Mone Zaidi, MD, PhD
A single hormone whose levels rise at menopause could be responsible for the weight gain and bone loss that many women experience in middle age, and blocking that hormone could help reverse those effects, according to a study in mice that was led by Mone Zaidi, MD, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease), at the Icahn School of Medicine at Mount Sinai. The strong clinical potential of these results has been noted in The New England Journal of Medicine, and in Nature Medicine, which in December 2017 named the study one of the year’s eight “notable advances.”
The work began about 10 years ago when Dr. Zaidi challenged endocrinology’s long-held notion that the pituitary follicle-stimulating hormone (FSH) controlled only reproductive targets: the production of estrogen in women and sperm in men.
Using animal models, Dr. Zaidi showed that FSH had direct effects in conserving bone. That discovery piqued Dr. Zaidi’s curiosity: Could FSH also play a role in the sharp increase in visceral fat that occurs in women during late perimenopause?
To answer the question, his group conducted a study that included injecting a polyclonal antibody that blocked FSH signaling into several groups of mice: females that had their ovaries removed and were fed a normal diet; male and female mice that were fed a high-fat diet; and female mice on a normal diet.
“What we found was that by targeting FSH and blocking its action, we could not only prevent bone loss but also reduce body fat and improve energy homeostasis,” he observes. “We thought to ourselves, ‘This is really a weird finding.’”
Dr. Zaidi, who is founding director of the Mount Sinai Bone Program, then enlisted the support of Clifford J. Rosen, MD, a bone and fat expert who is Director of the Center for Clinical & Translational Research at the Maine Medical Center Research Institute. For the next two and a half years, the scientists replicated each other’s work, culminating in the publication of a comprehensive study in the June 2017 issue of the journal Nature. Their findings confirmed that blocking access of FSH to its receptor using an epitope-specific polyclonal antibody resulted in increased bone mass and a marked reduction in visceral fat in ovariectomized mice. As for the possible mechanism behind these changes, Dr. Zaidi found that the antibody reduced white adipose tissue—where fat is stored—and converted it to brown (or beige) adipose tissue, the type of fat that is burned to provide energy.
Images from the study in Nature show CT scans of the abdomens of mice that were fed a high-fat diet. The amount of visceral fat (in red) was significantly lower, right, when a mouse was injected with an antibody to the follicle-stimulating hormone, compared with a mouse injected with the control substance IgG.
In humans, a version of the antibody used in his study might be able to simultaneously treat bone loss and fat accumulation in women, offering a new approach to associated medical conditions, such as osteoporosis, cardiovascular disease, cancer, and diabetes. And because the antibody was found to be effective in both male and female mice, the benefits could extend to both genders in humans, particularly in controlling obesity.
Dr. Zaidi points out that two classes of obesity drugs are currently on the market: those that suppress appetite and those that reduce the absorption of fat from the gut. Both classes, however, come with significant side effects.
“The FSH-blocking antibody works on neither of these sites, but instead acts directly on fat cells by converting white to brown fat tissue,” Dr. Zaidi says. “This is truly a new game.”
In collaboration with Mount Sinai Innovation Partners, Dr. Zaidi is exploring opportunities to realize the vast potential of this research through commercial partnerships.