Arya M. Sharma, MD

Klinikum Benjamin Franklin, Charite, Berlin

Continuing in my series of past publications on obesity, today’s post is special, because it is about an event that ‘officially’ launched my shift from hypertension into obesity research and for the first time made some of the leading obesity researchers of the time aware of my very existence.

Back in 1998, I had already well-established myself in the hypertension field, being widely recognized as an expert on salt-sensitive hypertension. I was already being invited to speak at various hypertension meetings around the world and was nationally and internationally recognized for this work.

However, it would be fair to say that despite having published a few minor papers on obesity, no one in the obesity arena had ever heard of me. This was by no means surprising as, having attended a few obesity conferences by then, it was evident that few hypertension researchers interacted with obesity researchers and vice versa. Apparently, no one had yet thought of bringing the two research communities together - surprising perhaps, given the fact that obesity is the most common and powerful risk factor for hypertension.

So, perhaps for the first time demonstrating my potential talent as a ‘networker’, I decided to organize the 1st International Symposium on Obesity and Hypertension (ISOH), to which I rather cheekily ventured to invite some of the most distinguished researchers from the obesity field - cheeky, because these folks had certainly never heard of me and I was not offering any honoraria or expensive airplane tickets. I just looked for big names in obesity on the internet and sent out the invitations.

Little would I have imagined that I would assemble a roster of cutting edge ‘big names’ from both the hypertension and obesity communities for a tightly packed two day event in Berlin.

To my lay readers, the names may mean nothing, but to my professional colleagues, the following list probably reads like a ‘who-is-who’ of obesity.

W. P. T. James (Chairman, International Obesity Task Force, Aberdeen, UK) presented new data suggesting that obesity-associated comorbidity may increase rapidly in non-Caucasians with a body mass index as low as 18 kg/m2.

M. E. J. Lean (Department of Human Nutrition, University of Glasgow, UK) presented new data indicating that waist circumference (measured midway between the lowest rib and the iliac crest) is the best clinical marker of intraabdominal fat accumulation and that risks are high enough to warrant professional guidance with a waist over 102 cm in men or 88 cm in women.

R. Negrel (Centre de Biochimie, UMR6543CNRS & IFR349, Faculty of Sciences, Nice, France) and G. Löffler (University of Regensburg, Institute of Biochemistry, Regensburg, Germany), who provided convincing evidence on the presence of the renin-angiotensin system in adipose tissue.

D. L. Crandall (Wyeth Ayerst Research, Radnor, PA, USA) presented a comprehensive review, inncluding historical review of the classical experiments that identified early hemodynamic changes observed in obesity and the important role of neovascularization for the growth and development of adipose tissue.

H. Hauner (Diabetes Research Institute at the University of Düsseldorf, Germany) stressed the point that stromal cells from adipose tissue can undergo differentiation in the presence of defined adipogenic factors, including a variety of hormones and cytokines.

T. Unger (Institute for Pharmacology, Christian-Albrechts University of Kiel, Germany) presented evidence that the AT1 and AT2 angiotensin receptors may play an important role in the growth and development of a variety of tissues, including cardiac, endothelial, and neuronal cells.

F. C. Luft (Franz Volhard Clinic and Max Delbrück Center, Humboldt University of Berlin, Germany) presented the results of linkage analysis in an Arab pedigree with familial hypercholesterolemia in which heterozygous persons with normal LDL levels were identified.

T. W. Kurtz (University of California, San Francisco, CA, USA) and M. Pravenec (Czech Academy of Sciences, Prague, Czech Republic) presented data indicating that a Cd36 Mutation in some strains of spontaneously hypertensive rat may be associated with insulin resistance in these strains.

X. Jeunemaitre (INSERM U36, College de France, Paris, France) provided new evidence indicating that several polymorphisms located in the 5’ region and in the first intron of the angiotensinogen gene may contribute to the variability of plasma angiotensinogen levels.

M. L. Tuck (Veterans Administration Medical Center, Sepulveda, CA, USA) presented an up-to-date review on the role of the systemic renin-angiotensin system in obesity-related hypertension.

