Dr. Sharma's Obesity Notes

As not everyone may have a chance during the week to read every post, here’s a roundup of last week’s posts:

• Should We Outsource Obesity Treatments To Weight Watchers?
• Alberta’s Obesity Initiative: Not Just Diet and Exercise
• Is There Any Path For Approval of Anti-Obesity Drugs?
• GLP-1 Receptor Agonists, Obesity and Psoriasis
• Bariatric Surgery For Osteoarthritis of Hips and Knees?

Have a great Sunday! (or what’s left of it)

AMS
London, UK

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I have previously discussed the not too uncommon association between obesity and psoriasis, a chronic, autoimmune disease that causes red, scaly patches to appear on the skin, and affects 2-3% of the population in Western countries.

Hogan and colleagues, St Vincent’s University Hospital, University College Dublin, Ireland, in a paper just published in Diabetologia, now report improvement of psoriasis in three obese patients with type 2 diabetes several weeks after the initiation of therapy with the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists exenatide and liraglutide.

Regular readers may recall that GLP-1 receptor agonists were recently introduced for the treatment of diabetes and are currently under investigation for the treatment of obesity.

In addition to the clinical improvement, with reduced itching and/or a reduction in Psoriasis Area and Severity Index (PASI) scores, they also provide evidence that GLP-1 receptor agonist treatment had immunological effects in that it increased the number of natural killer T (NKT) cells in the circulation and reduced the number of invariant NKT cells in the psoriatic plaques.

In an accompanying commentary, Drucker and Rosen from the University of Toronto, point out that apart from the ‘classical’ metabolic effects of GLP-1 (e.g. on the secretion of insulin and glucagon), GLP-1 receptors are also found in numerous immune cell subpopulations, including thymoyctes, splenocytes, bone marrow-derived cells, and regulatory T cells.

It is therefore biologically ‘plausible’ that administration of GLP-1 analogues could have anti-inflammatory effects on psoriasis (and perhaps other inflammatory abnormalities).

Obviously, a few cases do not yet make an indication, but they certainly suggest that this hypothesis may well be worthy of further study.

I certainly wonder, if any of my readers have experienced similar improvements in inflammatory conditions like psoriasis with the use of GLP-1 analogues.

AMS
Edmonton, Alberta

Hogan AE, Tobin AM, Ahern T, Corrigan MA, Gaoatswe G, Jackson R, O’Reilly V, Lynch L, Doherty DG, Moynagh PN, Kirby B, O’Connell J, & O’Shea D (2011). Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia PMID: 21744074

Drucker DJ, & Rosen CF (2011). Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology. Diabetologia PMID: 21892687

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 will undo the ’scarring’ in these key centres of the brain (in the same way that no diet, exercise, medication or surgery will undo a scar in your skin or anywhere else in your body) - which is perhaps why none of these interventions will ever lead to ‘permanent’ weight loss unless they are continued in the long-term.

Although this may sound very disappointing and discouraging, these findings may eventually lead to new treatment strategies that can help prevent the ‘resetting’ by reducing or preventing the ‘inflammation’ that promotes the formation of astrogliosis with weight gain.

Perhaps, as in rats, those ‘rare’ people who appear to be (genetically?) weight-gain resistant or have less problem losing weight and keeping it off, can do so simply because they have more synapses in their POMC neurons to start with, easily grow more synapses when exposed to excess calories, or simply do not develop the ‘micro-scarring’ in their brains with weight gain.

Of course, scar or no scar, none of this means that treatments don’t work - of course they do, as long as the treatments continue.

So, the runners, who lost weight running, will have to keep running, the dieters, who lost weight dieting, will have to keep dieting, the patients who had bariatric surgery, can expect weight regain if they ever reverse the surgery - when the ‘treatment’ stops, the weight comes back!

As I have said before, the first measure of success in obesity management is stopping the gain - less weight gain - less scarring?

Successful obesity management is prevention!

AMS
Edmonton, Alberta

Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Brönneke HS, Levin BE, Diano S, Cowley MA, & Tschöp MH (2010). Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proceedings of the National Academy of Sciences of the United States of America, 107 (33), 14875-80 PMID: 20679202

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

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 (2011). B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nature medicine PMID: 21499269