Our gut reaction to fat is that it’s bad. But fat refers to thousands of different molecules, and not only dietary lipids but those made by our bodies. Some of these synthesized lipids, according to a recent study from the lab of Gökhan Hotamisligil, may be good for us.
“There are so many fats that come from all over the place, but really the best fat is made by yourself,” said Haiming Cao, a postdoctoral fellow and lead author of the study, which was reported in the Sept. 19 Cell. Cao and his colleagues found that lipid synthesis by adipose tissue produced beneficial metabolic effects in mice, such as enhancing insulin action. They identified a particular fatty acid, palmitoleate, as being a circulating factor that regulates whole-body metabolism rather than serving as fuel. Because it performs long-distance, specific signaling, palmitoleate qualifies as a hormone. Taking a cue from a different class of signaling molecules, the cytokines of the immune system, the researchers dubbed palmitoleate a “lipokine.”
Dysregulation of lipid metabolism contributes to a wide range of metabolic diseases, but how lipids are involved—for example, in diabetes, ostensibly a disease of glucose metabolism—is not well understood. Lipids make for pesky experimental subjects, in part because it is difficult to track specific ones. Quantifying them is typically done with large mixtures. “That, I think, has led to this deductive view that … lipids go up, you get sick; lipids go down, you get well—and this is absolutely incorrect,” said Hotamisligil, who is the James S. Simmons professor of genetics and metabolism and chair of the Department of Genetics and Complex Diseases at HSPH.
Methods have emerged instead to catalog specific lipid species, known as lipid profiling, or “lipidomics.” In this study, more than 400 lipids were quantified by liquid and gas chromatography and mass spectroscopy at Lipomics Techologies in West Sacramento, Calif.
Yet making long lists of lipid levels is not all that is needed to elucidate the functions of specific lipids; having the right experimental system is critical. Here, that system was mice carrying genetic deficiencies in two adipose-specific fatty-acid binding proteins, FABP4 and FABP5 (fatty acid chaperones aP2 and mal1). Hotamisligil’s lab showed earlier that this defect protected the mice from diet-induced obesity, type 2 diabetes, and fatty liver disease. Here, they used lipidomics to track down why the mutations had these systemic beneficial effects.
The researchers found that the FABP deficiencies altered adipose lipid profiles, boosting palmitoleate levels most dramatically. Palmitoleate was also enriched in blood plasma, indicating an increase in de novo lipogenesis, since dietary palmitoleate levels are low. A high-fat diet in wild-type mice decreased adipose and plasma palmitoleate, but the mutations kept palmitoleate levels up and promoted metabolic homeostasis. Using the mutant mice and cell culture, the researchers found that palmitoleate was responsible for many of the beneficial effects of the mutations; for example, it enhanced insulin signaling and glucose uptake in muscle and suppressed lipid biogenesis in liver.
The team is now looking toward how palmitoleate operates, particularly how it is targeted to the liver. “We definitely showed a physiological effect … but we don’t understand how it happens—it’s pretty much a black box,” Cao said.
Looking to the clinic, palmitoleate levels might be a diagnostic tool. “Think about how much cholesterol put its mark on the medical field. ‘Cholesterol’ is measuring the crudest collection of lipids,” Hotamisligil said. “The possibility remains … that in humans we could produce a much higher precision and fidelity biomarker.” If palmitoleate proves to play a beneficial role in humans, Cao said, “we can eventually come to the point of starting to manipulate or boost human de novo lipogenesis.” Whether dietary palmitoleate might be beneficial is unknown.
It is tantalizing that levels of many lipids besides palmitoleate were altered by the mutations. Whether they too play specific roles is yet to be found.
Conflict Disclosure: Gökhan Hotamisligil is a member of the scientific advisory board of Lipomics Technologies, which was acquired by Tethys Bioscience in September. Two other authors, Michelle Wiest and Steven Watkins, are employees of Lipomics.
Funding Sources: The National Institutes of Health, the American Diabetes Association
