Hungering for obesity treatments

Fueled by chips, cookies, and other high-calorie snacks, our expanding waistlines pose a hefty problem. The World Health Organization dubbed obesity a global health epidemic in 2003. As of 2015, one-third of adults in the U.S. are obese, and an additional one-third are overweight. As obesity rates soar, so do their associated health problems, which include diabetes, heart disease, and more. With an epidemic of these proportions, researchers have long sought simpler cures—ones that can be bottled.

Early weight-loss drugs, which used molecules such as dinitrophenol and sibutramine, were introduced and later withdrawn because of their dangerous side effects. Until a few years ago, the only obesity medication approved in both the U.S. and Europe was orlistat, a molecule that blocks intestinal nutrient absorption but does little to abate appetite.

But that’s changing. The discovery of two key hormones that control weight and appetite—leptin and ghrelin—in the 1990s electrified researchers hunting for obesity medications. Although drugs targeting these molecules met with little clinical success, their discovery paved the way to a better understanding of the complex mechanisms that control our cravings and how our bodies respond to food.

“A few years ago there were really no pharmaceutical treatments for obesity,” says Gregory J. Morton of the University of Washington. “Now, there’s a pipeline of certain viable treatments that act in part through the central nervous system—that’s where a lot of the basic science is starting to reap some rewards.” In addition to looking to the central nervous system (CNS) for targets, researchers are also testing combinations of medications that reach more than just one biochemical pathway as a way to finally effectively control obesity.

Searching for hunger hormones

In 1994, Jeffrey M. Friedman of Rockefeller University discovered leptin, a hormone secreted by fat cells that acts in the brain to suppress eating, keeping weight gain in check. Mice lacking the leptin gene are grossly overweight and can’t stop eating. And when normal animals (or people) lose weight, leptin levels drop as fat cells disappear, so the individuals get hungrier, often leading to weight gain once again.

Leptin acts over days and weeks. But what makes us hungry for lunch mere hours after breakfast, when we haven’t lost any significant fat stores between the two meals?

Six years after leptin’s discovery, researchers led by Masayasu Kojima of Kurume University found a clue: the so-called hunger hormone, ghrelin. Kojima’s and other researchers’ work revealed that ghrelin is a peptide secreted by the stomach that spikes before mealtimes and travels to the brain via the bloodstream. There, among other things, it acts on the hypothalamus to boost appetite and triggers hunger-related neurotransmitter release. Ghrelin was “the long-sought mediator of appetite and meal initiation signal,” says David E. Cummings of the University of Washington, who did some of the early work on ghrelin.

To this day, ghrelin is the only known appetite-stimulating hormone; other molecules signal satiety or suppress appetite. Several studies have proved its dramatic effects: Animals lacking ghrelin eat less and are resistant to diet-induced weight gain, and humans and animals who are given doses of ghrelin eat more and pack on the pounds. A human genetic condition called Prader–Willi syndrome increases ghrelin levels and can cause uncontrollable eating and obesity in children.

Ghrelin’s potent effects led to a flurry of research on ghrelin-blocking molecules as a new route to potential obesity drugs. But in animal studies, even when ghrelin antagonists were found safe and capable of blocking the hormone’s activity, they failed to treat obesity. “No one has designed a ghrelin receptor antagonist that actually suppresses feeding behavior,” says Roy G. Smith of Scripps Research Institute Florida.

In addition to leptin and ghrelin, other factors that control feeding behaviors have been discovered over the decades, some as early as the 1970s. Protein sensors in the stomach register stretch, pressure, and volume changes when food enters the organ, creating a sense of fullness. Intestinal endocrine cells also release a slew of signaling hormones when they encounter food, including glucagon-like peptide (GLP-1), peptide YY, and oxyntomodulin. “All these peptide hormones have been considered as potential drug targets to treat obesity,” Cummings says.

But drugs designed with specific peptide hormones in mind have failed, in part, because our responses to food are surprisingly complex. The drive to eat is powerful; over millennia, it has motivated humans and animals—both predator and prey—to venture beyond safe shelters to hunt and forage in the wild. To encourage these risky behaviors, many of the gut and brain signals that trigger hunger and satiety also evolved to be intricately linked to motivators such as stress, fear, and reward seeking. The hormonal, neural, and physical signals that sync up to control eating create multiple, often redundant, links between short-term eating behaviors and long-term body weight.

Shifts over time mean many people now eat as a reward, to control stress, or in response to other cues. “The human brain has a much more complex reaction to food and control of appetite than rodent or primate brains,” says Olivia M. Farr of Harvard Medical School. “To get at the heart of obesity, we really need to study the human brain.”

