Arya M. Sharma, MD

Prof. Raymond Négrel, Director of the Faculty of Sciences, University of Nice-Sophia Antipolis.

Following our 1999 report on the existence of a local renin-angiotensin system in human adipose tissue, we thought it appropriate to write a review on the now rapidly accumulating evidence from human and animal studies on the physiology and potential health-related effects of this system, especially in relationship to cardiometabolic problems (although this term had yet to coined).

So, in 2000, I invited Raymond Negrel from the Centre de Biochimie, Université de Nice-Sophia Antipolis, Nice, France, to join Stefan Engeli and myself in co-authoring this paper for HYPERTENSION.

At the time, renin-angiotensin system had already long been recognized as an important regulator of systemic blood pressure and renal electrolyte homeostasis. In addition, it had become evident that local renin-angiotensin systems in a wide range of tissues, including the heart, blood vessels, and the brain, may play a role in pathological changes of organ structure and function by modulating gene expression, growth, fibrosis, and inflammatory response.

With regard to the function of this system in adipose tissue, we reviewed the literature on the emerging evidence for a role in adipogenic differentiation and in the regulation of body weight.

We also discussed how such changes in adipose-tissue renin-angiotensin could affect systemic activity of this system, thereby influencing blood pressure.

We concluded our review by noting that:

“..future studies with more carefully described phenotypes are necessary to conclude whether obesity (by stimulation of adipogenic differentiation) and hypertension are associated with changes of renin-angiotensin system activity in adipose tissue. If so, the physiological relevance of this system in animal models and humans may warrant further interest.”

Stay tuned for future posts on this topic, as my lab began addressing some of these ideas in subsequent studies.

According to Google Scholar, this paper has 312 citations to date.

AMS
Edmonton, Alberta

Engeli S, Negrel R, & Sharma AM (2000). Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension, 35 (6), 1270-7 PMID: 10856276

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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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I am currently in Cambridge, UK, as part of the faculty of SCOPE (Specialist Certification of Obesity Professional Education), the official inter-professional educational program of the International Association for the Study of Obesity (IASO).

This year’s participants include a significant delegation from India, which is in the midst of its very own obesity epidemic.

While it is rare to see severe obesity (BMI levels over 40) in people of South Asian origin, there is now ample evidence suggesting that this population is particularly prone to the cardiometabolic complications of obesity even at a rather moderate increase in BMI.

In a study I co-authored with Sonia Anand and other colleagues from McMaster University, Hamilton, ON, published online today in PLoS one, we show that this increased risk may be attributable to adipocyte hypertrophy and increased ectopic fat deposition.

For this study, we recruited 108 healthy South Asians (defined as parents and grandparents who originated from India, Pakistan, Sri Lanka, or Bangladesh) and white Caucasians (ancestors originated from Europe) into one of three BMI strata: ≤25 kg/m2, 26–29 kg/m2, ≥30 kg/m2, matched for sex and age.

Measurements included body composition, adipocyte size, abdominal fat area (MRI studies), and hepatic adiposity (MRI-spectroscopy) were assessed and related to fasting glucose, insulin, lipids and adiponectin levels.

After adjustment for age, sex, and BMI, South Asians had more body fat, lower lean muscle mass, increased waist to hip ratio, less superficial subcutaneous abdominal adipose tissu, more deep/visceral to superficial adipose tissue ratio, and more liver fat than their Caucasian counterparts.

South Asians also had higher fasting insulin, lower HDL cholesterol, and lower adiponectin levels.

Most interestingly, fat cell size, measured as adipocyte area, was increased in South Asians compared to white Caucasians, and this difference in adipocyte size accounted for almost all of the observed differences in metabolic parameters and fat distribution.

Thus, this form of ‘ethnic’ lipodystrophy’ may well play an important role in the increased risk of South Asians even at lower BMI levels.

Although, this is a small cross-sectional study, the consistency of our findings with other reports in the literature, lead us to consider the following clinical implications:

1) Young, apparently healthy South Asians have greater metabolic impairment compared to white Caucasians who tend to develop metabolic changes at higher levels of obesity and at a more advanced age, supporting earlier screening for abdominal adiposity and elevated glucose among South Asians.

2) It is likely that the metabolic changes observed in South Asians may be prevented by avoiding chronic over nutrition, thereby preventing its consequences (including adipocyte hypertrophy, abdominal adiposity, and ectopic fat deposition).

3) It is also likely that adipocyte cell size and metabolic risk factors in South Asians could be reduced by treating obesity and/or by shifting fat deposition from ectopic sites to subcutaneous depots using pharmacologic agents (i.e. PPAR gamma agonists).

These findings obviously also apply to those of South Asian descent living in countries like Canada, where specific measurement and treatment guidelines may need to address the specific needs of this important visible minority.

