Leptin's Effect on the Brain's Body Weight Regulation System is More Complex Than Previously Thought, Yale Researchers Find

Leptin, a hormone known for its hunger-blocking effect on the brain, operates in a more complex way than previously thought, researchers from Yale and The Vollum Institute find, possibly leading to development of drugs that can better interfere with appetite and eating behavior to fight obesity and diabetes.

The researchers say the new finding furthers understanding of how the area of the brain known as the hypothalamus regulates food intake and body weight.

“For the first time, we’ve shown that leptin does not work like a traditional hormone and affects the brain in more complex ways than a simple hormone does,” said Tamas Horvath, associate professor of obstetrics and gynecology and neurobiology at Yale School of Medicine and an author on the study. “Our results show that leptin affects many different levels of neurotransmission.”

Published in the May 24 issue of Nature, the study’s authors wanted to understand what mechanism leptin uses to regulate brain circuitry, which in turn regulates food intake and energy expenditure. They used genetically altered mice to select, record and label the particular neurotransmitter systems in the hypothalamus that are responsible for food intake and body weight regulation. This allowed for targeted assessment of synaptic transition in the melanocortin system, which is in the core of food intake and energy expenditure regulation.

Horvath said melanocortin-producing neurons were selectively visualized in the laboratories of Malcolm Low and Roger Cone by targeted expression of green fluorescence protein, allowing selective patch-clamp recording from these neurons and parallel assessment of their synaptology. “The fact that the multiple pre- and post-synaptic sites were found to be targeted by leptin offers the possibility of developing drugs with various single and multiple targets, thus development of resistance during chronic administration of one compound could be eliminated by replacement of another,” said Horvath.

Past studies on leptin have found that in addition to being critical in body weight regulation and obesity, it also may play a role in diabetic eye disease. Leptin exists in the fatty tissues in areas of the body such as the placenta, ovaries, mammary glands, gastric mucosa and in the liver. The hormone regulates body weight, promotes satiety, decreases appetite, decreases the degree to which the body synthesizes fat and increases the body’s ability to burn fat. Overweight or obese people may have a surplus of leptin that is not functional in regulating body weight.

Horvath and his team are currently working with a recently discovered hormone called ghrelin, which has the opposite effect of leptin. “We’re trying to see how these two opposing hormones interact in the same circuitry and how either of them are impaired in obesity to enhance understanding of weight disorders,” Horvath said.

Co-authors on the study included Michael Cowley, Malcolm J. Low, John L. Smart and Roger Cone of the Vollum Institute, Oregon Health Science University; Marcello Rubinstein and Marcelo G. Cerdan from the University of Buenos Aires; and Sabrina Diano of The Reproductive Neuroscience Unit of the Department of Obstetric and Gynecology at Yale School of Medicine.

For further information on the study, Tamas Horvath may be reached at (203) 785-4597.

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Karen N. Peart: karen.peart@yale.edu, 203-432-1326