In 1959, Jules Hirsch, a research physician at Rockefeller University, started a simple experiment about weight loss in the obese. Dr. Hirsch found eight people who had been fat since childhood and who agreed to live at the Rockefeller University Hospital for eight months while scientists altered their diets to make them lose weight -- a liquid formula providing 600 calories a day. The study was rigorous and demanding. Finally, the subjects spent another four weeks on a diet that maintained them at their new weights, 100 pounds lower than their initial weights, on average. Dr. Hirsch answered his original question — the subjects’ fat cells had shrunk to normal size. Paradoxically, all the subjects eventually regained weight while on maintenance diet. So Dr. Hirsch and his colleagues repeated the experiment over and over. Every time the result was the same. Weight painstakingly lost, came right back. The researchers learned that metabolism slowed down with weight reduction. Dr. Ethan Sims at the University of Vermont, did the opposite: he got people who never had a weight problem deliberately fat. His subjects were prisoners at a nearby state prison who volunteered to gain weight. With great difficulty, they succeeded, increasing their weight by 20 percent to 25 percent. When the study ended, the prisoners had no trouble losing weight. Within months, they were back to normal and effortlessly stayed there. Apparently metabolism increased with weight gain, bringing weight back to baseline.

There must be a reason that fat people cannot stay thin after they diet and that thin people cannot stay fat when they force themselves to gain weight, why the body’s metabolism speeds up or slows down to keep weight within a narrow range. This message never really got out to the dietary world, it sounded bad for business to realize that losing weight can be hopeless cause. But it reflects a common clinical observation, why our obese and overweight patients stay obese despite what they do. It takes a lot of motivation to withstand the dietary regime similar to Dr. Hirsch, and explains a lot of adherence failures to special diets from Atkins to Zone. There were few patients who maintained their weight loss in Dr. Hirsch’s eight year study, but it did take a lot of will power and motivation to keep them on their diet and it is really a wonder how their physiologies found equilibrium to the starvation physiology Dr. Hirsch documented them to be in.

It is only now that we can make sense of the findings of Dr. Hirsch. There are peripheral and central pathways in the regulation of feeding behavior and body weight. The endocannabinoid system in the brain, when activated, drives more food intake, which leads to weight gain and fat storage. These hormones have receptors in appetite and satiety centers in the brain: hypothalamic area, nucleus accumbens, and limbic system, as well in adipose tissue, in muscle, in the liver, in the gastrointestinal tract, and the pancreas. Its regulatory counterpart are the body's fat cells which constantly produce and release leptin and adiponectin. Leptin down-regulates the expression of endocannabinoids, it curbs appetite and promotes weight loss. Adiponectin similarly promotes weight loss, insulin sensitivity, and promotes glucose flux and lipid metabolism. These are very complex mechanisms with multiple overlapping loops to keep the body weight in equilibrium. Interestingly the system is asymmetrical, gaining weight is easier than losing it. Obese people may have an unusually high circulating concentration of leptin but become resistant to its effects. The high sustained concentrations of leptin from the enlarged adipose stores result in leptin desensitization. The pathway of leptin control in obese people might be flawed at some point so the body doesn't adequately receive the satiety feeling subsequently to eating. Lack of sleep produces ghrelin, another hormone that stimulates appetite by lowering leptin levels. Ghrelin has emerged as the first circulating hunger hormone. Ghrelin is a hormone produced mainly cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates appetite. It increases food intake and increase fat mass by an action exerted at the level of the hypothalamus. With this complex system of hormones and counterhormones it is not hard to conceive why most of our patients, despite all their honest effort to heed our advice to lose weight, reach a plateauing phenomenon.

Is body weight inherited, or is obesity more of an inadvertent, almost unconscious response to an environment where food is easily accessible and irresistible?

Studies have shown that obesity is indeed influenced strongly by genetic factors. Adopted children tend to get the habitus of their biological parents than their adoptive parents, and that even identical twins brought up separately tend to gravitate to the same weight. This simply means that those with the genetic predisposition will have to constantly battle their genetic inheritance if they want to reach and maintain a significantly lower weight. These corroborate the findings of Dr. Hirsch: each person has a comfortable weight range to which the body gravitates. The range might span 10 or 20 pounds above or below a certain weight. Going much above or much below the natural weight range is difficult; the body resists by increasing or decreasing the appetite and changing the metabolism to push the weight back to the range it seeks.

Nonetheless , one cannot sit back blame obesity as a mere consequence of genetic predisposition, and that nothing can be done to alter this cardiovascular risk factor. In the clinics, waist circumference and weight, computation of BMI must be part and parcel of cardiovascular assessment, it gives a message to patients that it is a parameter as valuable as blood pressure. If waist circumference measured at the iliac crest is greater or equal to 35 inches in women (greater or equal to 40 inches in men), then patients must be adviced accordingly. What we have learned from Dr. Hirsch is that any weight gain was a step toward an almost irreversible condition. Obesity is an insulin-resistant and proinflammatory state that interacts with other risk factors and make patients prone to heart attack and stroke. A 5% to 10% reduction in weight results in a marked reduction in the cardiovascular risk factors: lower blood glucose and insulin levels, decreases in blood pressure, decreases in bad cholesterol and triglycerides, increases in good cholesterol.

Finally, I think that we must try and understand what it is about fat that directly affects the structure and function of the cardiovascular system. There are lean patients and there are obese ones. Obese people with normal visceral fat accumulation and obese people with high visceral fat accumulation. Weight and waist circumference are but an indirect measurement of visceral adiposity, as they also measure subcutaneous fat. Maybe someday there will be a bedside tool available to assess visceral fat as distinct from subcutaneous fat. Visceral fat is different, it surrounds internal organs such as the intestines, the perivascular fat lining our blood vessels, the epicardial fat on top of coronaries, and the fat in the liver. All of these have the same cellular infiltrates, a wide variety of activated leukocytes. Visceral fat produces inflammatory cytokines that can lead to heart attack and stroke, subcutaneous fat ordinarily does not.

Diet and exercise remain the cornerstone of weight loss. In the studies of Dr. Hirsch the researchers also found that the way the body adjusts its metabolism is by making muscles more or less efficient in burning calories. The key thing is to use the muscles, they speculated. The researchers suggested that we must learn the to understand what makes the muscles more or less efficient with weight gain or loss, rather than focusing on diets and psychological counseling only. They toyed with the idea that muscle fibers themselves may change their composition slightly. The red muscles, which are used for long-distance walking or running, for example, use fewer calories to do their work. The white muscles, used for sudden bursts of energy in activities like lifting weights or sprinting, burn more calories. Shifting from predominantly red to predominantly white fibers, thru training, may facilitate the weight reduction process. But that’s another story.

Meanwhile here we are in the dawn of a new era of with weight reduction formulas sprawled over our dailies, some old and some new. Diet sodas and diet portions, magic concoctions, exercise machines that promise perfect bodies. Did I mention the clinic where they spread a burning towel over a patient’s tummy to burn fat? New pharmacotherapy that addresses the endocannabinoid system is about to enter the market, interesting prospect there. There is really more to learn about this obesity epidemic and what can be done, the muscle physiology pointed out by Dr. Hirsch and the flux of fat from visceral to subcutaneous intrigues me. I would like to dwell on that next time.