America’s weight problem – Where is the pharmaceutical industry?

By George M. Ekema, Ph.D.

Drug Discovery Scientist, Alexa Biotherapeutics, Inc.

Http://www.alexabt.com

The obesity problem in the United States is beyond control, and
we are clearly in a crisis. Fat is not just making America look
big, it is making America ill, very ill. Obesity causes many
health problems directly or indirectly, including; type II
diabetes, hypertension, many cancers, heart disease, stroke,
emotional problems, etc. With only about 33.5% of Americans at a
healthy weight, it is time to wonder if America has waived the
white flag at obesity. With the weight loss market at about $50
billion, it may appear that America hasn’t given up the battle
with obesity. If America has not surrendered to obesity, why
then is America getting fatter? America is getting fatter
because she is using the wrong weapons. America wants to fight
this war with a magic bullet. Where is the magic pill? The
answer is not forthcoming from the pharmaceutical companies, but
too many concoction makers seem to have the answer. For decades
America has been swallowing weight loss supplements, concoctions
and potions but her weight hasn’t budged, has it? America, why
are you still wasting your hard-earned money on these
supplements, concoctions and potions? Anyone who has lost weight
and maintained it has done so through a lifestyle change that
had proper dieting at its core. There is no one who has lost
weight and maintained it by using a magic bullet, because there
is no magic bullet.

No magic bullet? Where is America’s pharmaceutical industry?
Don’t they realize that there is a killing to be made in
inventing the magic bullet? The fact is that most pharmaceutical
companies have an obesity portfolio, and are very much engaged
in the discovery and development of obesity drugs. Some of these
companies are in the very early stages of drug development,
while others are already in clinical trials. It is normal for
about 10 years to pass between day one research and day one
market, when it comes to drug discovery and development. It is
important to state how long the drug discovery and development
process takes, to save America from turning purple. Yes, don’t
hold your breath America; you are not going to be popping the
magic pill any time soon. Time is not the only limiting factor;
the greater limiting factor is the content of the research
pipeline. What type of drugs are the pharmaceutical companies
developing for America? Is the magic bullet among these drugs?
You don’t have to wait to find that out America because I have
the keys to the vaults and I will give you the answer right now.

The pharmaceutical companies are developing as many obesity
drugs as there are companies. These drugs fall into one of the
following categories:

(1) Anorectic drugs (drugs that suppress appetite). These drugs
have the potential to prevent overeating, and they obviously
will only be useful to the people who are obese due to
overeating. There are several classes of appetite suppressant
drugs, based on their mode of action. These classes include;

(a) Drugs that act in the brain to increase the amounts of
certain chemicals (norepinephrine, serotonin, and dopamine) or
to mimic the action of these chemicals in the brain. Meridia®
(sibutramine hydrochloride monohydrate) from Knoll
Pharmaceuticals, one of two weight loss Rx drugs that have been
approved by the Food and Drug Administration (FDA) for use in
the US, falls in this category.

(b) Drugs that act in the brain to block the cannabinoid
receptor1. Stimulation of the cannabinoid receptor is linked to
the sensation of hunger. The ‘munchies’ that follow cannabis
intoxication is due to stimulation of this receptor. It is
believed that blocking the action of this receptor may result in
appetite suppression. Many companies have potential drugs that
bind to the cannabinoid receptor at different stages of
development.

(c) Drugs that inhibit the peptide hormone ghrelin2. Ghrelin is
a small hormone (messenger) that is produced in the stomach when
the stomach is empty. Ghrelin is transported in the bloodstream
to the brain, where it binds to its receptor. When ghrelin binds
to its receptor in the brain, it produces the sensation of
hunger. Inhibiting ghrelin or its receptor may therefore result
in appetite suppression. Many companies are developing potential
drugs that have this mode of action.

(d) Drugs that inhibit the action of orexigenic
(appetite-stimulating) hormones in the brain. There are many
orexigenic peptide hormones that are secreted into the brain.
These small messengers that turn on the appetite switch include
melanin-concentrating hormone (MCH)3 and neuropeptide Y (NPY)4.
Chemicals that inhibit the action of these hormones are expected
to produce an appetite suppressing effect. There are therefore
many companies developing drugs that have this mode of action.

(e) Drugs that mimic or increase the action of anorectic
(appetite-suppressing) hormones in the brain. There are many
anorectic hormones that are secreted into the brain, so that at
any moment there is a complex balance between anorectic hormones
and orexigenic hormones in the brain. These anorectic hormones
include; alpha-melanocyte-stimulating hormone (α-MSH)5,
neurotensin6, and glucagon-like peptide-1 (GLP-1)7, etc.
Chemicals that can mimic or increase the action of these
anorectic hormones have the potential to be appetite-suppressant
drugs, and many pharmaceutical companies are working to produce
these chemicals.

(2) Drugs that act on the gastrointestinal-brain axis.

Ghrelin, a peptide hormone that is secreted by the stomach has
already been mentioned. There are several other peptide hormones
that are secreted by the stomach and intestines that are
potential targets for obesity drugs. These potential drugs
include;

(a) Chemicals that may mimic or increase the activity of the
peptide hormone cholecystokinin (CCK).

