Arya M. Sharma, MD

Iron is essential for numerous bodily functions not least the production of the red blood cell oxygen transporter hemoglobin and myoglobin, a related molecule essential for muscle function. Iron deficiency is one of the most common nutritional deficiencies, especially in, but not limited to, premenopausal women.

Clinical signs of iron deficiency include anemia, difficulty in concentration, poor memory, depression, dizziness, weakness, labored breathing, anginal pain, brittle lusterless, flattened or spoon-shaped nails, swollen ankles, hair loss, pale skin, and exhaustion.

Paradoxically, obesity, a state more commonly considered in the context of over- than under-nutrition, is associated with a higher risk of iron deficiency compared to normal-weight individuals.

Several hypotheses have been suggested for this paradox including dilutional (pseudo) hypoferremia, poor dietary iron intake, increased iron requirements (in part due to the earlier onset and often more severe periods associated with excess weight), and/or impaired iron absorption in obese individuals.

However, there is now accumulating data that iron deficiency in obesity may also be mediated by the low-grade chronic inflammation commonly seen in individuals with excess weight.

This topic is elegantly reviewed by Ana Cepeda-Lopez and colleagues from the Netherlands, Mexico and Switzerland, in a paper just published in the International Journal of Vitamin and Nutrition Research.

The article summarizes the abundant data from epidemiological studies, dating as far back as 1962, documenting the inverse associations between adult and childhood adiposity and poor iron status (defined in most studies as low serum iron concentration).

With regard to possible mechanisms, the authors describe their own work in obese volunteers demonstrating decreased intestinal iron absorption using stable iron isotopes.

Iron absorption from the gut is dependent on both a divalent metal transporter and the iron exporter ferroportin, which delivers enteral iron to the blood stream and appears to be the rate-limiting step in this process.

Ferroportin in turn is largely regulated by hepcidin, a 25-amino acid peptide hormone, which is both an inhibitor of intestinal iron absorption as well as macrophage iron release.

Hepcidin is produced both in the liver and in fat tissue and is modulated by body iron stores and hypoxia, but also, as recently recognised, by proinflammatory cytokines, which are commonly elevated in individuals with excess weight and can promote hepcidin formation.

In addition, lipocalin 2, an iron binding protein is also produced by fat cells and could lead to sequestration of iron stores making them unavailable for hemoglobin or myoglobin formation.

Thus, irrespective of actual iron intake, a ‘low’ iron status in obese individuals may result both from reduced absorption and functional iron deficiency - the latter perhaps being more important than the former.

The authors conclude their article by summarizing the findings from three recent intervention studies: one in 15 obese children, where weight loss resulted both in a decrease in hepcidin levels and improved enteral iron absorption as well as two studies in bariatric surgical patients showing reduction in inflammation markers, decrease in hepcidin levels and improved iron status.

These findings are important as both low ‘absolute’ and ‘functional’ iron deficiency have been associated not only with anemia but also a wide range of other health problems including myocardial dysfunction and heart failure.

Clinicians should monitor obese patients for both absolute and functional iron deficiency and be aware that iron deficiencies may well be independent of and unresponsive to enteral iron intake.

AMS
Edmonton, Alberta

Cepeda-Lopez AC, Aeberli I, & Zimmermann MB (2010). Does obesity increase risk for iron deficiency? A review of the literature and the potential mechanisms. International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition, 80 (4-5), 263-70 PMID: 21462109

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

As blogged before, overweight and obese patients frequently present with fibromyalgia, characterized by chronic pain, fatigue and depressed mood.

A paper by Akiko Okifuji from the University of Utah, Salt Lake City, just published in the Journal of Pain, examines the relationship between fibromyalgia and obesity in pain, function, mood, and sleep.

The study examines the impact of obesity on hyperalgesia, symptoms, physical abilities, and sleep in 215 fibromyalgia patients, who also underwent tender point examination, physical performance testing, and 7-day home sleep assessment.

Almost 50% of participants were obese and an additional 30% were overweight.

Obesity was positively related to greater tender point sensitivity, reduced physical strength and lower-body flexibility, shorter sleep duration, and greater restlessness during sleep.

The results confirmed that obesity is a prevalent comorbidity of fibromyalgia and the authors suggest that weight management may need to be incorporated into treatments.

In the paper, Okifuji and colleagues also discuss several potential mechanisms linking obesity to fibromyalgia including alterations in the endogenous opioid system, the endocrine system, and systemic inflammation, whereby adipose-tissue derived cytokines may enhance central sensitization.

Clinicians should be aware of the relationship between excess weight and fibromyalgia, which can often pose an important contributor to weight gain and a major barrier to weight management.

AMS
Edmonton, Alberta

Okifuji A, Donaldson GW, Barck L, & Fine PG (2010). Relationship Between Fibromyalgia and Obesity in Pain, Function, Mood, and Sleep. The journal of pain : official journal of the American Pain Society PMID: 20542742

Today, I am attending the 8th World Congress on Trauma, Shock, Inflammation and Sepsis in Munich, Germany.

Interestingly, this conference features a whole series of seminars on the interdisciplinary management of obesity (under the rather unfortunate title ‘Fat Man – We Will Help You’ [sic]).

I have been invited to chair and speak at the session on medical therapy, but there are also sessions on adipose tissue biology, perioperative management, bariatric surgical procedures, and the emergency management of bariatric patients.

As I often say in my presentations to colleagues: it does not matter what discipline in medicine you practice – you will be seeing an increasing number of heavier patients with their own issues and complications.

The fact that a world conference on trauma should devote this much time to sessions on obesity assessment and management is clearly to be commended in the light of the global obesity epidemic.

The more all health professionals learn and understand the complexities and problems posed by heavier patients, the better we can serve this particularly vulnerable patient population.

AMS
Munich, Germany

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