Father of fat sheds more light on this growing human condition

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Related tags: Obesity

New ways to combat the global obesity epidemic could be on the way
as recent findings from influential obesity researcher Jeffrey
Friedman improves our understanding of leptin resistance and
obesity. New studies show that the appetite-regulating hormone
leptin causes rewiring of neurons in areas of the brain that
regulate feeding behaviour.

This latest discovery is another clue as to how leptin exerts its effects on the brain to cause decreased food intake and increased energy expenditure, said the researchers. The study also suggests that natural variability in the "wiring diagrams" of the neural feeding circuits of individuals may influence whether a person will be obese or lean.

The research team, led by Jeffrey Friedman at the Howard Hughes Medical Institute and Tamas Horvath at Yale University School of Medicine, published their findings in the 2 April, 2004, issue of the journal Science.

Friedman and his colleagues discovered leptin in 1994, findings that represented a major breakthrough in obesity research. They also showed that it is produced by fat tissue and secreted into the bloodstream, where it travels to the brain and other tissues, causing fat loss and decreased appetite.

In the brain, leptin affects food intake by acting on distinct classes of neurons in the hypothalamus that express the leptin receptor.

While the action of neurons had been inferred, said Friedman, there had been no direct studies exploring the specific mechanism by which leptin affected the neurons.

"There are a number of theoretical ways in which a molecule such as leptin might modulate the activity of neurons," hed added. "And I'm sure it's the case that leptin can act in many different ways. But what we have discovered is a particularly striking modality of action that wasn't what we initially would have suspected was the likeliest."

The major problem in studying in detail the action of leptin on NPY and POMC neurons was in distinguishing the two classes of neurons, said Friedman. The solution, said the researchers, was to genetically engineer mice to have NPY and POMC neurons that each expressed a distinctive version of a green fluorescent protein. These fluorescent proteins literally lighted the way for the scientists to perform detailed studies of the action of leptin on the two neuronal types.

The researchers generated both normal mice and those deficient in leptin production - called ob/ob​ mice - containing the fluorescently labeled neurons. They then compared the neurons in the two strains of mice.

Results revealed that leptin acted directly to rewire the neuronal feeding circuitry itself in the brains of mice, specifically suppressing NPY neurons and exciting POMC neurons.

The researchers also found that administering leptin to the leptin-deficient ob/ob​ mice produced changes in neuronal connections - and their electrical activity - to mimic those of normal mice. The neuronal changes preceded the behavioral changes in the ob/ob​ mice. This is significant, according to Friedman, because it suggests a cause-and-effect relationship between the rewiring and feeding behaviour.

When the researchers tested the effects of ghrelin, another appetite-stimulating peptide, on the two types of neurons in normal animals, they also observed a decrease in excitatory connections to POMC neurons. "Overall, these findings begin to suggest that the wiring diagram of the feeding circuit is highly dynamic,"​ said Friedman. "And they lead us to at least ask to what extent is the wiring diagram of these neural circuits different in obese people relative to lean people.

"If we knew that the basic circuitry that controls feeding is wired differently in different people, it might change public perception of the causes of obesity,"​ he added. Some people might have a more potent drive to eat and to weigh more than do others. And it might mean that conscious factors can not fully explain how a person eats.

These latest findings could lead to new tools in fight against the growing global tide of obesity. According to the World Health Organisation approximately 300 million people worldwide are believed to be obese and 750 million overweight. Evidence suggests that obesity significantly increases the risk of heart disease, diabetes and other life-threatening conditions.

Related topics: R&D

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