Solving Obesity, Simple But Not Easy

By: Dr. David L. Katz*

The obesity epidemic, biomedical advance and the inherent promise in the dawn of the Genomic Age collided in the press over the past couple of weeks. Specifically, we heard about a new “obesity gene” and a breakthrough new drug for treating obesity. A lot more smoke than fire, in my opinion. And when it clears, we will be left to contend with the fact that solving the obesity problem is just as simple as ever, but not a whit easier.

The gene study was published in the prestigious journal Science. Researchers at the Oregon Research Institute demonstrated, quite elegantly, that overweight people experience a reduced pleasure response in the dorsal striatum region of their brains when consuming a chocolate milkshake than lean counterparts. The resultant barrage of media coverage all suggested that this variable response highlights the importance of the underlying gene as a cause of obesity.

Perhaps so. But there is no obesity gene.
Not because no gene plays a role in weight regulation, but because many genes do.
Consider trying to find the gene that helps fish breathe under water. All the genes responsible for their fundamental fishiness are so implicated. Genes that make polar bears tolerant of the cold? They are there, but would be hard to distinguish from the genes that make polar bears ... polar bears.

No single gene makes Homo sapiens vulnerable to weight gain. Rather, every gene that contributes something to the fundamentals of our metabolism that has survived through countless generations of caloric scarcity and high levels of physical activity is guilty of this charge. Were we not good at storing calories as body fat to get us through times of deprivation, we wouldn’t be here to debate the genetic underpinnings of epidemic obesity.

Imagine that instead of acknowledging and dealing with the fact that the ship was sinking, the captain ordered the crew to investigate and explain the variation in degrees of lower extremity soddenness. There might, in fact, be explanatory power in some variables. The upper decks, for instance, would certainly take on water later than the lower decks. But here, of course, is my point: If the investigation went on long enough, the very variation it set out to explain would be gone, because everyone would be comparably wet. The ship would have sunk.

Folks, our ship is sinking. A recent paper in the journal Obesity by researchers at Johns Hopkins projects that by 2048, should current trends persist, all American adults will be overweight or obese. If we work long enough at explaining variation in our vulnerability to obesity, there will be no variation in obesity left to explain. Which, in turn, explains why no drug will ever be the answer.

A trial just published in the Lancet suggests that the drug tesofensine facilitates considerable weight loss over a 6-month period, more than twice as much as the two drugs currently FDA-approved for the job, sibutramine and orlistat. Related headlines go so far as to announce a new “wonder pill.”

But consider this sobering coincidence: Even as this paper was making headlines, the most promising weight loss drug to be seen in years, rimonabant, was being withdrawn from the European market where it had been approved because the psychological side effects (depression and suicidality) may be more common and severe than originally thought. The drug was denied FDA approval in the United States last summer because of these very side effects.

I found rimonabant of greater promise than tesofensine, because it works by a novel, and potentially more fundamental mechanism. Tesofensine is only slightly novel, working in ways similar to sibutramine, and many antidepressant drugs. In the newly published trial, tesofensine elevated both heart rate and blood pressure. This has been rate-limiting with all such drugs before, so it is an ominous finding.

I believe we are unlikely ever to find a drug that is both highly effective for weight control, and safe. The quest is like seeking a drug that would help polar bears thrive in the heat, or help fish breathe out of water. Human beings are subject to obesity because our metabolisms were shaped in a world where calories were relatively scarce and hard to get, and physical activity unavoidable. We now live in a world where physical activity is scarce and hard to get, and calories unavoidable. You can’t medicate that away.

The causes and cures of epidemic obesity are comparably obvious and simple: We consume too many calories and need to consume fewer; we burn too few calories and need to burn more. Getting there from here, however, will be anything but easy. Looking for more genes to implicate or holding out for a wonder drug have the potential to distract us from the obvious, and delay the necessary. My recommendation is we accept the simple reality of this crisis, and get down to the hard business of solving it.