April 02, 2004
Obesity: It May Be How You're Wired
New studies by Howard Hughes Medical Institute researchers at The
Rockefeller University show that the appetite-regulating hormone leptin
causes rewiring of neurons in areas of the brain that regulate feeding
behavior.
The discovery is another important clue about how leptin exerts its
effects on the brain to cause decreased food intake and increased
energy expenditure, said the researchers. The research 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.
“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.”
Jeffrey M. Friedman
The research team, which was led by Howard Hughes Medical Institute
investigator Jeffrey
M. Friedman at Rockefeller and Tamas L. Horvath at Yale University
School of Medicine, published its findings in the April 2, 2004, issue
of the journal Science.
Friedman and his colleagues discovered leptin in 1994. 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.
Leptin decreases feeding and fat deposition by acting on two classes
of neurons. Leptin suppresses the activity of neuropeptide Y (NPY)
neurons and it enhances the activity of proopiomelanocortin (POMC)
neurons. Conversely, the absence of leptin increases feeding and fat
deposition by exciting NPY neurons and suppressing the activity of POMC
neurons.
While the action of these two types 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,” said
Friedman. “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. “If you just look at a region of the brain, you can't
tell one neuron from the next,” he said. “And in this case,
you had in one brain region neurons theorized to stimulate appetite
right next to those believed to inhibit appetite.”
The solution, said Friedman, 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.
One of the co-lead authors in the Science paper — Aaron G.
Roseberry in Friedman's laboratory — compared the electrophysiological
properties of the two types of neurons, in both normal and ob/ob
mice. These studies revealed the relative activity of the two types of
neurons in the two mouse strains.
Another co-lead author — Shirly Pinto in Friedman's laboratory —
worked with Horvath to perform comparative microscopy studies of the
labeled neurons in the two strains of mice. These studies revealed the
relative numbers of excitatory and inhibitory neuronal connections in
the two types of mice.
Both sets of studies 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 behavior.
Furthermore, 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. “Taken together, the findings with leptin and
ghrelin suggests that the findings of this rewiring are general,”
said Friedman.
“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,” said Friedman. “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't fully explain
how a person eats.”
Such findings might also contribute in time to a broader
understanding of why administering leptin can reduce weight in some
obese people and animals, but not in others. The variable response to
leptin suggests that some individuals are obese because they are leptin
resistant. Advances about how leptin works in the brain could
contribute to a better understanding of leptin resistance and obesity,
and may ultimately lead to new ways to combat obesity, said
Friedman.
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