Adipocytes

Anyone taking an antidiabetic drug belonging to the group of “glitazones” has probably experienced some weight gain (despite improvements in diabetes control). This is because this group of compounds stimulate the nuclear hormone receptor PPARg, believed to be one of the key switches that turns on the growth and expansion of fat cells. In fact, till now, the PPARg receptor was considered both necessary and sufficient for the differentiation and growth of fat cells.

This is no longer true, according to a paper just published in the Journal of Biological Chemistry by Craig Younce and colleagues from the the University of Central Florida, Orlando, FL.

In their study, the researchers convincingly demonstrate that a molecule called MCPIP (for MCP-1-induced protein) is not only essential for promoting fat cell differentiation but is in fact effective even in cells that do not express PPARg. 

MCP-1 is found to be increased in obesity, possibly due to increased formation in macrophages, hypoxic fat cells, or perhaps even as a response to increased endotoxin levels produced by gut flora.

While the identification of what now appears to be the new key molecule that allows and drives fat cell formation, several caveats are in order.

Firstly, these experiments were performed in 3T3-L1 cells, a commonly used mouse cell line, which does not always behave in the same manner as human fat cells.

Secondly, findings in cell culture are of course not always reflective of what happens in the whole tissue or the whole animal.

Nevertheless, research that leads to a better understanding of the complex biology of fat tissue formation can potentially provide important insights ultimately paving the way to new treatments for obesity and its complications.

AMS
Edmonton, Alberta

Obesity is widely associated with low grade inflammation and previous studies have noted increased incidence of allergic responses in obese individuals pointing to a possible role of immune response in the regulation of metabolism and body weight.

Last week Nature Medicine published three separate articles, which together may well herald in an entirely new area of obesity research: immunometabolism or metabolic immunology. Although all studies reports finding in mouse models of obesity and diabetes, their observations may well have important implications for human obesity.

In the first study, Satoshi Nishimura and colleagues from the University of Tokyo show that CD8+ effector T cells play an important role in macrophage recruitment and adipose tissue inflammation. They not only found that large numbers of CD8+ T cells infiltrated obese epididymal adipose tissue in mice fed a high-fat diet (while there was a depletion of CD4+ T ells), but also that this infiltration preceded the accumulation of macrophages in fat tissue. On the other hand immunological and genetic depletion of CD8+ T cells lowered macrophage infiltration and adipose tissue inflammation and ameliorated systemic insulin resistance. Coculture and other in vitro experiments revealed a vicious cycle of interactions between CD8+ T cells, macrophages and adipose tissue. These results support the notion that CD8+ T cells have an essential role in the initiation and propagation of adipose inflammation.

In the second study, Markus Feuerer and colleagues from Harvard Medical School, Boston, USA, showed that CD4+ regulatory T cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but, similar to the observation by Nishimura and colleagues, their numbers were strikingly and specifically reduced in insulin-resistant models of obesity. Loss-of-function and gain-of-function experiments revealed that these regulatory T cells influenced the inflammatory state of adipose tissue, insulin resistance, and glucose uptake.

In the third study, Shawn Winer and colleagues from The Hospital for Sick Children, University of Toronto, Canada, showed that immunotherapy with CD4+ (but not CD8+) T cell transfer into lymphocyte-free obese mice reversed weight gain and insulin resistance. In other obese mice, brief treatment with CD3-specific antibody or its F(ab’)2 fragment reversed insulin resistance for months, despite continuation of a high-fat diet.

Together these papers not only document the important role of immune response in the development of obesity and its complications but also identify a number of novel targets and strategies that could be harnessed to treat obesity in manners similar to the treatment of other immunological abnormalities including allergies.

The studies certainly lend credence to those who have long suggested that obesity may be related to allergic or other immunological responses to allergens and environmental toxins.

How these findings will translate into better treatments for obesity obviously remains to be seen.

AMS
Edmonton, Alberta

On Tuesday, the Hong Kong-based Shaw Prize foundation awarded Ontario-born Douglas Coleman, an emeritus scientist with Jackson Laboratories in Maine, and Jeffrey Friedman of Rockefeller University in New York, this year’s $1 Million prize for their work on the hormone leptin (for CBC report click here).

