responder than individuals with two wild-type alleles. Similarly, carriers of at least one rs6923761 allele were about three times as likely to high responders compared to homozygous carriers of the wild type.

Although my previous work in these type of genetic studies have made me highly critical (not to say sceptical) of these types of small studies, the notion that genetic variability in the GLP-1 receptor (the molecular target of liraglutide) may well lead to differences in response is not all that far fetched.

Thus, whether true or not, I have little doubt that indeed much of the variability in pharmacological response to liraglutide (or for that matter any other drug for anything) may well be determined by genetics.

Whether testing people for genetic markers before starting a specific treatment will ever become reality for obesity and whether or not, the genetic variability seen in this study will still be seen when lirglutide is used at the actual dose approved for obesity treatment remains to be seen.

In the meantime, the easiest way to see who responds and who does not is to try it. This why the regulatory approval of liraglutide for obesity comes with a simple stopping rule – if it doesn’t work for you – stop taking it!

@DrSharma
Edmonton, Alberta

Disclaimer: I have received consulting and speaking honoraria from Novo Nordisk, the maker of liraglutide.

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Childhood Cranial Radiation Therapy May Increase Obesity Risk in Adults

sharma-obesity-cancer-cellsAmong all of the possible factors that may contribute to obesity, one that is seldom discussed (and most people are largely unaware of) is surviving cancer.

While this is increasingly being appreciated in adults, data on childhood cancer survivors is rather sparse.

Thus, a study by Carmen Wilson and colleagues, published in Cancer, which follows the development of obesity in individuals treated for cancer as kids is of particular interest.

The study looks at 1996 cancer survivors who previously received treatment for cancer at a large Children’s Research Hospital, who survived ≥10 years from diagnosis (median age at diagnosis, 7.2 years; median age at follow-up, 32.4 years).

Interestingly, 47% of survivors, who received cranial radiation therapy developed obesity compared to only 30% of those who did not.

This risk was greatest in those who also received glucocorticoids or were the youngest at the time of treatment.

The researchers also found a significant modifying effect of genetic markers, some of which are known to be involved in neural growth, repair and connectivity.

Thus, this study shows that survivors of childhood cancer appear to be prone to developing obesity as adults particularly if they were treated with cranial radiation therapy and/or corticosteroids.

Clinicians should be aware of this increased risk and should consider measures to prevent excess weight gain in individuals with a history of childhood cancer.

@DrSharma
Edmonton, AB

ResearchBlogging.orgWilson CL, Liu W, Yang JJ, Kang G, Ojha RP, Neale GA, Srivastava DK, Gurney JG, Hudson MM, Robison LL, & Ness KK (2015). Genetic and clinical factors associated with obesity among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort. Cancer PMID: 25963547

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When Identical Twins Are Different

Professor Aila Rissanen, University of Helsinki, Finland

Professor Aila Rissanen, University of Helsinki, Finland

This year’s prestigious Fredrich Wassermann Award of the European Association for the Study of Obesity presented at the 22nd European Congress on Obesity goes to Helsinki’s Aila Rissanen, Europe’s grande dame of obesity research.

I have personally known Aila for as lo as I have been involved in obesity and there is much in her work and approach to obesity that has stimulated my own thoughts on this issue.

In her acceptance address, Aila chose to focus on her work in BMI-discordant twins (among the many topics she has worked on) due to the remarkable insights into the “natre-nurture” discussion that this model offers.

Indeed, it is extremely rare to find genetically identical twins, who differ in body weight (demonstarting just how highly heritable body weight actually is). Thus, body weight in identical twins is remarkably homogeneous not only because of the heritability of weight per se but also due to heritability of weight gain.

Cining the work of her wildly successful trainee Kirsi Pietilainen, Aila described the efforts it took to identify just 30 obesity discordant (weight difference of >10 Kg) identical twins from well over 500 identical twin pairs.

These discordant twin pairs have now been extensively phenotyped with every imaginable laboratory test, measurement and tissue biopsies.

The most consistent difference between the discordant twins appears to be a greater level of physical activity in the leaner twin, which appears to precede the onset of weight gain.  In addition to voluntary physical exertion, there also appears to be a significant difference in fidgeting between the twins.

Compared to their co-twins, the obese twins had greater pro-inflammatory lipid profiles, lower antioxident activity and higher pro-coagulation markers. The reasons for these differences remains unclear.

Finally, Aila provided a brief overview of some of the exciting work that is now going on to further study the differences between these genetically identical but obesity disparate twins – metabolomics, lipidomics, epigenomics and even bacteriomics.

Although any of this has yet to translate to better obesity prevention or management, you never know where these fundamental insights into human biology may lead you.

For know, this is certainly a space I intend to watch.

@DrSharma
Prague, Czech Republic

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