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The Pathway Less Traveled
08.27.04
 
Altered gravity plays an unexpected role in obesity and weight loss.

Astronauts have long known that space travel is a good way to diet. The excitement of launch. Thrilling vistas seen from Earth orbit. Floating weightless. Maybe a touch of motion sickness. Who can eat at a time like that?

Rats, apparently, feel the same way. Rats in space (they've been there onboard the space shuttle) also under-eat. They grow lean compared to rats on Earth. Curiously, rats experiencing high gravity (inside gently-spinning centrifuges) under-eat, too. And this suggests there's more to the story than thrilling vistas:

Astronaut Loren Shriver eats M and Ms onboard the space shuttle Atlantis.

"Altered gravity somehow disrupts the natural ability of animals to maintain their own weight," says Barbara Horwitz, a professor of physiology at the University of California. No one understands exactly why that should be, but it's probably an important clue to the inner workings of weight control--something that interests people on Earth just as much as astronauts in space. Horwitz is studying the phenomenon in rats at her laboratory in Davis, California.

Image Right: Astronaut Loren Shriver eats M and Ms onboard the space shuttle Atlantis. Credit: NASA

Although some of us who struggle with weight issues may find it hard to believe, animals, including humans, have evolved a complicated system for maintaining appropriate weight. You'd expect that: the bodies of animals that are too heavy, or not heavy enough, don't function properly.

Feeding behavior is essential, not only to the health of individuals, but also to the survival of whole species. The body stores energy in fat, and there's a minimum amount an organism must have before it can get pregnant. "Animals that lose a lot of fat don't reproduce," says Horwitz.

But the complex network that signals when to eat and when to stop eating can go awry. This could be a contributing cause of, e.g., the "obesity epidemic" in the United States, under-eating among astronauts, and maladies such as the "wasting syndrome" linked to AIDS.

Horwitz is particularly interested in leptin regulatory pathways. Leptin is a hormone that's key to regulating appetite: when it was first discovered in the mid-1990's it was regarded as a possible way to treat obesity in humans. Leptin is produced by fat cells. The more fat cells an organism has, the more leptin circulates through its body.

Leptin manages appetite by activating receptors in the hypothalamus, a part of the brain. These receptors control the production of small signaling proteins called neuropeptides. Leptin increases the amount of neuropeptides that make you feel full, and decreases the amount of neuropeptides that make you feel hungry.

An artist's concept of the brain-body appetite control system.

Image Left: An artist's concept of the brain-body appetite control system. [Larger image] Credit: Mediagnost. All rights reserved.

Horwitz is studying leptin regulatory pathways in rats: The animals live in a 2-g (twice normal gravity) centrifuge in individual, free-swinging cages, for as long as eight weeks. Even though they're working against twice the gravity they're used to, the rats don't seem to mind. They move around, they groom themselves. If they're allowed, they'll even breed on the centrifuge, says Horwitz.

Living in double gravity naturally requires more energy. The rats were offered all the food they wanted, yet, at first, they ate less than they needed to maintain their body mass--much like astronauts in low gravity.

Horwitz and colleagues tested the rats (along with 1-g control groups) at 1, 2 and 8 weeks. During the first week, some of the rats' neuropeptides were mixed up. One, in particular, which stimulates feeding and therefore should have increased, actually went down.

By the eighth week, things were back to normal--almost. The animals produced the same amount of neuropeptides in both 1-g and 2-g habitats. Double-gravity rats were finally eating as much as they needed. But they remained lean: they never regained the fat they lost at the beginning of the study.

"That means that the pathway somehow was changed," says Horwitz. "The relationship between the amount of fat, and how much leptin was secreted, and the functioning of the feedback system is altered in high gravity."

Horwitz hopes to pinpoint the exact mechanisms by further testing the rats' genes: Each neuropeptide in the appetite feedback loop is produced or "expressed" by a gene that has been activated. Using a technology called DNA microarrays, Horwitz and colleagues examine thousands of rat genes at a time. They can see which genes have been activated, and how active they are.

Prof. Barbara Horwitz of the University of California, Davis.

Understanding the chemical pathways at this basic level could lead to "countermeasures," i.e., treatments to restore broken leptin regulatory systems.

Image Right: Prof. Barbara Horwitz of the University of California, Davis. [More] Credit: Barbara Horwitz

Many researchers now believe that leptin's main role in humans is protecting against weight loss more so than weight gain. It makes sense: food surpluses are a relatively new phenomenon. Humans have evolved to withstand deprivation, not excess.

This makes leptin, potentially, even more important to astronauts: It's part of a regulatory pathway that keeps them from becoming too lean when stress, motion sickness and bland food take away their appetites.

Horwitz's research is important here on Earth, too. People with weight control problems like obesity may have defective leptin regulatory pathways: they tend to have plenty of leptin coursing through their bodies, but it does not cause them to eat less. The big question is why. Maybe their leptin receptors don't work well, or their neuropeptides aren't produced properly. Or it could be something else entirely.

Somewhere, along the pathway less traveled, lies the answer.

More Information
Prof. Barbara A. Horwitz -- (UC Davis) Home Page

Cellular Warriors at the Battle of the Bulge -- (Science Magazine) A 2003 summary of what's been learned about leptin since its discovery in 1994

Leptin -- (Wikipedia) Leptin's concentration in the body provides the brain with a rough indication of adipose mass for the purposes of regulating appetite and metabolism.

Leptin -- (Colorado State University) Leptin, from the Greek leptos, meaning thin, is a protein hormone with important effects in regulating body weight, metabolism and reproductive function.

Space Nutrition -- from the 2001 Bioastronautics Workshop in Galveston, TX: Studies have shown that 'the average astronaut consumes 500 to 1000 kcal/d less energy than required for spaceflight. This leads to weight loss and accelerates muscle atrophy and bone loss. The cause of, and countermeasures for, this dysregulation are unknown.'

Astro-appetites -- (NASA/Bioastronautics Roadmap) Reduced caloric intake is routinely reported during long space missions and may partially explain the loss of tissue including muscle, bone and red cells.

Leptin and Obsesity -- (Eurekalert) For nearly a decade, scientists have known that leptin plays an important fat-burning role in humans. But the map of leptin's path through the body -- the key to understanding how and why the hormone works -- is still incomplete.
 
 
Feature Author: Karen Miller, Dr. Tony Phillips
Feature Production Editor: Dr. Tony Phillips
Feature Production Credit: Science@NASA