Leptin regulates brain growth

Studies of leptin-deficient mice reveal new roles for the hormone in the hypothalamus

Apr 2, 2004
David Secko(dmsecko@interchange.ubc.ca)

In the 10 years since the discovery of the hormone leptin and its appetite-suppressing activity in mice, the hormone has provided a good deal of insight into how a metabolic signal can affect the central nervous system. In the April 2 Science, two papers report that leptin regulates synaptic plasticity and neuronal development.

Both teams used leptin-deficient mice (ob/ob) and investigated the effect of leptin on two distinct populations of neurons in the hypothalamic arcuate nucleus—one producing the appetite-stimulating neuropeptide Y (NPY) and the other producing appetite-suppressing proopiomelanocortin (POMC).

“These findings are important for the study of leptin and its potential therapeutic value in the treatment of obesity and related disorders like diabetes,” said Jenni Harvey, Wellcome Trust Research Fellow from University of Dundee, who was not involved in the studies.

“We were working on the POMC and NPY system,” said Tamas Horvath, associate professor at the Yale School of Medicine and senior author of the first paper. “We were finding a tremendous amount of plasticity in the hypothalamus with regard to estrogen,” he said, leading him and his colleagues to wonder if the feeding circuitry involving leptin had similar plasticity.

The team then created transgenic mice expressing distinct green fluorescent proteins (GFPs) in POMC and NPY neurons. “It's easy to visual these neurons with the GFP,” Horvath told The Scientist, enabling investigation of the “wiring between the fat and lean ob/ob animals.” Using this technique, ob/ob mice were found to have altered excitatory and inhibitory inputs into POMC and NPY neurons, which could be reversed within 6 hours of the addition of leptin to the ob/ob mice.

“There is probably an actively ongoing plasticity of the system [which]… adds another layer of complexity to the system that is already considered very daunting,” said Horvath.

In the second paper, Sebastien Bouret and colleagues from the Oregon Health and Science University report that ob/ob mice have permanently disrupted neural projection pathways from the hypothalamic arcuate nucleus. Leptin treatment of ob/ob mice had no effect on these defects, but treatment of neonatal ob/ob mice with leptin reversed the effects, suggesting leptin involvement in hypothalamic development is restricted to a neonatal period.

“I think both [papers] are very interesting in terms of how the hypothalamus may process hormonal information and regulate feeding behavior,” said Harvey. Since both leptin and leptin-receptor deficient rodents show “abnormal development and also display deficits in a number of synaptic proteins,” it is plausible that leptin may play a key role in neuronal development. “However, these are the first publications showing directly that leptin has neurotrophic actions in the hypothalamus,” she said.

“One thing that I am cautious about is the linking of the trophic action of leptin to the general mechanisms of synaptic plasticity,” said Harvey, since the process reported in the first paper was relatively slow. Horvath agreed, but added that although “we find it is not that rapid, we may find it to be more rapid on further study.”

Abhiram Sahu, associate professor at the University of Pittsburgh, said “both papers are really outstanding [and] generate new concepts about neuronal plasticity and development with regard to how leptin works.” Sahu, who was not involved in the studies, said that he is interested to see the work expanded into investigations of these novel leptin actions in wildtype mice. “Both of the studies open up new areas of research into leptin's actions,” Sahu told The Scientist.

The results, said Horvath, “offer new targets as well as raising the question: Is this effect also present in other brain sections and will these hormones effect higher brain function?”