AMS
Cambridge, UK

p.s. I’d like to personally thank the many participants in this trial, who volunteered their time and subjected themselves to a daunting battery of tests, including fat and muscle biopsies.

Obesity is characterised by the accumulation of excess fat but we have long known that the same amount of excess fat can have very different health effects on different people.

While some individuals with a higher BMI may appear metabolically healthy, others are prone to develop type 2 diabetes, dysplipidemia and other metabolic complications.

One of the consistent findings from biopsy studies has been that metabolically healthy obese individuals tend to have smaller (but larger numbers of) fat cells than their less healthy counterparts.

More recently, large fat cells have been associated with adipose tissue inflammation, now believed to play an important role in the development of the metabolic complications.

However, how exactly large fat cells mediate or augment adipose tissue inflammation is not clear.

A study by Kirsi Pietiläinen and colleagues from the University of Helsinki, Finland, just published in PLoS Biology, suggests a possible role for alterations in adipocyte membrane composition as a mediator of tissue inflammation.

In their studies, Pietiläinen and colleagues performed lipidomic analyses of human adipose tissue in twin pairs discordant for obesity as well as severely obese individuals with and without metabolic disease.

Their findings suggest that as adipocytes increase in size, the composition of their lipid membrane phospholipid composition changes in a manner that may make these cells more prone to triggering inflammatory pathways.

Thus, normal membrane function (fluidity and integrity) is maintained in the expanding adipose tissue at the expense of increasing its vulnerability to inflammation.

The researchers also used complex simulations and cell culture experiments to validate their findings.

Importantly, as the authors point out, these findings may open doors to using pharmacological and/or nutritional changes to influence adipocyte cell membrane composition and to thereby attenuate or inhibit adipose tissue inflammation and its metabolic consequences.

AMS
Edmonton, Alberta

As any clinician knows, patterns of fat deposition tend to vary greatly even in people with similar amounts of total body fat.

Not only are there the typical “male” and “female” patterns (commonly referred to as “apple” and “pear” shape) but there are also important differences in how much of excess fat is stored underneath the skin versus inside the abdomen or in other organs.

These patterns of fat distribution have important consequences for the health risks associated with excess fat - excess skin or subcutaneous fat tends to have little impact on cardiometabolic risk (some even claim it may be protective) whereas excess fat stored in muscle or internal organs are linked to a wide range of health problems like diabetes, fatty liver disease, or sleep apnea.

Why people differ in their propensity to deposit fat in these different locations is not entirely clear. Some of this is certainly regulated by sex hormones and cortisol but it has long been suspected that there may also be genetic factors at play.

In a rather surprising twist, this notion is now supported by a paper just published in PLoS one by Kyung-Tai Lee and colleagues from the National Institute of Animal Science in Suwon, North Korea.

Based on previous studies that showed a high heritability for backfat thickness (between 50% and 70%) and intramuscular fat (38% and 67%) content in pigs, Lee and colleagues first sequenced a region of pig chromosome 6 that had been shown to affect fatness traits in these animals.

This led to the identification of 13 genes, 8 of which are interestingly also involved in psychiatric disorders and can affect nerve growth and function. All of these genes appeared to be related to back fat thickness (i.e. excess skin fat) rather than to muscle fat.

The researchers next examined the relationship between markers of these genes and skin fat thickness in a cohort of 8,842 Korean individuals. Surprisingly 8 of the same genes that were associated with back fat in pigs were also associated with skin fat thickness in this population. (For expert readers, the 8 neuronal genes responsible for subcutaneous fat thickness were: NEGR1, SLC44A5, PDE4B, LPHN2, ELTD1, ST6GALNAC3, ST6GALNAC5, and TTLL7).

From these studies the researchers conclude that common variations in these neuronal genes may surprisingly determine not only the genetic risk for obesity but also play an important role in the development of excess skin fat.

How exactly these genes regulate skin fat will certainly now be the focus of intense research.

To clinicians, these studies should serve as a reminder that the regulation and function of fat tissue is staggeringly complicated and fascinating.

Clearly fat distribution is not just a function of calories in and calories out.

AMS
Edmonton, Alberta

Lee KT, Byun MJ, Kang KS, Park EW, Lee SH, Cho S, Kim H, Kim KW, Lee T, Park JE, Park W, Shin D, Park HS, Jeon JT, Choi BH, Jang GW, Choi SH, Kim DW, Lim D, Park HS, Park MR, Ott J, Schook LB, Kim TH, & Kim H (2011). Neuronal genes for subcutaneous fat thickness in human and pig are identified by local genomic sequencing and combined SNP association study. PloS one, 6 (2) PMID: 21311593