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Obesity has increased at an alarming rate in recent years and is now a worldwide public health problem. In addition to suffering poor health
and an increased risk of illnesses such as hypertension and heart disease, obese people are often stigmatized socially. Recent major advances have been
made in identifying the components of the homeostatic system that regulates body weight, including several of the genes responsible for animal and human
obesity. A key element of the physiological system is the hormone leptin, which acts on nerve cells in the brain (and elsewhere) to regulate food intake and
body weight. The identification of additional molecules that comprise this homeostatic system will provide further insights into the molecular basis of
obesity, and possibilities for new treatments.
Leptin: In 1994, Friedman et al. discovered that defects in a hormone called leptin made mice grossly fat.1 Leptin,
the product of the ob gene, is a circulating hormone produced by white adipose tissue that has potent effects on feeding behavior, thermogenesis and neuroendocrine responses. Leptin regulates energy homeostasis, as its absence
in rodents and humans causes severe obesity. The hormone appears to act by suppressing the appetite center of the brain and there was great enthusiasm
that injections of the normal leptin hormone into obese patients might be effective in inducing significant weight loss. Unfortunately, clinical trials
have shown even high doses of leptin produce only a modest weight loss.2 Research has continued, however,
and leptin still appears to be a very important molecule, along with several others, in regulation of weight and new avenues of research promise an eventual therapeutic agent.
Leptin’s role in obesity appears to be that of a lipostat. As fat stores increase, leptin levels increase as well - fat cells being the main
source of leptin synthesis. In animals, the hormone signals the brain to eat less and the body to do more. In humans, however, there does not appear to be
such a direct response. Indeed, many obese patients have high levels of the hormone in their blood and yet have no suppression of appetite. This apparent
leptin resistance has led to the following proposal of a complex interacting process within the brain.
Neuropeptide Y(NPY) is a small protein that has long been associated with boosting appetite in
experimental animals. Studies involving with crossing leptin-deficient mice with mice whose NPY gene had been knocked out have suggested that some - but
not all - of leptin’s appetite-dampening effects are due to its inhibition of NPY activity.
Alpha-melanocyte-stimulating hormone
(a-MSH), a hormone best known for its brown pigmentation of the skin, acts to blunt appetite within the brain. This new
function was demonstrated by a mutant mouse strain, called agouti, that has a striking gold-colored coat and is grossly obese. These mice produce large
amounts of a protein, called agouti, which blocks a-MSH’s action on both skin cells and in the brain, thus accounting for the animal’s obesity and their lack
of dark pigmentation (a similar protein is produced in humans called agouti-related protein AgRP).3
The link between a-MSH and leptin was made when it was found that leptin deficient mutant mice make very little a-MSH. Leptin was thought to stimulate
production of a-MSH, which in turn decreases appetite. A similar process has been shown to occur in humans. Mutation in the gene encoding the brain receptor
for a-MSH, a protein called MCR-4, may account for up to 2-3 percent of patients with severe obesity - the mutation preventing a-MSH from exerting its
appetite suppressing effects.
Melanin-concentrating hormone (MCH)
is a neuropeptide that is known to lighten the color of fish scales. Maratos-Flier et al. found the gene for MCH is
significantly more active in the brains of obese leptin-deficient mice. When they injected MCH into the brains of rats, food consumption was found to
dramatically increase.4 Conversely, when they knocked out the MCH gene in mice, the animals ate less
and lost weight compared to normal controls.5 Contacts between the neurons making MCH in the lateral hypothalamus and the
cerebral cortex, especially to olfactory centers, suggest that the smell of food may stimulate release of MCH and enhance appetite, even when otherwise not hungry.
Leptin resistance might also be due to blockage of its entry into the brain or interference with signaling by the leptin receptor. A
shortened form of the leptin receptor has been identified, called OBR-A, that is apparently not tethered to the cell membrane and therefore would not
function to signal the brain.
It has also been found that injection of leptin into normal animals results in increased production of a protein called SOCS3 (suppressor of cytokine signaling-3) in cells of the
hypothalamus that bear leptin receptors. SOCS-3, in turn, halts the leptin receptor from further signaling and, although normal function would halt leptin
signaling when the hormone has done its job, abnormal function might mediate resistance to leptin in obese people.
Orexins: One final population of neurons are under investigation. These neurons, which also lie in the lateral
hypothalamus, produce peptides called orexins. Orexins are potent stimulators of appetite and have been shown to arouse appetite in mice, dogs, and humans.
Summary: There are at least two sets of neurons in the arcuate nucleus of the hypothalamus that respond in
opposite ways to leptin stimulation. One population of neurons produce appetite-inhibiting peptides such as a-MSH (Alpha-melanocyte-stimulating
hormone), and this set of neurons respond to leptin by expressing genes that signal activation. A second population of neurons produce two appetite-boosting
proteins - NPY (Neuropeptide Y) and AgRP (agouti-related protein) and these shut off in response to leptin. The shutting down is in part mediated by
production of the leptin-receptor inhibitor SOCS3 (suppressor of cytokine signaling-3). Why these two distinct physiologic responses are present is
unknown but the net result of leptin action is a profound suppression of appetite. The complex interactions are further compounded by neural circuitry
between the arcuate nucleus and neurons in the lateral hypothalamus that produce the appetite stimulator MCH (Melanin-concentrating hormone). These
neurons are probably inhibited by neurons producing a-MSH and stimulated by neurons producing NPY and AgRP, and also connect with the smell centers of the
cerebral cortex.
References
Halaas, J.L., Gajiwala, K.S., Maffei, M., Cohen, S.L., Chait, B.T., Rabinowitz, D., Lallone, R.L., Burley, S.K., and Friedman, J.M.: Weight-reducing effects of the plasma protein encoded by the obese gene. Science, 269:543-546, 1995.
Gura, T.: Obesity research. Leptin not impressive in clinical trial. Science, 286:881-882, 1999.
Gura, T.: Obesity sheds its secrets. Science. 275:751-753, 1997.
Qu, D., Ludwig, D.S., Gammeltoft, S., Piper, M., Pelleymounter, M.A., Cullen, M.J., Mathes, W.F., Przypek, R., Kanarek, R., and Maratos-Flier, E.: A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature, 380:243-247, 1996.
Shimada, M., Tritos, N.A., Lowell, B.B., Flier, J.S., and Maratos-Flier, E.: Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 396:670-674, 1998.
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