Published: January 4, 2011. By Cell Press
http://www.cellpress.com
Researchers have found what appears to be a critical tuning dial for
controlling whole body energy, according to a new report in the January
issue of Cell Metabolism, a Cell Press publication. When energy
levels within cells drop, it sets off a series of events designed to
increase the amount of calorie-rich dietary fat that the body will
absorb.
This energy reset mechanism is surely critical for survival under
natural conditions of scarcity to ensure a steady supply of fuel, the
researchers say. Today, many of us who enjoy a Western diet loaded with
fat might do better if we could find a way to turn the activity of the
so-called AMPK-SRC-2 pathway down.
"Thousands of years ago, this would have been crucial," said Bert
O'Malley of Baylor College of Medicine. "Now it's trouble because we eat
so much fatty food."
Earlier studies had shown the enzyme AMPK to be an ancient energy
sensor. The enzyme causes cells to consume less energy in the form of
ATP and to produce more. AMPK also drives appetite.
The new work shows that AMPK also allows for the optimal absorption
of the most energy-rich fuel from the diet: fat. That effect of AMPK
depends on its activation of SRC-2, a master control gene whose job is
to switch other genes on.
When SRC-2 springs into action, it controls genes that lead to the
secretion of bile from the gall bladder into the intestine. "You need
bile to emulsify and absorb fat," O'Malley explained.
Mice lacking SRC-2 fail to absorb fat normally, they report. Those
deficiencies can be corrected by restoring bile acids to the gut.
Together with earlier work, the findings present a "pretty picture"
in which SRC-2 is involved in absorbing and storing fat. SRC-2 is also
known to play a role in releasing stored glucose from the liver. "It's
all about energy accretion, storage and delivery," O'Malley says.
This process takes place on a daily basis even when there is already
plenty of fat stored in the body. "It's designed to get in more fat," he
says. "Over evolutionary time, when you didn't know when the next meal
would be, you really couldn't get enough fat. Now, our next meal is at
the corner McDonald's."
The discovery reveals a key mechanism linking the cellular energy
state with the whole-body energy state and may ultimately have important
clinical implications, the researchers say.
"Obesity is all about fat absorption and storage," O'Malley said. "If
you could turn that down, you could have a major effect on a disease
that is slowly killing the population." He says his team is now
conducting studies in search of SRC-2 inhibitors that might do exactly
that.
