The paper is a review of the work from my laboratory. It was written in late 2005 and published in 2006. There is currently an enormous interest in the hypothesis that there is an enhanced release of inflammatory cytokines/adipokines by adipose tissue from obese humans which contributes to the worst side effects of obesity, such as diabetes and cardiovascular disease. Our unique contribution outlines how this is probably due to the nonfat cells in human adipose tissue rather than the fat cells.

jLEFT TABLE “Our research supports the growing consensus that massive obesity is a major health problem.”

As of November 2007, two other papers by our group, which have been cited 154 and 66 times, respectively [ISI Web of Knowledge^SM] since their publication, are: Fain JN, et al, "Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans," Endocrinology 145 (5): 2273-2282, MAY 2004 and Fain JN, et al, "Resistin release by human adipose tissue explants in primary culture," Biochemical and Biophysical Research Communications 300 (3): 674-678, JAN 17, 2003.

It is essentially a synthesis of knowledge about the key role of nonfat cells in the release of 23 different cytokines/adipokines by human adipose tissue. The data on 12 cytokines/adipokines were in the two papers cited above and the data on nine others have since been published. After the review was written, we have published data on another three cytokines, bringing the total to 27.

The report is highly cited because it provides information, based on studies with human fat (adipose tissue), indicating that it is the greater release of cytokines/adipokines by adipose tissue as the amount of tissue expands in obesity, which is probably responsible for the epidemic of obesity and cardiovascular disease. Our unique contribution is to emphasize that most of these cytokines/adipokines come from cells other than fat cells.

These cells are involved in support, as well as in nutrient and oxygen delivery to the fat cells. The non-fat cells increase in fat when there is an increase in the amount of fat just as roads are widened when the number of cars increases in a country. We know that the harmful effects of obesity can be reversed by weight loss, which is essentially a reduction in fat mass, but we don’t yet know how to accomplish this with a pill.

I have worked on the metabolism of fat tissue for over 40 years but most of my studies were with rodents. It became clear that what were needed were studies using human fat tissue. I found it could be obtained from surgeons during bariatric surgery on morbidly obese humans.

One major problem was funding, which could not be obtained from the NIH, because I wasn’t doing a mechanism-based research, the kind that is difficult to do with human fat. I persevered, using sources of institutional, hospital, and commercial funding. Over the past 10 years the budget for this research has averaged less than $60,000 per year; this total only covered the cost of one research assistant and the necessary supplies.

Another roadblock occurred when the surgeon I was collaborating with suddenly quit doing surgery and it was almost a year before a new surgeon could be recruited. Originally I had been investigating leptin, which is the only adipokine released exclusively by fat cells, using subcutaneous adipose tissue from morbidly obese humans. To occupy my time, I turned to looking at other putative adipokines released by human fat samples that I had been working with.

During this interim period another surgeon, who occasionally did bariatric surgery, but primarily did so-called "tummy-tucks" on formerly obese patients a year after bariatric surgery, when the amount of fat in each human was reduced from an average of 56 kilograms to 32 kilograms. Since surgery was done so seldom, I decided to look at fat from these patients and compare subcutaneous adipose tissue with visceral omental adipose tissue. I soon left leptin and concentrated on comparing the release of every adipokine that I could measure using enzyme-linked immunosorbent assays (ELISA) by both omental and subcutaneous adipose tissue from morbidly obese patients and similar patients one year after surgery.

It is established that the enhanced incidence of diabetes in morbidly obese individuals—those with a BMI averaging 45—is reversed in over 90% of them after bariatric surgery, when the BMI drops to 32, even though this BMI indicates that they are still obese. Furthermore, the visceral omental fat which is so prominent in men with a so-called "beer belly" obesity, is thought to contribute more to the adverse effects of obesity than fat in the peripheral tissues, where all the fat is subcutaneous. We now work almost exclusively with human omental fat, which became a necessity when new bariatric surgeons arrived and did only minimally invasive surgery.

We are continuing our research on cytokine/adipokine release by omental fat by examining the mRNAs for many proteins in freshly isolated samples of human fat and in the fat cells derived from this tissue. These studies indicate that the enhanced release of adipokines during in vitro incubation of adipose tissue from obese humans is reflected in the mRNA distribution between the non-fat cells and fat cells. We are also examining the correlation between waist circumference—the easiest to obtain and reliable clinical index of visceral obesity—and the mRNA content of cytokines and regulatory factors in visceral omental adipose tissue.

In another study we are also investigating the effect of diabetes, by correlating blood glucose values with mRNA values in omental adipose tissue.

A further expansion of my research is in collaboration with cardiovascular surgeons and a local endocrinologist. During so-called "coronary artery bypass graft surgery" (CABG), when the right coronary artery is replaced with a blood vessel from another area, it is possible to obtain small samples of adipose tissue from five different depots. We will examine the correlation between waist circumference and the extent of diabetes with the level of the mRNAs for over 50 proteins.

Our research supports the growing consensus that massive obesity is a major health problem. The good news is that the deleterious effects of enhanced cytokine/adipokine research by adipose tissue can be reversed by weight reduction. The bad news is that, apart from bariatric surgery, which is major surgery with a risk of death or other serious side effects, there is no effective way to accomplish this using a pill. Exercise and diet work in some obese individuals, but even when successful over the short-term, most individuals will regain the weight within the following year.

Hopefully, research such as we are doing will result in new knowledge that could result in a pill which would be as effective in the treatment of obesity as anti-hypertensive pills are for the treatment of hypertension.