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

When the adipocyte-derived protein leptin was first discovered almost 20 years ago, it was touted as a possible “cure” for obesity. This idea never proved clinically effective with the exception of rare cases of genetic leptin deficiency.

However, as reviewed by Theodore Kelesidis and colleagues from Harvard Medical School, Boston, MA, in the latest issue of the Annals of Internal Medicine, there are a number of other interesting uses of leptin treatment that may well prove to soon be clinically relevant.

Thus, while circulating leptin levels certainly serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism, it appears that leptin’s physiological role is more as an indicator of energy deficiency, rather than energy excess.

Thus, decreases in leptin levels (as see with caloric restriction, weight loss, or loss of adipose tissue as in lipodystrophy) may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization (as seen with anorexia or excessive exercise).

Currently a number of studies are exploring the role of leptin (particularly long-acting leptin homologues, e.g. metreleptin) in helping prevent weight regain in patients with intentional weight loss.

Replacement of leptin in physiologic doses also restores ovulatory menstruation in women with exercise-induced hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy.

Thus, although leptin treatment may not be an effective way to promote weight loss, it may well prove to have a number of clinical applications that may be relevant to weight management and treating the complications of excessive weight loss or lipodystrophy.

AMS
Edmonton, Alberta

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