What if controlling the appetite were as easy as flipping a switch? It sounds like the stuff of science fiction, but Jeffrey Friedman of Rockefeller University and his colleagues did exactly this in genetically engineered mice to try to shed light on how the brain influences appetite. Friedman and his colleagues used magnetic stimulation to switch on neurons in a region of the brain called the ventromedial hypothalamus and found that doing so increased the rodents' blood sugar levels and decreased levels of the hormone insulin. Turning on the neurons also caused the mice to eat more than their control counterparts. The ultimate confirmation came when they inhibited these neurons and saw the opposite effects: it drove blood sugar down, elevated insulin levels and suppressed the animals' urge to consume their chow.
That the brain influences hunger is not an unexpected finding, but scientists have recently narrowed in on how it has sway on what ends up in the gut—and how the gut talks to the mind. This two-way communication, defined as the 'gut–brain axis', happens not only through nerve connections between the organs, but also through biochemical signals, such as hormones, that circulate in the body.
“The idea that there is bidirectional communication between the gastrointestinal tract and brain that affects metabolism traces back more than a century,” Friedman says, referring to the work of the nineteenth-century French scientist Claude Bernard, who made seminal discoveries into how the body maintains physiological equilibrium. “Our new findings that insulin-producing cells in the pancreas can be controlled by certain neurons in the brain that sense blood sugar provides further experimental evidence supporting this notion.”
The gut–brain axis seems to influence a range of diseases, and researchers have begun to target communication pathways between the nervous system and the digestive system in an attempt to treat metabolic disorders specifically. This makes sense to neuroscientist Daniele Piomelli, who has studied the connection at the University of California, Irvine. “There's every reason to be excited, because clearly the gut and brain are two peas in a pod and they really work together,” Piomelli sees potential in learning more about how the gut and brain communicate. “If we are able to find ways to understand that and to leverage that for therapeutic purposes, that will be key,” he says.
There are still some lingering worries about targeting the brain for metabolic disorders and their symptoms. Some of the concern traces back to a decade ago in June 2006, when European drug regulators approved the medication rimonabant for sale as a weight-loss medication. Rimonobant worked by blocking certain receptors in the brain involved in the so-called endocannabinoid system—switching off the same circuits that induce hunger from cannabis use—and it was effective. But because it sometimes caused psychiatric side effects, including a possibly heightened risk of suicide, the drug never made it through the approval process in the US. The maker of the drug, Sanofi-Aventis, pulled the product off the market a couple of years later, and in 2009, the European Commission withdrew its approval of the drug.
Still, the urgency of treating metabolic disease compels researchers and pharmaceutical companies to strive for new solutions. Worldwide, the number of people who are obese continues to climb, and last month, US government statistics showed that, for the first time, around four in ten women in the country fell into this category—more than the proportion of men classified as obese. Meanwhile, the number of individuals with diabetes has nearly quadrupled worldwide since 1980, now affecting around 415 million adults, the majority of whom have type 2 diabetes. Given the twin epidemics of obesity and type 2 diabetes, the new wave of efforts to target the gut–brain axis to reverse these conditions has great momentum behind it.
Companies planning to target the gut–brain axis have raised upwards of $40 million in initial financial backing from investors. From industry to academia, researchers are deploying an array of different tools to target the ongoing dialogue between the two organs as a way to treat metabolic disorders and help people to lose weight. The approaches range widely, from surgical interventions and devices, to probiotics and even drugs delivered via nasal sprays.
Mimicking the benefits of bariatric surgery
Aayed Alqahtani, who directs King Saud University's obesity treatment center in Saudi Arabia's capital Riyadh, has performed more than 4,000 bariatric surgeries, a broad category of procedures in which a patient's stomach size is reduced or in which their digestive system is rerouted. Of this number, around 700 of the treatments were for individuals with diabetes. Alqahtani stresses that, over the past decade, the medical community has come to appreciate the ability of bariatric surgery to reverse diabetes in many people, which culminated in guidelines published in May that recommend the procedure for individuals with diabetes. The new guidelines received support from numerous organizations, including the American Diabetes Association. “It's a historic moment,” Alqahtani says, stressing the benefits of surgery for those with diabetes. “It's the most effective option.”
Many of the mechanisms that underlie how gastric bypass and bariatric surgery produce metabolic benefits remain unclear, but researchers do know, for example, that these procedures elevate levels of the hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), which help to reduce appetite and have effects on the central nervous system. Still, Alqahtani notes that only a fraction of those who would benefit from these procedures receive them, with many prevented by a lack of health-insurance coverage, among other reasons.
