‘Feeding’ Hormones Affect More Than Hunger

by Kayt Sukel

September, 2008

Ghrelin and leptin, hormones that regulate appetite and food intake, have been found also to influence depressive behaviors as well as learning and memory processes.

The findings indicate that these chemical messengers may play profound and sophisticated roles in human cognition.

Ghrelin’s Impact on Stress, Learning and Memory

A recent study suggests that the feeding hormone, ghrelin, may play just as important a role in the brain as it does in the stomach. Ghrelin is produced by the stomach; increased levels stimulate appetite before meals, and levels drop once the stomach is full.

In the July 1 issue of Nature Neuroscience, Michael Lutter, a psychiatrist at the University of Texas

Southwestern Medical Center in Dallas, and colleagues published a study that demonstrated that ghrelin also showed anti-depressant effects in depressed mice.

The researchers used two common tests for looking at depression in mice: the forced swim and social defeat tests.

In the forced swim test, depressed animals stop swimming much earlier than their normal counterparts. In the social defeat paradigm, the mice are repeatedly stressed until they show depressive behaviors, such as social isolation and indifference to sweet foods

In the forced swim test, Lutter and colleagues increased ghrelin levels in the depressed animals both naturally, by withholding food, and then artificially through an injection. In both cases, the mice returned to normal swimming behaviors.

With the social defeat test, the mice already had elevated ghrelin levels. “It appears that something about stress increases the ghrelin released,” says

Lutter. Mice that have a ghrelin deficiency “get more stressed and show more avoidance behavior.”

Ghrelin also influences learning and memory. Ewan McNay, a researcher at the Yale School of Medicine who studies the impact of metabolism on cognitive function as we age, has found that ghrelin enhances memory processing.

Rodents who are given insulin or ghrelin can navigate more quickly in a maze and will show better memory for hidden objects—but more is known about how insulin works. “With ghrelin, the mechanism is less understood, but you see enhanced performance in [memory and learning] tasks,” says McNay.

“There is some evidence that ghrelin increases the number of synapses around and probably also increases plasticity.”

That plasticity, or the formation and strengthening of synaptic connections, may underlie the improved behavioral performance. McNay is planning future work to better understand how ghrelin mediates these processes.

Leptin Beyond the Hypothalamus

A second hunger hormone, leptin, also has demonstrated some antidepressant effects and learning and memory enhancement. But it works in a slightly different manner than ghrelin.

“Ghrelin is a short-term measure of what food is coming in, while leptin is a long-term indicator of energy stores,” says Lutter. “Both act largely through the hypothalamus to integrate peripheral signals about how much energy is available and how much an organism should eat.”

In 2007, Xin-Yun Lu found that leptin, a hormone produced by fat cells instead of the stomach, may have antidepressant potential.

“Leptin works as a negative feedback signal in regulation of fat stores,” says Lu, a pharmacology researcher at the University of Texas Health Science Center at San Antonio. As fat stores are depleted, more leptin is produced. That increase causes the hypothalamus, home to many leptin receptors, to trigger hunger to replenish those stores.

But other parts of the brain also possess leptin receptors. Pharmacological studies have demonstrated that leptin levels also change with chronic stress, independent of an individual’s body weight, with depressed individuals showing low leptin levels.

A 2006 study by Gregory Simon and colleagues at the Group Health Cooperative in Seattle found a strong association between obesity and mood and anxiety disorders. In a study of more than 9,000 participants, 25 percent of the obese individuals suffered from disorders such as depression.

“We think this is more than just a coincidence,” says Lu. She believes that both the obesity and depression may be linked to insufficient levels of leptin or perhaps a cellular malfunction that results in a resistance to it.

Lu and colleagues administered leptin to rats who had been repeatedly stressed and, as a result, isolated themselves and showed less interest in sugar water. These behaviors are considered an approximation of human depression. The researchers found that the hormone had an antidepressant effect, with the stressed rats returning to baseline behaviors.

But leptin not only shows antidepressant potential. It too appears to enhance learning and memory. Jenni Harvey, a neuroscientist at the University of Dundee in the United Kingdom, and colleagues reported in 2001 that leptin can influence the cellular events underlying learning and memory. “Brain cells have varying levels of communication, and it’s thought that when you learn and remember, pathways that are critical for that function in the hippocampus are strengthened and enhanced,” she says. “Leptin enhances this communication.”

Significant work since then has shown how leptin boosts long-term potentiation, or the persistent strengthening of the synapse, by enhancing the level of the neurotransmitter glutamate and promoting the growth of dendrites in hippocampal neurons. Rats with leptin defects show great difficulty in spatial learning and memory tasks that normal rats can easily perform.

Potential Pharmaceutical Targets

These hormones’ anti-depressant effects may be a target for future drugs. Lu, for example, believes strongly that leptin could be used for depression.

“Leptin has potential as a novel way to treat the disorder that may prove to be effective for those patients who aren’t helped by the traditional drugs,” she says.

Lutter sees some possibility for ghrelin as a treatment in conditions such as anorexia nervosa, but he advises caution.

He argues that we are only beginning to understand the reach of these hormones and what further roles they may play.

“I would hesitate to say that we should ignore these targets entirely; they will help guide us and gives us an idea of what to look out for,” he says. “But we need to be wary of what inhibiting some of these pathways might do in terms of other brain areas and functions.”