A. Natali (Department of Internal Medicine, University of Pisa, Italy) discussed the role of insulin resistance in obesity-related hypertension and provided data that suggesting that the sympatho-adrenergic system plays an important role in the development of obesity hypertension.

W. G. Haynes (Department of Internal Medicine, University of Iowa, Iowa City, USA), who discussed the important role of leptinergic and melanocortin influences on the sympathetic nervous system in obesity-related hypertension.

G. Seravalle (Clinica Medica, University of Milan, Italy) studied the effects of the acute blockade of corticotropin-releasing hormone (CRH) secretion induced by dexamethasone (DEX) on the sympathoexcitatory response elicited by insulin.

A. D. Strosberg (Institut Cochin de Génétique Molèculaire, Paris, France) discussed the potential role of beta-3 adrenergic receptors in the development of obesity.

S. L. H. Schiffelers (NUTRIM, Department of Human Biology, Maastricht University, Maastricht, The Netherlands) on the effects of beta 1- and beta 2-adrenoreceptors–stimulated thermogenesis and fat oxidation in lean and obese men.

S. Rössner (Huddinge University Hospital, Sweden) presented the first clinical data on a new lipase inhibitor orlistat which reduces the absorption of dietary fat by 30% and reduces weight and blood pressure.

R. Donelly (University of Nottingham, Division of Cardiovascular Medicine, Nottingham, UK) reviewed the pharmacological treatment of obesity-related hypertension.

P. G. Kopelman (St. Bartholomew’s Hospital and The Royal London School of Medicine, University of London, UK) provided an outlook of the management problems that will become apparent in the early part of the 21st century.

With this roster of leading experts, it was perhaps not surprising that we attracted over 150 attendees from over 30 countries to his ‘impromptu’ meeting.

It turns out that this was to be only the first of a total of four ISOH meetings, the last held in 2005, by which time I had not only made a name for myself in obesity (having been appointed to a Tier 1 Canada Research Chair in Cardiovascular Obesity Research and Management at McMaster University in 2002), but had also managed to build professional and personal relationships around the world that last to this day.

I also learnt important lessons that formed the very basis for eventually creating the Canadian Obesity Network, now with almost 7,000 members, by far the largest national professional obesity association in the world.

For those, who would like to read more about the symposium, the proceedings were published in Kidney and Blood Pressure Research in 2000.

For anyone who may have attended the event (or any of the subsequent ISOH meetings), I’d love to hear about your recollections of these Symposia.

AMS
Edmonton, Canada

Sharma AM, Distler A, & Hauner H (2000). International symposium on obesity and hypertension genetics and molecular mechanisms. Genetics and molecular mechanisms Kidney & blood pressure research, 23 (1), 49-72 PMID: 10567854

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Prof. Winfried Siffert, Universität Duisburg-Essen, Germany

Continuing in my series of revisiting some of the obesity research I was involved in, here is a paper to which I contributed a fairly significant number of DNA samples from my patients.

The paper, published in the Journal of the American Society of Nephrology in 1999, examined the relationship between obesity and a common genetic variant of the gene encoding the ß3 subunit of G protein, a molecule involved in transmitting chemical signals from outside a cell to the cell inside (though G-protein-coupled receptors).

G proteins regulate metabolic enzymes, ion channels, transporters, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate systemic functions such as embryonic development, learning and memory, and homeostasis.

The lead researcher on this project, Winfried Siffert, had just shown that the 825T allele of the GNB3, associated with the occurrence of a splice variant, termed Gß3-s (which, despite a deletion of 41 amino acids, is functionally active in a reconstituted system), was more common in individuals with high blood pressure.

This study explored the possible association with obesity in young male Germans (samples that I contributed), Chinese, and black South Africans with low, intermediate, and high 825T allele frequencies, respectively.

It turned out that in each of these three distinct cohorts, the 825T allele frequency was significantly higher in overweight and obese individuals compared to those with normal weight.

