08 Sep 2011 A new suspect in the obesity epidemic: our brains
The urge to eat too much is wired into our heads, in several complicated and overlapping ways. Tackling obesity may require bypassing the stomach and short-circuiting our brains. [A compelling and informed look at past and latest research into obesity. Ed]
OUR WAISTLINES ARE laying waste to human health and health-care costs around the globe. We all know what we should do — eat less, exercise more — but to no avail.
The urgent question is, why do our bodies seem to be fighting against our own good health? According to a growing number of neurobiologists, the fault lies not in our stomachs but in our heads. No matter how convincing our conscious plans and resolutions, they pale beside the brain’s power to goad us into noshing and hanging on to as much fat as we can….
With that in mind, some scientists were hopeful that careful studies of the brain might uncover an all-powerful hormone that regulates food consumption or a single spot where the cortical equivalent of a neon sign blinks “Eat Heavy,” all the better to shut it off.
After extensive research, the idea of a single, simple cure has been replaced by a much more nuanced view.
The latest studies show that a multitude of systems in the brain act in concert to encourage eating. Targeting a single neuronal system is probably doomed to the same ill fate as failed diets themselves. Because the brain has so many backup systems all geared toward the same thing — maximizing the body’s intake of calories — no single silver bullet will ever work.
“I call it the ‘hungry brain syndrome,’ ” says Hans-Rudolf Berthoud, an expert in the neurobiology of nutrition at the Pennington Biomedical Research Center in Baton Rouge, Louisiana.
The brain’s prime directive to eat and defend against the loss of fat emerged early in evolution, because just about every creature that ever trotted, crawled, swam, or floated was beset by the uncertainty of that next meal. “The system has evolved to defend against the slightest threat of weight loss, so you have to attack it from different directions at once.”
With the obesity epidemic raging, the race for countermeasures has kicked into high gear. Neuroscientists are still seeking hormones that inhibit hunger, but they have other tactics as well.
One fruitful new avenue comes from the revelation that hunger, blood sugar, and weight gained per calorie consumed all ratchet up when our sleep is disrupted and our circadian rhythms — the 24-hour cycle responding to light and dark — thrown into disarray. All this is compounded by stress, which decreases metabolism while increasing the yen for high-calorie food.
We might feel in sync with our high-tech world, but the obesity epidemic is a sombre sign that our biology and lifestyles have diverged.
Seeking silver bullets, shooting blanks
The path forward seemed so simple back in 1995, when three papers in Science suggested a panacea for the overweight: A hormone that made animals shed pounds, rapidly losing body fat until they were slim. Based on the research, it seemed that doctors might soon be able to treat obesity the way they treat diabetes, with a simple metabolic drug.
Fat cells release that “diet” hormone—today named leptin, from the Greek leptos, meaning thin—to begin a journey across the blood-brain barrier to the hypothalamus, the pea-size structure above the pituitary gland. The hypothalamus serves as a kind of thermostat, setting not only body temperature but playing a key role in hunger, thirst, fatigue, and sleep cycles. Leptin signals the hypothalamus to reduce the sense of hunger so that we stop eating.
In early lab experiments, obese mice given extra leptin by injection seemed sated. They ate less, their body temperature increased, and their weight plummeted. Even normal-weight mice became skinnier when given injections of the hormone.
Once the pharmaceutical industry created a synthetic version of human leptin, clinical trials were begun. But when injected into hundreds of obese human volunteers, leptin’s effect was clinically insignificant. It soon became clear why. In humans, as in mice, fat cells of the obese already produced plenty of leptin—more in fact than those of their thin counterparts, since the level of leptin was directly proportional to the amount of fat.
The early studies had worked largely because the test mice were, by experimental design, leptin-deficient. Subsequent experiments showed that in normal mice—as in humans—increases in leptin made little difference to the brain, which looked to low leptin levels as a signal to eat more, essentially disregarding the kind of high levels that had caused deficient mice to eat less. This made leptin a good drug for maintaining weight loss but not a great candidate for getting the pounds off up front.
Despite that disappointment, the discovery of leptin unleashed a scientific gold rush to find other molecules that could talk the brain into turning hunger off.
By 1999 researchers from Japan’s National Cardiovascular Center Research Institute in Osaka had announced the discovery of ghrelin, a kind of antileptin that is released primarily by the gut rather than by fat cells. Ghrelin signals hunger rather than satiety to the hypothalamus. Then, in 2002, a team from the University of Washington found that ghrelin levels rise before a meal and fall immediately after. Ghrelin (from the Indo-European root for the word “grow”) increased hunger while jamming on the metabolic brakes to promote the body’s storage of fat…..