Scott Shikora, who leads the Center for Metabolic and Bariatric Surgery at Brigham and Women's Hospital in Boston, says medical devices might provide an alternative if they can mimic the benefits of bariatric surgery. Shikora also serves as chief medical officer of EnteroMedics, a company that makes a weight-loss device called the Maestro Rechargeable System. The device sends electrical pulses to the vagus nerve, thereby blocking some of the signals the nerve carries between the brain and digestive tract. The procedure for inserting the Maestro device is minimally invasive and involves only a handful of small incisions around the abdomen. Two miniature, candy-cane-shaped electrodes are hooked around the left and right trunks of the vagus nerve near where the esophagus joins the stomach. For 12 hours a day, the implanted device interrupts signals from these extensions by applying a constant electrical current, and this, for reasons that are still not totally clear, encourages a feeling of fullness.
The data are encouraging: in a clinical trial published in May, 53 participants with moderate obesity who received the Maestro device lost about 11% of their total weight, as compared with 6% among those who received the sham treatment. According to Shikora, data from a two-year follow up of an earlier study found that individuals who received the device kept the weight off, whereas those in the control group regained the pounds that they had initially shed.
The Maestro device received approval from the US Food and Drug Administration (FDA) in January 2015, becoming the first new medical device for obesity approved by the agency in a decade.
The oversized mice studied by Michael Schwartz, who directs the University of Washington Diabetes Institute in Seattle, belong to a strain prone to obesity. These mutant rodents eat excessively, and as their weight balloons, they develop many of the hallmarks of metabolic disease—including elevated blood sugar levels that resemble those seen in humans with diabetes. By using these animals as a model organism, Schwartz provided evidence that targeting the brain directly could perhaps offer a possible treatment for diabetes. In a paper published in Nature Medicine, he and his collaborators show that a single injection of a fibroblast growth factor 1, or FGF1, into the ventricles of these hefty mice caused sustained remission of the diabetic-type condition in the mice for the entirety of the 18-week study. The group also demonstrated FGF1's ability to cause remission in genetically normal mice that have developed diabetes-like traits due to the loss of insulin-secreting cells.
Schwartz is looking towards developing a nasal spray to deliver a drug to the brain that mimics the activity of FGF1. He is collaborating with the pharmaceutical company Novo Nordisk in an effort to translate the findings from his preclinical work to humans. Other growth factors similar to FGF1 have also been shown in rodent studies to influence blood sugar levels when administered to the brain. “Since the brain is doing the heavy lifting of actually impacting glucose homeostasis, I think the brain is capable of doing remarkable things with respect to antidiabetic properties,” Schwartz says. “In my view, that's where the best opportunity for breakthrough treatment exists.”
Sadaf Farooqi, who studies obesity at the Wellcome Trust–MRC Institute of Metabolic Science in Cambridge, UK, is also exploring the idea of targeting the brain. She has set her focus on specific populations of neurons in the hypothalamus, a part of the brain measuring about one centimeter in diameter that integrates innumerable body functions, including hunger and satiety.
The satiety hormone leptin works by encouraging certain neurons in the hypothalamus to produce pro-opiomelanocortin (POMC), which in turn contributes to the activation of melanocortin-4 receptor (MC4R) in nearby cells, and ultimately encourages signals sent through the vagus nerve and other circuits that suppress food intake. Mutations in MC4R can make the receptor work less efficiently and are estimated to affect up to 6% of people who have experienced severe obesity since childhood.
Farooqi has collaborated with Boston-based Rhythm Pharmaceuticals to test the company's potential therapeutic called setmelanotide, which acts on the hypothalamus to activate MC4R. In January, Rhythm Pharmaceuticals announced that the drug had received breakthrough therapy designation from the FDA for the treatment of obesity caused by POMC deficiency. The designation means that setmalontide can undergo an expedited review by the agency, and it is the first such designation from the FDA's Division of Metabolism and Endocrinology Products.
Investors are eager to jump into the metabolic-disorder space. Last August, Rhythm Pharmaceuticals announced that its subsidiary, Rhythm Metabolic, which is developing setmelanotide, raised $40 million in a recent financing round. And in December, the newly formed biotechnology company Kallyope announced its launch in New York with financing of $44 million in hopes of “harnessing the potential of the gut–brain axis”. The company is building a platform technology to enable the discovery of new targets in the field of gastrointestinal biology (as well other areas beyond metabolic disorders). Kallyope's CEO, Nancy Thornberry, told Nature Medicine that the technologies that it plans to use to explore the gut–brain axis “include single-cell sequencing, bioinformatics, functional imaging, optogenetics and chemogenetics.”
