Clues To How Major Weight-loss Drugs Work - RESEARCH

SHORT SUMMARY

Serotonin (neurotransmitter) has been known to be central to the
workings of weight-loss drugs, but little has been known about this
molecular mechanism of appetite suppression.

Mice studies have revealed some of the details of how this works - a
protein called AgRP that stimulates appetite and a protein called áMSH
that curbs appetite.

It is possible to block the appetite suppression by disrupting the
function of receptors for a substance called melanocortin.

No hints given for when this could be applied to weight loss therapy for
humans.

----------------------------------------------------------------------


Source: Cell Press

Posted: July 20, 2006



New Clues To How Major Weight-loss Drugs Work

Some of the most important weight-loss drugs work by enhancing the
effect of the brain chemical serotonin. These include sibutramine (trade
name Meridia) and fenfluramine, which was recalled after the combination
with dexfenfluramine, called fen-phen, was linked to potentially fatal
heart valve abnormalities.


However, little has been known about the molecular mechanism by which
serotonin suppresses appetite. Now, in an article in the July 20, 2006,
Neuron, published by Cell Press, researchers have pinpointed key
components in the mechanism of serotonin's action. The research was led
by Michael Cowley of Oregon Health and Science University, Joel Elmquist
of University of Texas Southwestern Medical Center at Dallas and
formerly of Beth Israel Deaconess Medical Center and Harvard Medical
School, and Lora K. Heisler of the University of Cambridge and formerly
of Beth Israel Deaconess Medical Center and Harvard Medical School.

In their experiments with mice, they sought to discover whether
serotonin acts on specific brain circuitry in the hypothalamus known to
regulate the body's energy balance. Their tracer experiments showed that
receptors for serotonin are, indeed, expressed on particular neurons in
this circuitry that are potent modulators of food intake and body
weight. What's more, the researchers found that both serotonin and drugs
that affect serotonin's action acted on these neurons to reduce the
release of a protein called AgRP that stimulates appetite and aid
release of a protein called áMSH that curbs appetite.

To trace the effect of these two proteins downstream in the
appetite-regulating pathway, the researchers analyzed the effects of
various drugs that enhance or interfere with serotonin on feeding
behavior in mice. They found that the drugs acted to disrupt function of
receptors for a substance called melanocortin. It was known that AgRP
and áMSH both act on these receptors to regulate appetite.

The researchers also identified a specific type of melanocortin
receptor, called melanocortin receptor-4, as a critical target of the
serotonin pathway. This pathway appears to be central to appetite
regulation, wrote the researchers, since their experiments showed that
blocking just this receptor type was sufficient to render ineffective
the reduction of food intake caused by serotonin-enhancing drugs.

The researchers include Lora K. Heisler of Addenbrooke's Hospital,
University of Cambridge in Cambridge, United Kingdom and Beth Israel
Deaconess Medical Center and Harvard Medical School in Boston, MA; Erin
E. Jobst of Oregon National Primate Research Center at Oregon Health and
Science University in Beaverton, OR and Pacific University in Forest
Grove, OR; Gregory M. Sutton and Andrew A. Butler of Pennington
Biomedical Research Center, Louisiana State University System in Baton
Rouge, LA; Ligang Zhou of Addenbrooke's Hospital, University of
Cambridge in Cambridge, United Kingdom; Erzsebet Borok and Tamas Horvath
of Yale Medical School in New Haven, CT; Zoe Thornton-Jones and Peter G.
Clifton of Sussex University in Brighton, United Kingdom; Hong Yan Liu
and Jeffrey M. Friedman of Howard Hughes Medical Institute and The
Rockefeller University in New York, NY; Jeffrey M. Zigman, Nina
Balthasar, Charlotte E. Lee, Carl J. Aschkenasi, Chen-Yu Zhang, Jia Yu,
Olivier Boss, and Bradford B. Lowell of Beth Israel Deaconess Medical
Center and Harvard Medical School in Boston, MA; Toshiro Kishi of
Shimane University School of Medicine in Izumo, Japan; Kathleen G.
Mountjoy of University of Auckland in New Zealand; Joel K. Elmquist of
Beth Israel Deaconess Medical Center and Harvard Medical School in
Boston, MA and University of Texas Southwestern Medical Center in
Dallas, TX; Michael A. Cowley of Oregon National Primate Research Center
at Oregon Health and Science University in Beaverton, OR.

Data presented in this paper were supported by the following: L.K.H.
(NIDDK DK065171, American Diabetes Association, and Boston Obesity
Nutrition Research Center), N.B. (The Wellcome Trust, UK, ADA-EASD
Transatlantic Fellowship, and Boston Obesity Nutrition Research Center),
P.G.C. (BBSRC C505291), B.B.L. (NIDDK56116 and DK53301), A.A.B. (NIDDK
DK068330 and American Diabetes Association), T.H. (NIDDK DK074386 and
DK060711), J.K.E. (NIMH MH061583, NIDDK P01DK056116), and M.A.C. (NIH RR
00163, NIDDK, DK62202). M.A.C. and OHSU have a significant financial
interest in Orexigen Therapeutics Inc., a company that may have a
commercial interest in the results of this research and technology. This
potential conflict of interest has been reviewed and managed by the OHSU
Conflict of Interest in Research Committee and the Integrity Program
Oversight Council.

Heisler et al.: "Serotonin Reciprocally Regulates Melanocortin Neurons
to Modulate Food Intake." Publishing in Neuron 51, 239--249, July 20,
2006 DOI 10.1016/j.neuron.2006.06.004 www.neuron.org



--
1) Eat Till SATISFIED, Not STUFFED... Atkins repeated 9 times in the book
2) Exercise: It's Non-Negotiable..... Chapter 22 title, Atkins book
3) Don't Diet Without Supplemental Nutrients... Chapter 23 title, Atkins
book
4) A sensible eating plan, and follow it. (Atkins, Self Made or Other)