Arya M. Sharma, MD

Regular readers may recall that recently brown adipose tissue, long thought to be only present in new born infants, is also present in varying amounts in human adults.

Furthermore, variations in the amount of brown adipose tissue, which is primarily a heat-generating organ, can contribute to substantial variations in daily total energy expenditure between individuals.

To produce heat, brown adipose tissue directly burns fatty acids derived from circulating triglycerides.

Now Alexander Bartelt and colleagues from the University of Hamburg-Eppendorf, Germany, in a paper just published in Nature Medicine, demonstrate that this property of brown adipose tissue can significantly contribute to clearance of triglycerides from the blood stream.

In their studies, the researchers stimulated activity of brown adipose tissue in mice by exposing the animals to low temperatures. Cold exposure drastically increased clearance of triglycerides via increased uptake into brown adipose tissue and corrected increased lipid levels in insulin resistant mice.

Given that elevated plasma triglyceride concentrations, especially in diabetic dyslipidemia, is an important risk factor for cardiovascular disease, activation of brown adipose tissue may be a novel therapeutic approach to reduce elevated triglyceride concentrations.

Of course, increasing brown adipose tissue would perhaps also help burn excess calories, thereby reducing the risk of obesity.

Unfortunately, the best known way to increase brown adipose tissue activity is to increase sympathetic nervous activity, a side effect of which may be an increase in heart rate and blood pressure.

On the other hand, short burst of cold exposure may suffice to stimulate brown adipose tissue activity, without persistent effects on sympathetic activity. Whether such cold exposure can indeed improve triglycerides levels and help burn extra calories in humans remains to be seen.

Thankfully, with our winters here in Edmonton, I am in the right place to get plenty of cold exposure for free.

AMS
Edmonton, Alberta

Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmüller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, & Heeren J (2011). Brown adipose tissue activity controls triglyceride clearance. Nature medicine PMID: 21258337

Prof. Matthias Blüher, Leipzig

This week, I am hosting Matthias Blüher, Professor of Endocrinology from the University of Leipzig, Germany, who yesterday, presented a seminar on the topic of “Insulin Sensitive Obesity” at the Alberta Diabetes Institute.

As most readers will know, excess weight is typically associated with insulin resistance, which has been suggested to be a major underlying factor in the development of the metabolic syndrome.

However, as Blüher and other have shown before, there is a significant subset of individuals with excess weight, who are quite insulin sensitive and lack any sign or evidence for metabolic abnormalities. These individuals have also been described as being “metabolically healthy obese”.

Blüher’s group in Leipzig has performed extensive studies on this interesting group of subjects, which make up around 10-25% of individuals with severe obesity.

Using euglycemic insulin clamp studies (the gold-standard for measuring insulin sensitivity), Blüher and colleagues identified 30 individuals with typical insulin resistance and 30 individuals with atypical insulin sensitivity - both groups of subjects had a mean BMI of around 45 or severe obesity.

Among the many differences between the two groups, the best predictor of insulin resistance included more liver fat and increased visceral fat.

As reported previously, insulin resistant individuals had higher levels of glucose, HbA1c (although diabetic patients were excluded from the study), lower levels of HDL choldesterol, higher levels of CRP, larger adipocytes, greater macrophage infiltration of adipose tissue, and a higher leptin-to-adiponectin ratio.

Expression studies on fat tissue from both groups showed higher expression of various adipokines and biomarkers including AGT, MCP-1, PAI-1, Nampt (visfatin) endocannabinoids, ceramide, and oxidative stress in the insulin resistant group than the insulin sensitive controls.

In contrast, adipose tissue of the insulin sensitive subjects expressed higher levels of FTO, UCP-1, and adiponectin.

Blüher and colleagues were particularly thrilled to also see increased expression of vaspin (Visceral adipose tissue – derived serpin A12) in the insulin sensitive group, an enzyme that has been shown to increase insulin sensitivity and reduce food intake in animal studies. This molecule may provide a “drugable” target for treating obesity or related metabolic complications in the future.

Much of this work was undertaken as part of the newly funded Integrated Research and Management Centre for Obesity, which was recently funded by the German federal government in Leipzig.

As we discussed during Blüher’s meeting, we very much look forward to developing and expanding collaborations between the University of Alberta and the University of Leipzig as part of the recently negotiated Alberta-Saxony cooperation agreement.

I certainly look forward to working closely with Blüher and his colleagues over the coming years.

AMS
Edmonton, Alberta

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Klöting N, Fasshauer M, Dietrich A, Kovacs P, Schön MR, Kern M, Stumvoll M, & Blüher M (2010). Insulin-sensitive obesity. American journal of physiology. Endocrinology and metabolism, 299 (3) PMID: 20570822

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