Listening to everything in the gut
In the laboratory of endocrinologist Fiona Gribble and her husband, biochemist Frank Reimann, dozens of thin black cables run out from racks of electronic amplifiers, ultimately feeding input into computer terminals that display recordings that, from a distance, resemble the wave representation of an audio file. But the source of the data is not the sound of a person's voice or a musical instrument—it is the electrical activity of an intestinal cell. Gribble and Reimann share the lab space at the Wellcome Trust–MRC Institute of Metabolic Science. The two started working together on gut hormones in 2001, and the following year, they co-authored a paper showing that glucose can trigger cells derived from mouse intestinal cells, known as 'L cells' to fire electrical impulses and release a hunger-abating hormone called GLP-1.
“It wasn't known when we started out that the L cell is electrically excitable,” Reinmann explains. “It had to be discovered,” Gribble adds. “When we first did our electrical recordings and showed that they fired an action potential, this was the first time this had been shown. It was very exciting.” The findings of this cell behavior underscored the similarities between cells of the nervous system and those of the gastrointestinal system.
More recently, Gribble and Reinmann have also published data on how byproducts known to be produced by the gut microbiome, such as short-chain fatty acids, might influence appetite. For example, in a study in 2012 using colon cells and in mice, they showed that short-chain fatty acids prompt the secretion of the hormone GLP-1, which is already marketed as a treatment for diabetes and has a mitigating effect on hunger. In light of this, future therapies for metabolic disorders could hypothetically include ingesting prebiotics such as fiber, which is converted by gut bacteria into short-chain fatty acids.
There is growing awareness of and interest in how gut microbes listen in on—and modulate—the conversation between the gut and brain. Inspired by his early findings into how bacteria act in the gut and influence appetite, Serguei Fetissov of France's Rouen University incorporated a company called TargEDys in 2011 to develop treatments for metabolic disorders. The start-up remained dormant initially, but recent studies from Fetissov's lab show how much can change in a few years. In November, his group published a study in which they injected rats and mice with proteins normally produced by the common intestinal bacteria Escherichia coli about 10 minutes and 2 hours after eating. The infusions of proteins from these time intervals stimulated the release of the appetite-suppressing hormones GLP-1 and PYY, respectively, and also caused the animals to eat less.
Fetissov is trying to replicate these effects in the rodents by using a probiotic to hasten the proliferation of E. coli and boost production of appetite-reducing proteins, rather than by administering injections of the bacterial protein products. And, in April, TargEDys announced that it was gearing up for human clinical trials. Grégory Lambert, who is CEO of TargEDys, says that the company is developing a capsule containing freeze-dried probiotic bacteria to replicate the appetite-quelling benefits seen in rodent studies. Lambert adds that they also have another protein of interest, which is produced by bacteria and may activate hunger. They are studying it as a potential therapy for anorexia or in elderly people who have a loss of appetite.
Piomelli, meanwhile, has helped to uncover how digested fat is converted in the intestine into a lipid messenger called oleoylethanolamide (OEA), which ultimately helps to satisfy hunger. OEA seems to act on the brain, according to evidence from rodent studies and preliminary brain imaging data from humans. “OEA is a natural compound,” Piomelli says, which makes it difficult to patent and commercialize—a point of frustration for him because it makes it harder to drum up investment for further research. “It's a freaking shame. It's horrible. The compound works in rats, it works in mice, it works in dogs, it works in goldfish.” He notes that some nutriceutical companies are selling it as a supplement, but he says what is really needed is rigorous human clinical trials. Piomelli has evidence from a mouse model of Prader–Willi syndrome—a congenital disorder that causes obesity—showing that OEA stops overeating, and he hopes to obtain funding to test it in people with the human version of the rare genetic condition.
The range of interventions that target the gut–brain axis continues to expand with the science. Francesco Rubino, who heads the metabolic and bariatric surgery section of King's College London, explains that the initial thinking about how surgery worked so well to reverse metabolic disease focused heavily on the hormones involved. “We ended up finding out that, in addition to hormones, there are bile acids that are important as well for metabolism. And then we found that microbiota are important,” Rubino says. He notes that, more recently, researchers have uncovered how changes in the gut might be linked to inflammation in the brain, and how the alimentary canal is affecting metabolism in concert with the nervous system. “There are so many things that are starting to surface now as we discover that the gut is no longer just a digestive organ—it's a metabolic organ.”
This article is reproduced with permission and was first published on July 7, 2016.