Recent studies are starting to show how intestinal peptides, hormones such as leptin and ghrelin, and other cues converge in the brain. In addition to intestinal secretions, common neurotransmitters such as dopamine, serotonin, and norepinephrine also tweak sensations of hunger and satiety. And all these signals act in concert across multiple brain regions.

Farr, who works in Christos S. Mantzoros’s lab at Harvard, uses brain imaging techniques to study how different hormones and foods trigger distinct responses. For example, Farr and her colleagues tested a leptin analog in people and observed which areas of the brain it activated (J. Clin. Endocrinol. Metab. 2014, DOI: 10.1210/jc.2014-2774). “We saw that leptin acts in many areas of the human cortex, not just the hypothalamus.” But in obese people, leptin may fail to act on these targets correctly. Being able to pin these CNS pathways down and to identify drugs that could target specific sets of neurons could lead to powerful new therapies, according to the University of Washington’s Cummings.

Bottling a cure

So far, treatments targeting either leptin or ghrelin alone have proved ineffective, except in individuals with genetic disorders affecting these hormones’ functions. Some ghrelin analogs, such as macimorelin, are now being tested in clinical trials for another extreme problem: cancer cachexia, a form of severe weight loss and wasting that occurs in patients on chemotherapy.

In the meantime, researchers are looking for drugs that target the CNS and could therefore affect the entire hormonal symphony that regulates hunger, satiety, stress, and reward. Newer therapies aim to reach neurons that carry a medley of receptors activated by gut hormones such as leptin or ghrelin, neurotransmitters such as dopamine and serotonin, and neuropeptides such as pro-opiomelanocortin (POMC), which decreases appetite. Because these molecules act in concert to control appetite-specific pathways, drugs that target these networks have met with greater success than older drugs with less specific modes of action.

For example, in 2013, the Food & Drug Administration approved lorcaserin, which is thought to work by activating satiety-linked POMC neurons. Liraglutide, which mimics the actions of the satiety-signaling peptide GLP-1, was initially approved as a diabetes medication but, in 2014, was cleared for use at a higher dose to treat obesity. Farr and her colleagues have found that liraglutide decreases activity in parts of the brain that react to french fries, cake, or other enticing treats.

Further improving obesity treatment will likely involve targeting more than just one hormone, researchers say, because of the diversity of signals that control appetite and eating behaviors. “In a redundant system, it’s hard to imagine that removal of any one determinant is going to overpower the others,” Cummings says.

For now, combination therapies rely on simply giving two already known medications together. One combination prescribed by doctors is a mix of amphetamine-based phentermine, which stimulates the sympathetic nervous system and suppresses feeding behavior, and the epilepsy drug topiramate, which increases the body’s energy use. The second is a mix of bupropion and naltrexone, which work together on POMC neurons to decrease appetite and reduce food cravings by acting on reward pathways.

In addition to mixing independent molecules, pharmaceutical companies are trying to design compounds that can either bind to two independent receptors or cross-link two receptors at once. “Most companies recognize that combination therapies are the future, but they’re also very challenging to develop clinically,” says Kevin Grove, vice president of obesity research at Novo Nordisk, one of the makers of liraglutide. First you have to develop the two individual molecules separately and then prove that their combined action is even more effective, he explains. Overall, it’s a process that can be expensive for manufacturers.

But designing a single peptide that can bind two distinct targets at the same time is not easy either, and most work of this sort is still in animal studies. One such effort stems from Scripps, where Smith’s team has found that cross-linking a dopamine receptor known as D2 to the ghrelin receptor can suppress feeding behavior in mice. The ghrelin receptor antagonist the researchers use is one that previously failed to work as an obesity drug. But it works when complexed with a D2-binding antagonist.

None of these medications is free of side effects, and, importantly, none is as effective as bariatric surgery. Typically, obesity drugs cause an average weight loss of 5–15% when combined with diet and exercise, whereas bariatric surgery results in losses up to 30%. Although researchers initially thought the surgery worked purely because of physical changes—the stomach is reduced to a smaller size and simply cannot hold as much food—studies increasingly show that it also affects multiple hormonal systems. For example, after the procedure, ghrelin levels remain consistently low, and the body’s response to GLP-1 is severalfold higher.

“There’s a significant morbidity and mortality associated with surgery,” says Jon Archof the University of Buckingham. So ongoing efforts to create combination drugs that mimic the actions of two or more hormones simultaneously could capture the benefits of bariatric surgery without the risk of complications.

To control obesity, the best drug combinations will need to target more than just hunger and satiety, researchers say. In the long term, combination therapies that prove successful will likely need to simultaneously suppress appetite, boost the body’s energy use, and tamp down the reward cravings induced by the temptation of delicious treats. Clinical proof of such drugs’ utility may take a few years still, according to Novo Nordisk’s Grove. “But now, we understand the targets that we need to hit to get there,” he says.