Regular readers will know that obesity is the major driver of the world-wide diabetes epidemic. But not everyone who is overweight will ultimately get diabetes.

So why do some people with excess fat become diabetic while others don’t?

Since the discovery that some people show marked signs of inflammation in their fat depots, researchers have suggested that this chronic inflammation may cause fat cells to produce molecules that promote diabetes and other metabolic complications (this has been referred to as metainflammation).

A new study by John Wentworth and colleagues from the Walter and Eliza Hall Institute of Medical Research, Victoria, Australia, published in last month’s edition of DIABETES, shows that pro-inflammatory cells found in adipose tissue may promote insulin resistance and thereby increase the risk for diabetes.

The researchers examined white blood cells (macrophages) isolated from adipose tissue samples obtained from lean and obese women undergoing bariatric surgery.

In obese women, the density of activated CD11c(+) macrophages was greater in subcutaneous than omental adipose tissue and correlated with markers of insulin resistance.

Furthermore, the researchers showed that these CD11c(+) macrophages not only metabolize lipids and may initiate immune responses but also secrete substances that impair insulin-stimulated glucose uptake by human adipocytes.

The authors conclude that these pro-inflammatory CD11c(+) macrophages in adipose tissue may serve as of insulin resistance and may explain why some people may develop diabetes in response to obesity.

Obviously, the paper does not answer the question why some people are more likely to accumulate these pro-inflammatory cells in their fat tissues. For one thing, it is clearly not simply related to the amount of fat, as some people with substantial amounts of excess fat can go their entire lives without ever developing diabetes.

On the other hand, some people appear to be particularly prone to showing signs of inflammation with weight gain and for them the difference of a few pounds of extra fat can mean the difference between having and not having diabetes.

Perhaps, one day, targeting the inflammation in adipose tissue may prove a novel way to prevent and treat diabetes associated with excess weight.

AMS
Edmonton, Alberta

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Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, Wabitsch M, O’Brien PE, & Harrison LC (2010). Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes, 59 (7), 1648-56 PMID: 20357360

Brown Fat Cells in White Fat Tissue

Regular readers of these pages will recall previous posts on the role of brown fat tissue and its potential role in the prevention of weight gain. This tissue, helps burn excess calories by directly converting them into heat - people with more brown fat may be less likely to become obese (click here for TV interview with me discussing this finding).

One of the prime stimulators of brown fat formation is increased sympathetic activity that is mediated through beta receptors - but how does this signal cause fat cells to become brown (incidently, the brown colour is due to the presence of large amounts of calorie-burning mitochondria in these cells).

In a paper published last week in Science, Alexandros Veglopoulos and colleagues from the German Cancer Research Center in Heidelberg, identify a key enzyme in the formation of brown fat cells.

This enzyme turns out to be COX-2 (Cyclooxygenase-2), a well-known rate-limiting enzyme in prostaglandin synthesis.

Because prostaglandins also play an important role in pain and inflammation, inhibitors of COX-2 (including aspirin and ibuprofen) are commonly used to treat pain and inflammation.

As the researchers showed in their experiments in mice, overexpression of COX-2 in white adipose tissue induced de novo formation of brown fat cells in this tissue with an increase in systemic energy expenditure.

More importantly, perhaps, this increased activity of COX-2 also protected these mice against high-fat diet-induced obesity. The body weight of these animals was 20 percent lower than that of normal animals.

Thus, COX-2 appears integral to de novo BAT recruitment, suggesting that the PG pathway regulates systemic energy homeostasis.

Does this mean that taking pain medications which block COX-2 may lead to weight gain?

This is probably very unlikely because most adults (especially if older) have little brown adipose to start with. Furthermore, to my knowledge, weight gain does not appear to be a typical side effect of these medications.

Once again, the leap from mice to men may not be that straightforward. Rodents generally tend to have far more brown adipose tissue and I would like to see some of these studies replicated in human adipose tissue or (even better) humans.

Clearly the statement of Stephan Herzig, senior author of the paper, envisioning the removal of fat tissue from obese individuals, inducing it to produce more prostaglandins in a test tube, and then transplanting it back so that it can help burn calories, may well be a bit premature.

Nevertheless, understanding more about the biology of brown adipose tissue can certainly open the road to novel obesity treatments in the foreseeable future.

