Palmitoleate—an unconventional fat discovered in 2008 at the Harvard School of Public Health (HSPH)—prevents cardiovascular disease when fed to lab animals, according to a study published today in Science Translational Medicine. Senior author Ebru Erbay co-discovered the molecule (with Haiming Cao) while she was a postdoctoral fellow at HSPH from 2004 to 2010; she is now an assistant professor at Bilkent University in Ankara, Turkey. She and her Ankara co-authors, collaborating with Simmons professor of genetics and metabolism Gökhan Hotamışlıgil of HSPH and scientist Steven M. Watkins of Metabolon, show that oral delivery of palmitoleate at levels three times that found in the typical Western diet (currently, just .38 percent) was enough to prevent clogged arteries in mice.
Even more surprising, says Erbay, the palmitoleate is incorporated into the membranes of an intracellular organelle called the endoplasmic reticulum (ER), which is involved in triggering inflammatory responses to “bad lipids.” “This dynamic membrane remodeling of ER by oral palmitoleate intake has remarkable impact on the organelle’s functioning,” she says. The beneficial lipid makes the mice resistant to the stress caused by elevated levels of harmful fat in the blood, of the kind that might be caused by poor diet and lifestyle. Erbay says it is “an example of how we can manipulate our dietary fat intake to uncouple metabolic stress—largely felt at the level of our organelles—from inflammation that is causally associated with” the development of atherosclerosis and diabetes.
Hotamışlıgil notes that the mode of action of this lipid is highly unusual. “We initially identified [palmitoleate] as one that has a very beneficial hormonal activity in the context of diabetes and also fatty liver disease,” he says. “Now Erbay is describing that orally supplementing this lipid could actually have fairly significant impact on cardiovascular disease in experimental models. And she has found the mechanism by which it might be achieving at least some of its effects.”
Among lay people and scientists alike, fats are usually thought of as harmful substances to stay away from, he notes. “But lipids are a very rich and diverse and vast collection of molecules, and within that collection there are really untapped treasures. This is really an incredible one, actually—a very simple molecule with very dramatic physiological effects.”
A research group in Colorado, for example, has shown that circulating palmitoleate produced within the body by a variety of organisms, including humans, increases in pythons undergoing the extreme metabolic adaptation necessary to consume a large meal after a long period of starvation. This increase leads to organ growth, particularly of the python’s heart. The researchers also showed that feeding the snakes a lipid mix that included palmitoleate led to healthy heart growth.
And intriguingly, palmitoleate may be linked to caloric restriction: mice that had been genetically modified in a way that mimicked some aspects of caloric restriction (a drastic reduction in caloric intake that has been show to lengthen lifespan in many animals) began to release the fat in large quantities. That led to the initial discovery of the molecule at HSPH. Whether molecules like palmitoleate may actually be responsible for some of the beneficial effects of caloric restriction, says Hotamışlıgil, will require further investigation.
A recent trial in humans, says Erbay, showed that palmitoleate suppressed the levels of typical markers for cardiovascular disease. But epidemiological studies of its impact in humans have yielded mixed results—perhaps because its typical dietary sources also include harmful fats. Palmitoleate is present, for example, in macadamia nuts, which also contain palmitate, explains Hotamışlıgil; the latter’s effects directly oppose those of palmitoleate—so ingesting the fat from natural dietary sources is not recommended.
Hotamışlıgil is “extremely optimistic” about the possibility of synthesizing a pure form of palmitoleate and testing it in controlled intervention studies—human clinical trials. “It is a very simple molecule with really no predicted side effects. That is the beauty of finding molecules like this,” he adds. “But the danger is people think that you can just eat something and get it. It is not that simple.”
Update: a previous version of this article misspelled palmitoleate. It is palmitoleate, not palmiteolate.
