Contact: Sarah Yang
University of California - Berkeley
Mice stay lean with high-carb diet
Berkeley -- Researchers at the
University of California, Berkeley, have identified a gene that plays a
critical regulatory role in the process of converting dietary
carbohydrates to fat. In a new study, they disabled this gene in mice,
which consequently had lower levels of body fat than their normal
counterparts, despite being fed the equivalent of an all-you-can-eat
The authors of the study, to be published in the March 20 issue of the journal
say the gene, called DNA-PK, could potentially play a role in the
prevention of obesity related to the over-consumption of
high-carbohydrate foods, such as pasta, rice, soda and sugary snacks.
which stands for DNA-dependent protein kinase, has already been the
subject of much research because it helps repair breaks in the DNA.
Suppression of DNA-PK has been used as a technique by researchers to
enhance the ability of cancer treatments to kill tumor cells. Its role
in fat synthesis, then, came as a surprise to the UC Berkeley
"It turns out that DNA-PK is critical to a
metabolic process we have been trying to understand for 20 years," said
Hei Sook Sul, a professor in UC Berkeley's Department of Nutritional
Science & Toxicology and head of the research team behind these new
findings. "For the first time, we have connected DNA-PK to the
signaling pathway involved in the formation of fat from carbohydrates
in the liver. Identifying this signaling pathway involving DNA-PK
brings us one step forward in understanding obesity resulting from a
diet high in carbohydrates, and could possibly serve as a potential
pharmacological target for obesity prevention."
After a meal
of pizza and soda, it is known that levels of blood glucose - the
digested form of carbohydrates - go up. That rise in blood glucose
triggers the secretion of the hormone insulin, which helps different
cells in the body use glucose for energy. Glucose in the liver that
isn't burned for energy turns into fatty acids, which then circulate to
other parts of the body, primarily to fat tissue.
conversion of excess glucose into fatty acids occurs in the liver, but
the exact molecular pathway involved has not been fully understood
until now. Researchers have known that insulin binds to receptors on
the liver cells, which activates protein phosphatase-1 (PP1), the first
molecule of the insulin-signaling pathway inside the liver cell. Sul's
lab had previously shown that upstream stimulatory factor (USF) is
needed to activate certain genes, such as fatty acid synthase (FAS),
which converts glucose to fatty acids.
The link between PP1
and USF was still a mystery until Roger H. F. Wong, a UC Berkeley
graduate student in comparative biochemistry in Sul's lab, finally
connected the dots through proteomic sequencing. He found that DNA-PK,
which is regulated by PP1, controls the activation of USF and the
subsequent conversion of glucose to fatty acids.
link was DNA-PK," said Wong. "We determined that DNA-PK acts as a
signaling molecule in the chain reaction that begins when insulin binds
to receptors on liver cells. This helps explain why untreated Type 1
diabetics, who cannot produce insulin, may experience significant
weight loss. Without treatment, they basically have trouble making
"This insulin-signaling pathway is also disrupted
in Type 2 diabetes, in which the body still produces insulin, but the
cells become resistant to its effects," said Wong.
identifying DNA-PK, the researchers put the gene to the test in mice
fed a diet containing 70 percent carbohydrates, but no fat. A typical
lab mouse diet is made up of both fat and carbohydrates. Half the mice
had the DNA-PK gene disabled, and the other half comprised a control
group of normal mice.
"The DNA-PK disabled mice were leaner
and had 40 percent less body fat compared with a control group of
normal mice because of their deficiency in turning carbs into fat,"
said Wong. "The knockout mice were resistant to high
carbohydrate-induced obesity and had lower plasma lipids, which can
reduce the risk of cardiovascular disease. With all of these health
benefits, this gene can serve as a potential pharmacological target for
The researchers noted that although
interest in low-carb diets persists, there are many sources of
carbohydrates, including fruits and vegetables, legumes and whole grain
breads and pastas, that have important nutritional benefits.
best way to control your body weight is to eat a well-balanced diet and
limit your caloric intake," said Wong. "We hope that this research will
one day help people eat bread, pasta and rice and not worry about
study is part of the larger research effort by the Sul lab to
understand the molecular mechanisms underlying the synthesis of fatty
acids, creation of fat cells and how fat is stored in the body.
Recently, the lab published a study in the journal
describing how a molecule called Pref-1 blocks the creation of fat
cells. Two months ago, the discovery by Sul's lab of an enzyme called
AdPLA critical to the breakdown of fat cells, was published in the
Nature Medicine. This latest paper in
Cell details the very first step of fat synthesis - making fat from carbohydrate.
co-authors of this study are members of Sul's lab and include several
undergraduate students in the Department of Nutritional Science &
The National Institutes of Health helped support this study in