Coleman first identified a hormone that governs food intake and body weight while working on mice in the 1970s. From the 1990s and into this decade, Friedman, using gene mapping techniques, isolated that hormone — leptin, finding it was active only in body fat, a surprising and significant finding, given fat cells were not previously known to secrete major hormones.

The discovery of leptin was arguably the most significant stimulus for the modern biology of obesity leading not only to a renewed interest in adipocyte biology but also to a better understanding of central regulation of food intake and energy balance.

Last Fall, I had the privilege of introducing Friedman to an audience here at the University of Alberta. I have unfortunately never had the chance to meet Coleman.

Congratulations to both winners!

AMS
Washington DC

As a nephrologist, I come from a field in which many key decisions are based on the outcome of a biopsy specimen. There are indeed many areas of medicine in which tissue biopsies are routinely used to establish a diagnosis or to guide treatment. Could the same hold true for obesity?

We have long known that obesity is by no means a homogeneous condition and that the clinical manifestation of obesity related comorbidities covers a wide and unpredictable spectrum of disorders. It is thus only likely that different forms of obesity are heterogeneous at the tissue level and in their response to treatment.

A first indication of just how adipose tissue biopsies may be used in clinical practice now comes from a study published in this month’s issue of the International Journal of Obesity. In this paper, Wang and colleagues from the Pennington Biomedical Research Center, Baton Rouge, LA, USA, use microarray gene expression technology to group 72 otherwise healthy obese men and women into two distinct clusters (denoted red and green). Interestingly, the red cluster contained no men, had “red” patients had less visceral fat and smaller fat cells. More importantly, it appeared that the patients in the green cluster appeared to respond with slightly greater weight loss to adrenergic treatment with ephedra and caffeine (not exactly my choice of antiobesity drugs) in an 8 week intervention.

Although the authors may be a tad overenthusiastic in terms of proclaiming that this paper now “brings us into an era of personalized treatment in the obesity clinic”, there is certainly some hope that fat biopsies may someday prove to provide a clinically useful predictor for response to specific treatments.

Obviously much needs to happen before anyone would seriously consider routine fat biopsies in clinical practice. For one, we would need prospective studies on sensitivity and specificity to detect clinically significant differences in response. Obviously, cost-effectiveness analyses would also need to establish the cost/benefit ratio for what is still a very expensive technology.

For now, nonetheless, the study confirms what I have maintained all along - obesity is a heterogeneous disorder and there is no reason to assume that any one treatment will work for all.

AMS
Edmonton, Alberta

Curcumin is the principle ingredient of tumeric or “haldi” as it is called in Hindi. This is the spice that gives Indian curries their bright yellow color. The tumeric root (a relative of ginger) has long been thought to have all kinds of medicinal properties, and growing up in India, I remember my mother treating boils and abscesses on our household pets with tumeric paste. Curcumin is supposed to not only have antibiotic, antiinflammatory, antiarthritic, antioxidant and anticancer properties, regular consumption is also alleged to increase brain power.

Now, a study by Asma Ejaz and colleagues from Tufts University, Boston, MA, USA, just published in the Journal of Nutrition, suggests that curcumin may also reduce fat formation by blocking the angiogenesis (growth of new blood vessels) necessary for the expansion of adipose tissue and by positively changing fat cell metabolism.

The researchers studied the effect of curcumin both on cultured 3T3-L1 adipocytes as well as in mice fed a high-fat diet.

In cell culture studies, curcumin supressed preadipocyte differentiation, promoted adipocyte apoptosis (programmed cell death) and inhibited growth of adipokine-stimulated angiogenesis.

Consistent with these findings, in the high-fat fed mice, over 12 weeks, curcumin did not affect food intake but reduced body weight gain, adiposity, and microvessel density in adipose tissue. Curcumin also increased expression of key enzymes involved in fat oxidation. Blood cholesterol levels were also lowered by curcumin treatment.

Leaping from mouse to man, the authors speculate that dietary curcumin may not only help prevent obesity but may also have favourable effects on fat metabolism.

How much of an impact this finding may have on the obesity epidemic remains to be seen - clearly, eating a daily dose of curry (as most Indians do) is not a sure bet when it comes to preventing obesity as evidenced by the burgeoning obesity epidemic in India (but who knows, perhaps the Indian obesity epidemic would be far worse without the curry?)

In any case, I am certainly happy for any excuse to stop by my favourite Indian restaurants.

AMS
Edmonton, Alberta