Insights into how Novo Nordisk's Saxenda cuts food cravings may inspire new obesity drugs

Novo Nordisk’s obesity drug Saxenda, which shares the ingredient liraglutide with the company's diabetes treatment Victoza, has been shown to reduce appetite. The drug is an analog of naturally occurring GLP-1, a hormone that’s released after food intake to create the sensation of fullness. But the exact neuronal sites the drug affects remain largely unknown.

Now, scientists at the University of Pennsylvania have shown that a subset of neurons in the nucleus tractus solitarius (NTS) region of the brain may play a part in Saxenda’s appetite-suppressing effect, according to a new study published in Science Translational Medicine.

“This discovery opens up the door for future obesity drug treatments that could be used in conjunction with this FDA-approved therapy to treat obesity,” the study’s senior author, Matthew Hayes, Ph.D., said in a statement. “The more we understand how drugs act, the more we can understand what other brain systems can be manipulated in combination with them to help patients lose more weight.”

GLP-1 is produced in the small intestine and stimulates insulin secretion—a mechanism that’s leveraged by several popular Type 2 diabetes meds—and its activity in the brain is linked to satiety-inducing effects. Previously, researchers have found abundant expression of GLP-1 receptors in the NTS, which relays nerve signals from the gastrointestinal and cardiovascular systems. So Hayes and colleagues explored NTS’s role in helping Saxenda regulate food intake.

First, they knocked down the expression of GLP-1 receptors in the NTS of rats and compared them to normal rats. They found liraglutide reduced feeding behavior in normal animals at a more significant rate than it did in the modified rats. 

Further investigation of the exact NTS cells that bind liraglutide pointed to neurons that produce GABA, a key inhibitory neurotransmitter. The researchers found about 37% of NTS GLP-1 receptors are expressed on GABA neurons. They also demonstrated that selectively blocking NTS GABA neurons prevents liraglutide from exerting its appetite-suppressing effects.

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The liraglutide finding adds to a growing body of discoveries by UPenn scientists related to obesity. Another team there suggested in 2016 a protein called FLCN could be targeted to activate the “browning” of unhealthy white fat cells into energy-burning brown fat. And a group led by microbiologist Christoph Thaiss, Ph.D., showed gut microorganisms keep a biological clock, the disruption of which can make mice and humans more prone to becoming obese.

Since its 2014 FDA approval, Saxenda has become a top-selling obesity therapy, with about 56% share of the global obesity prescription drug market, according to Novo Nordisk. In 2019, sales of the product jumped 47% to reach 5.68 billion Danish krones ($850 million).

In clinical trials, Saxenda outperformed placebo in reducing weight by 4.5% in patients without diabetes. But Hayes’ team argues that improved weight-management drugs are still needed—and that NTS may serve as a new strategy for drug development.

“Our finding that GABA neurons in the NTS are important for the anorectic effects of liraglutide may prove to be meaningful in the future,” the study’s first author, Samantha Fortin, said in the statement. “Other compounds or genetic manipulations that would target this distinct population of cells in the brain could be useful in treating obesity.”

The researchers are also exploring other GLP-1 drugs and in combination with other experimental therapies to see whether GABA neurons in NTS are also key in their interactions.