Protein Flips Switch between Burning and Storing Fat, Highlights Potential Obesity Target

Studies in mice by researchers at the University of California, San Francisco (UCSF), have identified a role for a single protein in regulating diet-induced obesity. The research, reported in Nature Metabolism, found that weight gain in mice in which activity of the protein, called eIF4E, was inhibited either genetically or by using a compound that is in clinical development against cancer, was only half that of control mice, even if all the animals were fed the same high-fat diet. “These mice were basically protected from weight gain,” said senior author Ruggero, PhD, the Helen Diller Family Chair in Basic Cancer Research at UCSF, “and their livers were more healthy and not full of fat droplets.”

In their published paper, which is titled “The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity,” the authors say their results highlight a new potential drug target for treating obesity. “Targeting mRNA translation may become a novel way to cure obesity,” said UCSF co-first author Haujun Yang. This newly discovered fat-burning mechanism could also be of interest to athletes who want to increase their endurance, said co-first author, Crystal S. Conn, PhD, who is now assistant professor at the University of Pennsylvania’s Perelman School of Medicine.

Diet-induced obesity is an epidemic worldwide, the authors wrote, and the incidence has nearly tripled over the last half century. The team cites figures indicating that nearly 40% of all adults globally are either overweight or obese. Obesity develops when the body lays down excess fat as a consequence of taking in more calories—particularly consumed as fats—than are expended as energy over time, they explained. “It has been shown that an abundance of dietary fats, over carbohydrates or protein, plays the leading role in regulation of diet-induced obesity.”

The eIF4E protein plays a critical role in initiating protein synthesis and is found in all cells of the body. During the process of translation, strands of messenger RNA (mRNA) carry protein-making instructions from genes to ribosomes, the cellular machines in which proteins are made. In organisms ranging from yeast to mammals, eIF4E forms a key part of a complex that binds to a cap at the end of each mRNA strand and guides the mRNA to ribosomes. It’s thought that eIF4E is therefore essential for the production of all proteins.

Because of the importance of eIF4E in protein synthesis, a full complement of eIF4E was, until recently, viewed as essential to life. However, in 2015, Ruggero’s research group made the surprising discovery that mice that were genetically modified to carry just one copy of the gene for eIF4E (eIF4E+/- mice) – and thus only half the amount of the eIF4E protein found in normal mice—were still able to synthesize proteins and developed normally. “We previously showed that, surprisingly, reduction of the dose of eIF4E in vivo does not affect global protein synthesis and cellular homeostasis,” they noted in the Nature Metabolism paper.

The Ruggero team continued to explore whether there might be more subtle effects of eIF4E deletion in certain living conditions. “In asking what benefit an abundance of eIF4E may normally provide at the organismal level, we examined the role of eIF4E and cap-dependent translational control in response to metabolic stress.”

For their newly reported experiments, the team, led by former UCSF postdoctoral researcher Crystal S. Conn, PhD, and current Ruggero lab postdoc Haojun Yang, PhD, fed a high-fat diet to both normal, wild-type (WT) mice, and to the heterozygous eIF4E+/- mice, for five months. They found that the modified mice only gained half as much weight than their counterparts, suggesting that eIF4E activity is involved in fat storage.

An excess of dietary fats gets deposited as lipid droplets (LDs) in organs including the liver, and the study results showed that in comparison with the livers of control mice fed a high-fat diet, the livers of the eIF4E-modified mice contained far fewer, and smaller lipid droplets. Liver analyses indicated that eIF4E acts to alter lipid processing in the livers of animals fed a high-fat diet.

Given these findings, the Ruggero group also took a closer look at how eIF4E might control obesity. UCSF’s Alma Burlingame, PhD, professor of pharmaceutical chemistry, used mass spectrometry to profile proteins in both the normal and heterozygous eIF4E+/- mice. The resulting data showed that many of the proteins present in eIF4E-modified mice were not only reducing lipid storage in the liver, but also boosting lipid metabolism—essentially, the mice could eat more and also burn more fat. “If you put each type of mouse on treadmills or made them run a marathon, eIF4E-modified mice would always win—they could keep going because they can burn the lipids,” said Ruggero.

The team also tested a drug called eFT508 (tomivosertib), which inhibits eIF4E, and is currently in clinical trials for various forms of cancer. eFT508 is being developed by eFFECTOR Therapeutics, a biopharmaceutical company co-founded by Ruggero, which is developing cancer drugs that target translation. eFT508 selectively blocks eIF4E phosphorylation, a mechanism used by proteins to regulate one another that effectively works as a light switch to turn a protein “on” or “off.”

In the case of eIF4E, phosphorylation encourages cells to store fat, whereas blocking phosphorylation encourages them to burn fat as fuel. As a result, mice fed a high-fat diet that were also treated with the translation inhibitor gained much less weight than mice that received a control drug. “Strikingly, WT mice treated with eFT508 gained significantly less weight than littermates treated with vehicle,” the investigators wrote. “As with eIF4E+/− mice, eFT508 treatment markedly reduced both HFD-induced liver weight and lipid accumulation, leading to significantly less steatosis with a lower NAFLD activity score.”

They concluded, “Here we unexpectedly discovered that diminished eIF4E levels can enhance metabolic fitness and, in turn, prevent obesity while feeding a diet enriched in lipids … Importantly, we uncovered a unique mechanism for eIF4E-dependent translation in the control of lipid processing, transport, storage and LD growth.”

The findings have therapeutic implications for obesity and related disorders, the scientists noted. “Together, our study uncovers translational control of lipid processing as a driver of high-fat-diet-induced weight gain and provides a pharmacological target to treat obesity.” Obesity is a risk factor for cancer, and the studies provide an intriguing new perspective on this link, Ruggero said. He hopes that researchers will more deeply investigate the role of this translation factor in obesity, cancer, and the relationship between the two. As the team noted in the paper, eFT508 is already in Phase II clinical trials against cancer. “Because it is clear that reduction of eIF4E activity is advantageous in halting tumor growth, our results provide a compelling rationale to test eIF4E inhibitors in tumors associated with obesity …” they stated.

Moving forward, Ruggero is also keen to study whether the eFT508 translation inhibitor can prevent or treat other features of obesity, including non-alcoholic fatty liver disease, or NAFLD—a severe form of liver damage from obesity that may lead to liver cancer.