Does Neuronal Scarring Determine the Body Weight Set Point?
As regular readers are well aware, one of the major dilemmas in obesity management is the fact that virtually any attempt at weight loss is counteracted by complex mechanisms that aim to restore the body back to initial weight. So far, no one has discovered a way to reverse or ‘reset’ this mechanism so that, once weight is lost, the body ‘relaxes’ and ‘accepts’ that new, lower body weight again. This is why, no matter what program, diet, exercise, medication or surgery you chose for weight loss, when you stop the program, diet, exercise, medication, or reverse the surgery, your weight comes back – there are almost no exceptions to this rule. So how does weight gain lead to this apparently ‘permanent’ resetting of the body-weight ‘set point’? A recent paper by Tamas Horvath (Yale) together with colleagues from the US, Europe and Australia, published in the Proceedings of the US National Academy of Science, suggests that ‘micro-scarring’ of neurons that regulate hunger and satiety in the hypothalamus (the key homeostatic centre of eating behaviour) may play an important role in this process. The researchers first studied the microscopic organisation of synapses (nerve-nerve contacts) in the anorexigenic (hunger-suppressing) proopiomelanocortin (POMC)-expressing nerve cells of the arcuate nucleus in lean rats that were vulnerable or resistant to diet-induced obesity. There was a clear quantitative and qualitative difference in the synaptic organisaton of POMC cells between these animals, with a significantly greater number of inhibitory inputs in the POMC neurons in weight-gain susceptible rats compared with resistant rats. Then, when given similar high-fat diets, the POMC cells of weight-gain resistant rats formed more connections whereas the susceptible animals actually lost synapses. Importantly, this loss of synapses was associated with a process called ‘reactive astrogliosis’ or ‘glial-scarring’ whereby, in an ‘inflammatory’ response, astrocytes ensheath the POMC neurons, thereby making them ‘permanently’ inaccessible to new synapses (hence the use of the term ‘scarring’). In addition, this formation of glial ‘scar’ tissue, also made the POMC cells less accessible to blood vessels (i.e. increased the blood-brain barrier). As all ‘scarring’ processes in the body, these micro-scars are in essence, irreversible, or in other words, permanent. Thus, these findings clearly show how increased caloric intake in ‘obesity-prone’ rats (and humans?) can lead to permanent changes in the cell-architecture of the arcuate nucleus thereby essentially ‘locking in’ the new ‘set point’. Obviously, no diet, exercise, medication or surgery… Read More »
Why Big Fat Cells May Cause Inflammation
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
Is Type 2 Diabetes an Autoimmune Disease?
Insulin resistance is commonly observed in individuals with excess weight and has been considered a key mechanism underlying the rather strong association between obesity and increased risk for type 2 diabetes. However, the etiology of insulin resistance associated with weight gain or why this develops in some people and not in others remains unclear. As study by Daniel Winer and colleagues from the University of Toronto and Stanford University, just published in NATURE MEDICINE, now suggests a novel role of B-lymphocytes and autoantibodies in this relationship. B lymphocytes are immune cells that recognise antigens and ultimately lead to the production of anti-bodies. In this paper, the researchers show that B cells accumulate in the visceral fat of obese mice and that mice, lacking B cells appear protected against the development of insulin resistance with weight gain. The paper further shows that the B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment of these insulin-resistant obese mice with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from obese mice rapidly induces insulin resistance and glucose intolerance. Most importantly perhaps, the researchers also show that insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. Not only do these studies suggest a novel role for B cells and autoantibodies in the development of insulin resistance associated with weight gain, but if confirmed, these findings could lead to novel diagnostic tools (early detection of antibodies) and perhaps new treatments for type 2 diabetes (anti-CD20 antibodies are already used to treat some autoimmune diseases and cancers in humans). Differences (genetic or otherwise) in immune response may also explain why weight gain leads to insulin resistance and diabetes in some people but not in others (see previous post on insulin-sensitive obesity). Certainly, if anything, this study can only remind us of the biological complexity of obesity – anyone who still believes obesity and its complications are simply a matter of calories in and calories out probably also believes that health can be easily measured in pounds or kilograms. AMS Edmonton, Alberta Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, Tsui H, Wu P, Davidson MG, Alonso MN, Leong HX, Glassford A, Caimol M, Kenkel JA, Tedder TF, McLaughlin T, Miklos DB, Dosch HM, & Engleman EG… Read More »
Functional Iron Deficiency in Obesity
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… Read More »
Adipose Tissue Inflammation Promotes Diabetes?
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 Click here to follow me and post your comments on my FaceBook page 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,… Read More »
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