Pleasure, Not Fullness, May Be Key to 'Satiety Hormone'

by Carl Sherman

October 1, 2009

The balance between our food intake and energy expenditure is driven in large part by leptin, a “satiety hormone” released by fat cells. When fat stores are hefty, increased leptin acts on the brain to bring eating to a halt more readily; low levels of the hormone due to fasting or a very low calorie diet make hunger harder to satisfy.

Now research is suggesting that satiety—the feeling of fullness amplified by leptin—is just part of the hormone’s story; it may also reboot the brain’s reward circuitry  to make us desire food more intensely and take more pleasure in eating. The revised understanding may have important implications in the fight against increasing levels of obesity.

“Over the last several years, there’s been emphasis on hedonic, rather than homeostatic mechanisms,” says Christopher Morrison of Pennington Biomedical Research Center in Baton Rouge, La. “The brain doesn’t just tell us whether we’re hungry or full. We eat for other reasons, including pleasure, and in obesity that may play an important role.”

A rewarding hormone

Some of the hedonic, or pleasure-oriented interest has focused on the mesolimbic dopamine system, a brain circuit that regulates incentive and reward. Activity here contributes to our motivations to seek sex, excitement and illicit drugs as well as food.

Several years ago, researchers found leptin-responsive cells in the ventral tegmental area (VTA), a major component of this reward circuit. But the effect of these cells on eating appears limited, says Martin Myers of the University of Michigan. “We think those neurons are doing something else—they’re not controlling food reward directly.”

But a new study led by Myers and reported in the journal Cell Metabolism strengthens the argument that leptin regulates appetite by making food more or less rewarding. The researchers identified a previously unrecognized group of leptin-sensitive neurons in the lateral hypothalamus (LH). Injecting leptin directly into these cells in mice, the researchers found, led to a rapid reduction in food intake and body weight—apparently by a mechanism other than controlling satiety.

The researchers found that this cluster of LH neurons connected directly to the VTA. What did they do there? Leptin in the LH, the researchers found,  started a chain reaction that resulted in increased amounts of dopamine in the VTA.

This result baffled the scientists at first. “It’s different from what might have been expected,” Myers says. “There’s the general feeling that dopamine equals lust—for food, or drugs, or sex or whatever. But here, leptin increases the amount of dopamine in the reward system, while acting to decrease feeding.”

Leptin, however, has a slow, steady action—it doesn’t trigger spikes of increased dopamine, but rather raises its baseline level, “possibly preventing a ‘reward deficit’ that would drive eating for pleasure,” Myers says. When ample dopamine is available, there’s less need to generate more. Myers points out that drugs of abuse that raise dopamine levels dramatically, such as amphetamines and cocaine, have potent appetite-killing effects.

The research supplies “a neat new piece of the puzzle,” says Dianne Figlewicz Lattemann of the VA Puget Sound Health Care System in Seattle, who did much of the earlier work on leptin in the VTA. “It identifies another target for leptin and convincingly shows that it can have a modulatory effect on dopamine synthesis.”

Lattemann observes that leptin research has typically involved extreme cases—obese or leptin-deprived animals, in particular—and that this study adds to our understanding of “normal day-to-day physiology. It suggests the potential for pretty powerful action of leptin, that a little bit should go a long way.”

Research placing leptin in the pleasure pathway may provide particularly useful insights into today’s obesity epidemic, Myers says. “The problem in obesity isn’t a lack of satiety signaling, but overresponse to the rewarding foods that continually surround us. Our system to regulate reward-driven eating was never meant to survive in the face of mint chocolate decadence.”

“If we can tear apart the neurochemical pathway that tempers our response to rewarding foods,” he adds, “maybe we can find a way to manipulate it.”

How leptin works

Other leptin research is giving broader, deeper insights into the hormone’s function. “A lot of groups are discovering receptors in other areas of the brain, and even outside the brain,” Morrison says.

Leptin-responsive cells control energy expenditure by altering levels of metabolism-controlling hormones produced by the adrenal and thyroid glands and pituitary hormones involved in reproductive activity. In the hippocampus, leptin may also influence emotions and moods other than feelings of reward. The discovery that manipulating leptin levels in animals could cause or alleviate depression-type behavior suggests possible antidepressant properties. In certain parts of the brain, the hormone strengthens and promotes connections between neurons. More generally, it seems to have a neuroprotective effect, apparently by activating intracellular processes involving growth factors. In animal experiments, the hormone reduced neuron loss in a chemically-induced version of Parkinson’s disease,  tissue damage due to cerebral artery blockage and symptoms of chemically-triggered seizures.

“Labs are really starting to track the signaling pathways of leptin,” Lattemann says. “There’s more specific dissection of where and how, on a cellular level, the neurohormone activates chemical cascades to affect growth as well as metabolism.”

The actions of leptin appear to be “cell specific,” depending highly on the function of the target neuron, Myers says. “It is likely to do one thing in certain neurons—strengthen glutamate input, for example—and the opposite thing, weaken input, in others.”

The discovery that some animals continue to eat and gain weight despite high leptin levels has stirred particular interest. This “leptin resistance” can be induced by obesity or a high-fat diet; sensitivity to the hormone also declines beginning during middle age. This phenomenon may explain why administering leptin—once thought a promising treatment for overweight—hasn’t worked.

Is leptin resistance a cause of obesity, a consequence—or a bit of both? According to Morrison, no one really knows, but data are consistent with a causative role. Rats bred to become obese, for example, seem less sensitive to leptin even before they gain weight. “I think there’s an underlying genetic basis for differences in baseline leptin sensitivity, in humans as in rats,” he says.

One key question is what specifically causes leptin resistance. A study by Morrison, for instance, suggests an intracellular culprit. He found that older rats who failed to respond to a leptin injection had increased levels of an enzyme known to inhibit leptin signaling, protein tyrosine phosphatase 1B (PTP1B). When the animals received a PTP1B inhibitor an hour before the leptin, their response to the hormone was normal.

Much about leptin resistance—and the true relationship between leptin and weight gain—remains unknown, Morrison says, but manipulations to enhance leptin sensitivity could hold promise for  obesity treatment. Not all of these interventions need be drugs. In a recent study, injected leptin alone didn’t stop weight gain in rats on a high-fat diet. But the addition of moderate exercise caused food intake and weight to stabilize and led to increased levels of neurochemicals that reflect leptin activity.