Arya M. Sharma, MD

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.

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

Yesterday, at the ongoing 2010 European Society of Cardiology, I attended as session focussing on the potential role of excess fat tissue that may surround blood vessels or the heart. Regular readers will recall, that the role of these fat depots have been a focus of my interest in past years.

A new study by Olga Lamacchia and colleagues from the University of Foggia, Italy, published online in Nephrology Dialysis and Transplantation, suggests that increased fat deposition around the kidneys may also pose a risk marker for the development of chronic kidney disease in patients with type 2 diabetes.

The researchers performed a cross-sectional study in 151 patients with type 2 diabetes that included measurements of kidney function, blood flow and ultrasound assessment of the fat surrounding their kidneys.

Despite adjustment for both BMI and waist circumference, the amount of para- and perirenal fat predicted increases in renal resistance index and reduced glomerular filtration rate.

Furthermore, in subjects with waist circumference above the diagnostic values of metabolic syndrome kidney function significantly and progressively declined across tertiles of para- and perirenal fat thickness.

As explanations for this phenomenon, the authors discuss the potential role of increased intra-abdominal pressure of visceral obesity, direct physical compression of the kidneys, or mechanisms related to the secretion of adipokines and other factors by the surrounding fat tissue that may affect kidney function.

For anyone familiar with kidney anatomy, it may also be of interest to recall that as fat deposition grows within the renal sinus, compression of various renal structures, especially of the inner medulla that, unlike the entire kidney, is not protected by the fibrous capsule, may occur. Increases in renal interstitial fluid hydrostatic pressure tends to compress the medullary vasa recta and tubules, reducing blood and tubular flow through the distensible loop of Henle, which could ultimately result in greater fluid, sodium and urate reabsorption.

As my colleagues and I have previously suggested for epicardial fat, the authors suggest that measurement and recording of peri-renal fat should perhaps also be part of routine renal ultrasound assessments.

Although this recommendation, may be a bit premature, the study nevertheless adds to the continuing literature demonstrating that in obesity and the accumulation of excess fat it is not just the “how much” but rather the “exactly where”, that ultimately determines the development of certain weight-related health problems.

AMS
Stockholm, Sweden

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Lamacchia O, Nicastro V, Camarchio D, Valente U, Grisorio R, Gesualdo L, & Cignarelli M (2010). Para- and perirenal fat thickness is an independent predictor of chronic kidney disease, increased renal resistance index and hyperuricaemia in type-2 diabetic patients. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association PMID: 20798120

Okay, I just couldn’t resist this headline - I hope my female readers will forgive this tongue-in-cheek title after they read the rest of the story.

The acronym “SWAN” simply refers to the Study of Women’s health Across the Nation (SWAN) Fat Patterning Study, results of which are now published in a paper by Imke Janssen and colleagues from the Rush University Medical Centre in Chicago, in this month’s issue of OBESITY.

This study examined the relationship between the male hormone testosterone and the accumulation of visceral fat (VF) in 359 women (47.2% black), aged 42-60 years randomly selected from the community. VF was measured using computer tomography.

Bioavailable testosterone levels were strongly associated with the amount of VF independent of age, race, percent total body fat, and other cardiovascular risk factors.

This study suggests that the previously described tendency for women to develop visceral adiposity as they go through menopause is probably related to an increase in biologically active testosterone levels that happens during the menopausal transition.

As readers of these postings are probably well aware, male-pattern abdominal or belly fat deposition is a strong risk factor for the development of diabetes, hypertension, and other cardiometabolic risk factors. In contrast, female-pattern or lower-body obesity appears to be less dangerous and has even been associated with reduced risk of metabolic disease.

This study links the increased bioavailability of the male hormone testosterone to the change in fat patterning observed during menopause.

Interestingly, these higher levels of bioavailable (or bioactive) testosterone after menopause are not due to an increase in testosterone production but rather due to a decrease in sex-hormone binding-globulin (SHGB), possibly resulting from the menopausal decline in estrogen levels (a powerful stimulator of SHBG).

(SHBG, as the name implies, normally binds testosterone, thereby rendering it biologically inactive - the less SHBG there is to bind testosterone, the more free testosterone there is around to do its thing)

Of course, as a cross-sectional study, it is not possible to completely rule out the fact that other factors may lead to the accumulation of visceral fat, which in turn may lead to hormonal changes like higher insulin levels, which can also reduce SHBG levels.

However, given the fact that fat precursor cells are known to have androgen (testosterone) receptors, the testosterone hypothesis certainly merits consideration.

Whatever the precise mechanism, it certainly appears that menopause increases the risk of visceral fat accumulation and thus brings women closer to the cardiometabolic risk profile normally seen in men.

AMS
Edmonton, Alberta

Regular readers are certainly familiar with my many posts on the limitations of BMI and on the idea that not all fat is bad and that different fat depots may have quite different effects on cardiometabolic risk.

You can now find much more on this topic in a comprehensive review article by Konstantinos Manolopoulos and colleagues at Oxford University, UK, published in this month’s issue of the International Journal of Obesity.

The review not only concludes that there is now ample evidence to support the notion that not just the amount of body fat, but rather its distribution is an important determinant of the metabolic and cardiovascular risk associated with obesity. In fact there is now increasing evidence that being too skinny may well be bad for you and that carrying a few extra pounds of fat on your hips and thighs may actually be protective.

Thus, studies show that increased hip and thigh fat is independently associated with protective lipid and glucose profiles. This protective effect may be in part due to the fact that gluteofemoral fat can absorb and store excess fatty-acids, thereby removing them from the circulation. In addition, leptin and adiponectin levels tend to be positively associated with gluteofemoral fat while the level of inflammatory cytokines is negatively associated.

As the authors point out, the loss of gluteofemoral fat, as observed in Cushing’s syndrome and lipodystrophy is in fact associated with an increased metabolic and cardiovascular risk.

This may not be good news for people seeking medical help to reduce the size of their hips and thighs - I would probably have to advise them against it - definitely not a message many of my patients want to hear.

On the other hand, if the excess fat is largely located around your midsection, then, this excess “belly” fat is probably the biggest driver of your risk for type 2 diabetes and heart disease.

So really, not much new for regular readers of my blog, but certainly a noteworthy article that nicely summarizes what is currently known about this issue.

Wonder what it’ll take to make large butts and thighs more socially acceptable?

AMS
Edmonton, Alberta