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' pasta buffet.
The authors of the study, to be published in the March 20 issue of the journal Cell, 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.
DNA-PK, 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 researchers.
"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.
This 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.