Working with genetically engineered mice, Johns Hopkins
scientists have interfered with the brain's ability to
control an animal's response to a high-fat diet. The
report, published in the issue of the Proceedings of the
National Academy of Sciences online the week of May 1,
is based on the identification of a gene — CPT1c
— that the brain needs to manage body weight.
According to the researchers, the CPT1c gene protects
against weight gain caused by a high-fat diet. So-called
knockout mice lacking the CPT1c gene gain more weight than
their littermates carrying normal copies of the gene.
"We think our study reveals a direct weight management
pathway," said Michael Wolfgang, a postdoctoral fellow in
the Department of
Biological Chemistry at the School of Medicine and an
author of the report. "CPT1c seems to allow the body to
respond immediately to the level of nutrients and fat in
the bloodstream."
Hopeful that the discovery has broad implications for
understanding the genetic underpinnings of obesity and
weight management, the Johns Hopkins investigators say the
work affirms the central role of the brain in managing
hunger and satiety and offers up new targets for drugs that
manipulate CPT1c. But none have been developed so far,
Wolfgang said.
The newly discovered gene makes a protein found only in the
brain, notably in the hypothalamus — the region that
controls hunger, thirst and metabolism. Proteins similar to
CPT1c are known to help break down fat to release energy to
feed cells. Mice lacking the CPT1c gene are the same length
as their littermates who carry normal copies of the gene
but on average weigh 15 percent less when fed a low-fat
diet.
Further analysis revealed that when deprived of food for
four hours prior to feeding with standard laboratory mouse
chow, the knockout mutant mice ate about 25 percent less
food than their normal siblings. Therefore, the researchers
concluded, CPT1c must play a role in feeding behavior and
appetite control.
Moreover, when fed a high-fat diet (mouse chow laced with
lard) for 10 weeks, mice lacking CPT1c still ate less than
their normal littermates but were much heavier.
What scientists already know about the regulation of body
weight helps explain why the absence of CPT1c may have its
seemingly paradoxical effect.
Under normal circumstances, Wolfgang said, body weight is
maintained by a combination of food intake and energy
expenditure, how hungry the body is, and how much energy
cells need. Many cells in the body use a sugar called
glucose as a source of energy. When the body is starved,
the body literally feeds on itself, breaking down fat to
form fatty acids that fuel energy needs. When the cells of
the body are well fed and energy is in ample supply,
molecular signals from the brain tell cells in the body to
store the excess energy by converting it to fat. Weight
gain results when food intake greatly exceeds energy
expenditure. But when the brain's appetite/energy regulator
is out of whack, so are the rules for gaining and losing
weight.
"How do you know when to stop eating?" asks M. Daniel Lane,
senior author of the study and a professor of biological
chemistry in the Institute for Basic Biomedical Sciences at
Johns Hopkins. "The liver sure isn't going to tell you; it
just keeps storing fat as long as the body is well fed."
Instead, he noted, it is the control regions of the brain,
namely the hypothalamus, that govern eating behavior.
Previously, the same researchers showed that a molecule
called malonyl-CoA is critical for fat metabolism. And as
it turns out, malonyl-CoA interacts with CPT1c, Lane
said.
Increasing the amount of malonyl-CoA in the liver causes
those cells to synthesize fat, which is stored. Increasing
malonyl-CoA in the hypothalamus somehow tells the cells in
the body to break down fats for energy and the muscle cells
to use more energy. Therefore, identifying molecules that
interact with malonyl-CoA will help scientists understand
how energy balance and body weight are controlled.
"We are beginning to understand what the hypothalamus
inputs are, but unlike the liver, where nearly the whole
organ is involved in the same thing, the brain is very
specialized and only a few neurons do very specific
things," Lane said. The researchers hope to further
understand how malonyl-CoA and CPT1c function to control
body weight and appetite.
Funding for this study was provided by Astellas Pharma,
Tsukuba, Japan. Authors on the paper are Wolfgang, Yun Dai,
Seung Hun Cha and Lane, all of Hopkins; and Takeshi Kurama,
Akira Suwa, Makoto Asaumi, Shun-ichiro Matsumoto and
Teruhiko Shimokawa, of Astellas Pharma, Tsukuba.