AMS
Edmonton, Alberta

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Vegiopoulos A, Müller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A, Diaz MB, Rozman J, Hrabe de Angelis M, Nüsing RM, Meyer CW, Wahli W, Klingenspor M, & Herzig S (2010). Cyclooxygenase-2 Controls Energy Homeostasis in Mice by de Novo Recruitment of Brown Adipocytes. Science (New York, N.Y.) PMID: 20448152

Yesterday, I attended the annual Spring Meeting of CANNeCTIN (Canadian Network and Centre for Trials Internationally), a national network funded by the CIHR/CFI Clinical Research Initiative program to improve the prevention and treatment of cardiac and vascular diseases and diabetes.

CANNeCTIN is jointly led by Dr. Salim Yusuf, from Hamilton Health Sciences and McMaster University, and Dr. John Cairns, from the University of British Columbia. CANNeCTIN facilitates the development, conduct and leadership of large international clinical trials, registries and epidemiologic studies across Canada and the world.

As it so happens, yesterday, also saw the online publication in Diabetes Care of a paper I was involved in during my time in Hamilton on the ethnic variation of risk factors associated with obesity.

In this paper, we looked at the relationship between body weight (BMI), adipokines, and insulin resistance in 1,176 South Asian, Chinese, Aboriginal, and European Canadians in the SHARE study (Study of Health Assessment and Risk in Ethnic groups).

Adjusted mean adiponectin (a protein secreted by fat cells that improves insulin sensitivity) concentration was significantly higher in Europeans [12.9] and Aboriginals [11.8] compared to South Asians [8.8] and Chinese [8.5].

Serum leptin levels were also significantly higher in South Asians [11.8] and Aboriginals [11.1] compared to Europeans [9.2] and Chinese [8.3].

BMI and waist circumference were inversely associated with adiponectin in every group except the South Asians.

The increase in HOMA-IR (a measure of insulin resistance) for each given decrease in adiponectin was larger among South Asians and Aboriginals compared to Europeans.

Interestingly, a high glycemic index diet was associated with a larger decrease in adiponectin among South Asians and Aboriginals, and a larger increase in HOMA-IR among South Asians relative to other groups.

This study clearly shows that South Asians have the least favourable adipokine profile of the studied ethnic groups, and like the Aboriginal people, display a greater increase in insulin resistance with decreasing levels of adiponectin.

The reasons for these differences are not clear but we are studying possible mechanisms to explain these findings in South Asians in a “molecular” version of this study.

AMS
Hamilton, Ontario

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Mente A, Razak F, Blankenberg S, Vuksan V, Davis AD, Miller R, Teo K, Gerstein H, Sharma AM, Yusuf S, Anand SS, & for the SHARE, SHARE-AP investigators (2010). Ethnic variation in adiponectin and leptin levels and their association with adiposity and insulin resistance. Diabetes care PMID: 20413520

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

Obesity is often described as a state of low grade inflammation. Activated macrophages (white blood cells) in adipose tissue play an important role in this inflammatory response by secreting a number of pro-inflammatory molecules (cytokines) that can promote the development of insulin resistance and other complications of obesity.

Previous studies have shown that the “glitazone” class of antidiabetic agents can suppress inflammatory macrophage activation and can also increase the expression of an DGAT1 (triacylglycerol (TG) synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1), an enzyme that makes it easier for fat cells and macrophages to store excess fat.

Now a paper by Suneil Koliwad and colleagues from the Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA, published in this weeks’ issue of the Journal of Clinical Investigation, provides further evidence that increasing activity of DGAT1 in adipocytes and macrophages may protect animals from the pro-inflammatory effects of obesity.

The researchers found that although mice overexpressing DGAT1 in both macrophages and adipocytes were more prone to weight gain, they did not show signs of the inflammatory response commonly seen with diet-induced obesity.

Through a series of experiments, the researchers were able to establish that DGAT1 is indeed necessary to protect against this inflammatory response, thereby raising the question of wether stimulation of this enzyme may also protect against the complications of obesity in humans.

Thus, although this research may not lead to new ways of preventing or reducing obesity, it may open new avenues for attenuating some of the health consequences related to excess weight.

AMS
Copenhagen, Denmark