A paper in the latest issue of Cell Metabolism seems to promise a new generation of fat-loss drugs. The researchers knocked out sarcolemmal ATP-sensitive potassium (KATP) channels in mice, causing the animals’ muscles to burn more energy. As a result, the mice were thinner:
Inefficient fuel metabolism in KATP channel-deficient striated muscles reduced glycogen and fat body depots, promoting a lean phenotype. The propensity to lesser body weight imposed by KATPchannel deficit persisted under a high-fat diet, yet obesity restriction was achieved at the cost of compromised physical endurance. Thus, sarcolemmal KATP channels govern muscle energy economy, and their downregulation in a tissue-specific manner could present an antiobesity strategy by rendering muscle increasingly thermogenic at rest and less fuel efficient during exercise.
Of course, a fat-burning pill is the Holy Grail of the pharmaceutical industry, but if I were a drug developer, I’d hold off charging after KATP channel inhibitors. That’s because the abstract giveth, but the data taketh away. See, for example, Figure 7 (I don’t want to repost the figure here because Elsevier has been prickly about copyrights in the past, but the paper is open-access, so you can just click the link).
In the graph, note that the knockout mice are indeed less heavy than their wild-type colleagues on the obesity-inducing diet, but the weight curves are exactly the same. They’re both gaining. The experiment ends at 160 days, which means the mice were just hitting middle age.
There’s also the issue of side-effects, which we can practically guarantee in any potential KATP channel-targeting drug. The knockout mice had reduced endurance in an exercise test, but I’d bet a beer that’s not their only problem. Previous work has shown that this channel is a critical part of stress responses in both skeletal and cardiac muscle. Even taking a hypothetically perfect KATP channel-targeting compound for weight loss would be like popping a zit with a chainsaw: it might work, but is it worth the risk?
I’m not the only scientist skeptical of this approach, either. Greg Cooney, an Associate Professor at the Garvan Institute in Australia – who I’m guessing was a reviewer on the Cell Metabolism paper – just sent out a press release throwing some much-needed cold water on the weight-loss hype. In it, he reiterates the fundamental problem at the root of the obesity pandemic.
“The energy you use in your home can come from a coal-fired power station, hydroelectric power, or a wind turbine. You won’t know which because the end result is electricity. The energy that fuels your body can come from fats, proteins or carbohydrates. You won’t know which because the end result is ATP, or cellular energy,” says Cooney, concluding that “Your body will use the energy it needs and store the leftover fats, proteins or carbohydrates as fat. When you do the sums, it’s ultimately a matter of calories in and calories out.”
So how do you lose weight? Eat less and exercise more. Nobody likes that answer, but continuing to ask the question isn’t going to change it.