Thus, the 825T allele frequencies in these three BMI groups were, respectively, 29.5, 39.3, and 47.7% in Germans, 46.8, 53.9, and 58.6% in Chinese, and 83.1, 87.7, and 90.9% in South Africans. In each of these three distinct groups, the 825T allele was significantly associated with obesity with odds ratios between 2 and 3.

The paper also presents the results of genotyping of 5254 individuals from 55 native population samples from Africa, the Americas, Europe, Asia, Australia, and New Guinea showing the highest 825T allele frequencies in black Africans (82%) and intermediate values in east Asians (47%).

This finding prompted us to suggest that “high frequencies of the 825T allele in Africans and Asians may contribute to an obesity and hypertension epidemic if Westernization of lifestyles continues”.

While in hindsight, again, the notion, that a single genetic variant (no matter how common or functionally important) could even begin to explain increased general risk of such a complex multifactorial condition like obesity, may appear naive and it is therefore perhaps no surprise that this genetic variant never turned out to the the definitive “genetic marker” of obesity, at the time, this work did stimulate a lot of interest in the potential role of genetic variants in these important signalling proteins in complex medical conditions like obesity, hypertension and even a few mental health disorders.

According to Google Scholar, this paper has been cited 317 times.

AMS
Edmonton, Alberta

Siffert W, Forster P, Jöckel KH, Mvere DA, Brinkmann B, Naber C, Crookes R, Du P Heyns A, Epplen JT, Fridey J, Freedman BI, Müller N, Stolke D, Sharma AM, Al Moutaery K, Grosse-Wilde H, Buerbaum B, Ehrlich T, Ahmad HR, Horsthemke B, Du Toit ED, Tiilikainen A, Ge J, Wang Y, & Rosskopf D (1999). Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. Journal of the American Society of Nephrology : JASN, 10 (9), 1921-30 PMID: 10477144

Dr. med. Jens Ringel

Since my first publication in 1987, I have authored or co-authored well over 300 peer-reviewed papers, about half of which are on topics related to obesity. This year, I thought I would dedicate my Saturday posts to reviewing some of these papers and sharing the stories behind them. If nothing else, it may point readers to some of the topics that have found my interest me over the years.

The first of my obesity papers to come up in a PubMed search is that of my MD-doctoral student Jens Ringel, published in Biochem Biophys Res Commun (1999), looking at a common genetic variant of the peroxisome proliferator activated receptor-gamma (PPARg), a nuclear receptor, that regulates adipocyte differentiation and possibly lipid metabolism and insulin sensitivity.

In this study, we specifically examined the allelic frequencies of the missense C –> G mutation at codon 12 of this gene, which results in the substitution of proline with alanine (Pro12Ala) in subjects with type 1 (n = 522) and type 2 (n = 503) diabetes compared to that in healthy controls (n = 310) and found no differences between these groups. There was also no significant relationship between dyslipoproteinemia or obesity and the PPARg Pro12Ala genotype.

Thus, these findings did not support the hypothesis that this genetic variant is strongly associated with diabetes, obesity, or dyslipidemia in patients with type 1 or type 2 diabetes mellitus and we concluded that this genetic marker is therefore unlikely to serve as a clinically useful predictor of these disorders in Caucasian patients with diabetes mellitus.

In hindsight such an assumption may appear rather naive, given that today we know that it takes far larger sample sizes (10s of thousands of subjects) and far more sophisticated analyses to stand even a remote chance of identifying genes for complex diseases. But back in 1999, when this paper was published, many of us were churning out papers looking at single nucleotide polymorphisms (SNPs) of candidate genes in a few hundred samples.

According to Google Scholar, this paper has been cited 134 times, so I guess someone did find this study of interest after all.

AMS
Edmonton, Alberta

Ringel J, Engeli S, Distler A, & Sharma AM (1999). Pro12Ala missense mutation of the peroxisome proliferator activated receptor gamma and diabetes mellitus. Biochemical and biophysical research communications, 254 (2), 450-3 PMID: 9918859

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Nobel Laureate Dr. Olivers Smithies and Arya Sharma, Edmonton, Oct 2011

Last night, I had the pleasure of dining with Dr. Oliver Smithies, recipient of the 2007 Nobel Prize for Medicine, which he received jointly with Mario R. Capecchi and Sir Martin J. Evans “for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells”.

