Nighttime surge of ghrelin may point to new targets for treating obesity

UCLA scientists have discovered that lean people experience a huge nighttime surge of ghrelin — the hormone that stimulates hunger — but obese people do not.

Scheduled for online publication on June 28 in the Proceedings of the National Academy of Sciences, the study suggests that obesity suppresses the ghrelin spike, perhaps disrupting the body's internal cues for hunger and overpowering its ability to regulate appetite. Ghrelin helps the body control its weight as part of a complex system that regulates food intake and energy output.

"We expected to find a different ghrelin pattern in obese people, but the big shock was that it happened at night," said Dr. Julio Licinio, professor of psychiatry and medicine at the David Geffen School of Medicine at UCLA. "At first glance, our findings appear contradictory. You'd expect the blood levels of the heavier men to contain more hunger hormone. Something must be overriding obese persons' ghrelin."

The team's findings may point to new targets for treating obesity, said Licinio, who also is a senior research scientist at the UCLA Neuropsychiatric Institute.

"It's possible that obese people have developed biological mechanisms that make them resistant to their own hormones," he said. "We must try to solve this mystery and explore new drugs to make them more sensitive to their bodies' internal cues."

Cells in the stomach secrete ghrelin into the blood, where it rises and falls in predictable daily patterns, spiking before meals when you are hungry and dropping after you eat.

Licinio's colleagues monitored ghrelin patterns in five lean men and five obese men every seven minutes for 24 hours. The team collected more than 200 blood samples per subject.

The scientists were surprised to discover a giant burst of ghrelin in the lean men's blood between midnight and 6 a.m. that surpassed pre-mealtime peaks of the hormone. Yet ghrelin levels remained flat in the obese men.

"The most powerful ghrelin surge was missing in the obese men, suggesting that their regulatory system has gone awry or is no longer able to listen to its own cues," Licinio said.

"This defies the stereotype of overweight people waking up in the middle of the night to raid the refrigerator," Licinio said. "The men in our study slept through the night, and both groups ate meals designed to maintain their current weight."

Licinio's team also monitored leptin and adiponectin, two hormones produced by the fat cells. Leptin signals fullness and cues a person to stop eating. Adiponectin helps regulate energy metabolism.

In addition to lower levels of ghrelin overall, the obese men showed higher levels of leptin and lower levels of adiponectin than the lean men. This confirmed earlier findings made by Licinio and other researchers.

"Again, this runs counter to common expectations," Licinio said. "You'd assume obese individuals would have lower levels of leptin, the fullness hormone, not higher."

The men in the study ranged in age from 21 to 25 years old, were in good physical and mental health, and screened for recent weight gain or loss, smoking and drug abuse. None of the men worked night shifts or took any medications, hormones or dietary supplements 30 days before the study.

Licinio is a member of the UCLA Brain Research Institute, director of the pharmacogenomics laboratory and UCLA Pharmacogenetics and Pharmacogenomics Research Group, and founding editor-in-chief for The Pharmacogenomics Journal and Molecular Psychiatry.

His co-authors included Dr. Bulent Yildiz, Marc Suchard and Dr. Ma-Li Wong of UCLA, and Dr. Samuel McCann of Louisiana State University.

The National Institute for Diabetes, Digestive and Kidney Disease supported the study, as well as awards from Amgen, the Dana Foundation and the National Alliance for Research on Schizophrenia and Depression.

The UCLA Neuropsychiatric Institute is an interdisciplinary research and education institute devoted to the understanding of complex human behavior. It focuses on the genetic, biological, behavioral and sociocultural underpinnings of normal behavior, as well as the causes and consequences of neuropsychiatric disorders.

In addition to conducting research, institute faculty seek to develop effective treatments for neurological and psychiatric disorders, improve access to mental health services and shape national health policy regarding neuropsychiatric disorders. See www.npi.ucla.edu for more information.

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