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Science Spotlight

Good Fat, Bad Fat, Gut Fat, Gonad Fat

From the Priess Lab, Basic Sciences Division

[They] told us, when I was a kid, that eggs were good. So I ate a lot of eggs. Ten years later they said they were bad. I went, "Well, I just ate the eggs!" So I stopped eating eggs, and ten years later they said they were good again! Well, then I ate twice as many, and then they said they were bad. Well, now I'm really f***ed! Then they said they're good, they're bad, they're good, the whites are good, th-the yellows - make up your mind! It's breakfast I've gotta eat! -Lewis Black

Fat. To anyone who eats, it’s, well, complicated. There’s good fat. Bad fat. Saturated fat. Unsaturated fat. Trans fat. Animal fat. Vegetable fat. Too much. Too little. On top of that, many of our culture’s food revolutions over the past 50 years have revolved around society’s, and the food science establishment’s, uncertainties and evolving perspectives on how much, and what types, of fat are appropriate. There was lard vs. vegetable oil. Butter vs. margarine. Eggs vs. egg whites. Each argument swinging back and forth through the years as new evidence came to light, leaving heads spinning as folks tried to eat right in a world where the definition of right kept changing. Like it or not, fat is an integral part of our bodies – it forms the membranes around our cells, insulates, stores energy, and supports crucial cellular functions. But our understanding of what exactly it does in our cells is, like the dietary science, still evolving. In a new paper published in PLoS Genetics, the lab of Dr. Jim Priess, a professor in the Basic Sciences Division at Fred Hutch and a member of the UW/Fred Hutch Cancer Consortium, examined an unusual form of fat storage within our bodies. And their findings? Well, like all things fat, it’s complicated.

Even in fit and healthy people, fat is found nearly everywhere in our bodies. It sits under our skin, around our internal organs, even in the cytoplasm of our cells in the form of lipid droplets. One place that has not classically been considered to contain fat, though, is the cell’s nucleus. Not, that is, until recently. “The recent discovery that fat can develop inside the nucleus of a cell, the library of genetic information, was surprising on many levels,” explained Dr. Priess. Not only because of its unexpected location but because we know so little of why it’s there and what it’s doing. It wasn’t even clear whether nuclear fat was good or bad. To better understand this unexpected phenomenon, Dr. Priess set out to study nuclear fat in the nematode C. elegans.C. elegans has become an important model for the genetic analysis of both fat and aging, and we felt it might be a useful system to investigate the causes and consequences of nuclear fat,” he said.

Dr. Priess’s group, led by technician Jose Verdezoto Mosquera, first used lipophilic dyes to identify the cells in the worm that contained nuclear fat. They found that cells in both the intestine and the gonad accumulated nuclear lipid droplets under normal life conditions. To better understand these structures, the group next performed a genetic screen to identify genes involved in their formation. This approach identified three genes that, when mutated, caused an increase in nuclear fat. Dr. Priess was eager to highlight the surprising identity of one of these genes. “Our genetic studies also revealed an unexpected role for cytoplasmic vesicles, called COPI vesicles, in the formation of nuclear fat.” While it’s not clear how COPI, which is normally involved in retrieving proteins that have inappropriately escaped from the endoplasmic reticulum, might be involved in the production of nuclear fat, “we proposed that COPI vesicles might normally play a role in the quality control of nuclear proteins, and future studies will address this.”

Finally, the group asked what the effect of these droplets might be and found that the answer was quite different between the two tissues. In the intestines, the appearance of this fat was associated with nuclear rupture and other signs of nuclear damage. “Nuclear fat in the intestinal cells…likely contributes to age-related tissue deterioration,” Dr. Priess proposed. “Surprisingly, however, the nuclear fat in gonadal cells appears to be well tolerated. For example, we identified mutants where gonadal nuclei can be nearly half-full of fat, and yet the nuclei develop into healthy oocytes.” A striking difference, and a striking example of the difficulty in pinning down just what impacts fat has on our bodies and our health.

In addition to the scientific implications of this research, Dr. Priess was proud to note that this exquisitely detailed work was done entirely by technicians and support staff. While most of the work at the center is led by postdocs and graduate students, the success of this project highlights the value of members at all levels to the science we produce.

fat in nucleus of cells
A large lipid droplet (green, arrow) surrounded by DNA (blue) inside the nuclear membrane (red) of a C. elegans intestinal cell. No = nucleolus. Image provide by Jim Priess.

Mosquera J.V., Bacher M.C., Priess J.R. (2021). Nuclear lipid droplets and nuclear damage in Caenorhabditis elegans. PLoS Genetics 17(6):e1009602.

This work was supported by the National Institutes of Health.

Fred Hutch/UW Cancer Consortium member James Priess contributed to this work.