I have previously met Dr. Smithies, several years ago, when I was still active in hypertension research - at that time Dr. Smithies, who continues to work on (among many other topics) hypertension, had just targeted the renin-angiotensin system in mice.

Dr. Smithies is visiting the University of Alberta and will be speaking today at 4.00 pm “On Being a Basic Scientist for 60 Years” at the University Hospital Bernard Snell Hall.

During dinner, Dr. Smithies proved a most entertaining guest. Some of the lesser known details of his remarkable biography include the fact that he dropped out of medical school (Oxford), learnt to fly at age 50 on Toronto Island Airport and for almost 20 years held the world record for the shortest flying time for a single engine aircraft across the Atlantic from Goose Bay, Labrador, to Rekjavik, Iceland.

Other interesting ‘trivia’ included the fact that he invented starch electrophoresis (for protein sieving). He describes this episode in his autobiography as follows:

“Finding the best variety of starch and how to process it for making the gels became necessary when my supplier’s stock of processed starch was exhausted. Many hours were spent in testing all the raw starches that I could buy, and then in grocery stores finding potatoes from Holland Marsh, New Brunswick, Prince Edward Island and Idaho from which to make the raw starch. None gave as good gels as those made from my first batch. I eventually found out why: my original supplier had purchased starch processed by a second company that had used raw starch imported by a third company from Denmark because of an attack of potato blight in Canada!”

Dr. Smithies continues to work full time as Professor at the University of North Carolina and had to hurry back to his hotel room after dinner to work on a grant that is due for submission on Friday.

Dr. Smithies is 86!

It was certainly a most entertaining evening and I can only encourage anyone in Edmonton to show up for what I know will be a most remarkable talk from a most remarkable researcher and human being!

AMS
Edmonton, Alberta

Yesterday, I blogged about the rather weak relationship between BMI and health risks in the Manitoba Centre for Health Policy (MCHP) Report on Adult Obesity, and suggested that the results may have looked very different had the same data been analysed using the Edmonton Obesity Staging System.

Today, I want to address another interesting finding of this report, namely, the researcher’s attempts to identify the ’causes’ of obesity in Manitoba.

Variables examined included age, sex, marital status, education, employment, household income, activity restrictions, occupational physical activity, self-perceived life stress, satisfaction with life, self-rated mental health, sense of community, eating fruits and vegetables, physical activity leisure and travel, sedentary activities, current smoking, binge drinking, recent changes to improve health, food insecurity, and regular doctor.

Among these, location of residence, age, sex, education, employment, and marital status were particularly strong predictors of excess weight.

Interestingly, the psychological variables had little additional ‘effect’.

leisure– and travel–time activity level was the most strongly associated variable and showed a dose–response relationship—higher levels of activity were associated with lower likelihood of obesity. Other important variables were smoking (which was associated with a lower likelihood of obesity) and time spent in sedentary activities (more than 30 hours per week was associated with a higher likelihood of obesity).

Notably, only age and geography were significantly related to BMI values in youth.

Apart from the fact that such analyses cannot actually prove ‘causality’ as they are merely associated and therefore assumptions about modifying any of the modifiable variable will in fact reduce BMI, the researcher also made another notable observation:

“It is important to note that despite including many variables, this study was only able to explain a small amount of why people are obese. This means there are other reasons for the recent rises in weight, perhaps changes in our diets or our physical and social environment.”

Indeed, I would easily have predicted that factors not considered in this analysis, including parental BMI, birth weight, maternal weight at inception and birth of the participant, duration of sleep, etc. may well have accounted for some of the increase in obesity.

This should not detract from the importance of factors like sedentariness, stress, food insecurity and other variables that had some influence on obesity rates in this study.

It should, however, make us cautious in accepting the commonly held notion that the ‘root cause’ of obesity is simply increased sedentariness and eating too much.

Clearly, this is not the whole (and perhaps not even the biggest part) of this ’story’.

AMS
Edmonton, Alberta