(b) Chemicals that may mimic or increase the activity of the
peptide hormone peptide YY3-368.

(c) Chemicals that may mimic or increase the activity of the
peptide hormone glucagon-like peptide-1 (GLP-1).

(d) Drugs that inhibit the action of ghrelin, as already
discussed above.

(3) Drugs that inhibit the absorption of fat in the intestines.

Some companies are developing drugs that prevent the absorption
of fat in the intestines. Xenical® (Orlistat) from Roche
Pharmaceuticals is an FDA approved Rx drug that falls in this
category.

(4) Drugs that alter metabolism.

(a) Chemicals that may mimic or increase the activity of
uncoupling proteins. Increasing the activity of uncoupling
proteins may increase the rate of resting metabolism, hence may
increase the rate of expenditure of stored fat.

(b) Chemicals that may inhibit fatty acid synthesizing enzymes.
Fatty acid synthesizing enzymes are small proteins that speed up
the rate of fat production in the body. Inhibiting these enzymes
may therefore result in a decrease in fat production and
storage.

(5) Drugs that increase diet-induced thermogenesis (DIT).
Diet-induced thermogenesis refers to the post-prandial
generation of heat by the body. This is naturally occurring
phenomenon is significant for weight loss when the diet consists
of protein, and insignificant for weight loss when the diet
consists of carbohydrate and/or fat9,10. Activation of the
vanilloid receptor (VR1) in the mesenteric plexus has been shown
to increase DIT. Additionally, VR1 activation has been linked to
the up-regulation of uncoupling proteins. Chemicals that
activate VR1 may therefore result is weight loss by inducing DIT
and by up-regulating uncoupling proteins.

(6) Drugs that act on a broad range of systemic-brain peptide
hormones and other receptors.

There are many obesity therapeutic targets in this category,
including; (a) Drugs that mimic or increase the activity of
leptin11. Leptin is a peptide hormone that is secreted by fat
cells. As more fat is stored, more leptin is secreted as a
message to the brain to curb appetite and to regulate the
metabolism of fat. Chemicals that increase the secretion or
activity of leptin may therefore be potential obesity drugs.

(b) Leptin exerts its effects in the nervous system by either
increasing or inhibiting the activity of certain nerve cells.
The mode of action depends on the type of peptides in that nerve
cell. Some peptides of interest include; neuropeptide Y (NPY),
agouti-related peptide (AgRP), alpha-melanocortin stimulating
hormone (α-MSH), proopiomelanocortin (POMC), melanocortin-4
receptor (MC4R), ciliary neurotrophic factor (CNF)12, etc.
Chemicals that can alter the activity of these peptides and
receptors are also potential obesity drugs.

(c) There is a bunch of other obesity therapeutic targets that
are being investigated by many pharmaceutical companies,
including; carboxypeptidase inhibitors, adipocyte
11B-hydroxysteroid dehydrogenase type 1, amylase inhibitors,
synthetic human growth hormone, corticotrophin-releasing hormone
stimulators, etc.

So America, now you know that the pharmaceutical industry hasn’t
neglected the fight against obesity. Quite contrarily, it is the
one of the hottest areas of therapeutic discovery, as most
pharmaceutical companies have an obesity portfolio. Remember
that drug discovery scientists are also a reflection of America,
and only a few of us are at a healthy weight. We are just as
eager as you are to have effective and safe weight loss pills in
the market. That said, I guess it is time to make one point very
clear America; the magic pill is in no one’s pipeline. The next
decade may see the introduction of a dozen or more weight loss
pills into the US Rx market, however; don’t expect any of them
to be a magic pill. America I am sorry to say it, but it is true
- you will still need to make a lifestyle change that has
healthy dieting at its core. Start it today America, this battle
is not going to get easier anytime soon. As you can see from the
vast amount of therapeutic targets for obesity listed above, the
molecular bases of obesity are too many and there is too much
redundancy. A magic pill will have to be a combination of
compounds that have efficacy at most of these obesity
therapeutic targets. This is theoretically possible, but I would
be shocked if the adverse effects of such a drug combination do
not include precipitous death.

To win this fight against obesity we have to start by
confronting ourselves. Half of the battle is in figuring out
individually why we are obese. My poison may be the ladle and
yours the bottle; so we need to make different lifestyle changes
if we want to win. The next step is to understand the concept of
macronutrient (carbohydrate, fat, and protein) composition of
our meals and use that as the basis for a healthy and
sustainable weight loss diet. It is not part of our culture to
go around waving white flags America, and we surely don’t intend
to start now, do we? We are in this together – let’s fight a
good fight America!

References

1. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C. &
Bonner, T.I. Structure of a cannabinoid receptor and functional
expression of the cloned cDNA. Nature 346, 561-4 (1990).

2. Kojima, M. et al. Ghrelin is a growth-hormone-releasing
acylated peptide from stomach. Nature 402, 656-60 (1999).

3. Rance, T. & Baker, B.I. The teleost melanin-concentrating
hormone — a pituitary hormone of hypothalamic origin. Gen Comp
Endocrinol 37, 64-73 (1979).

4. Tatemoto, K., Carlquist, M. & Mutt, V. Neuropeptide Y–a
novel brain peptide with structural similarities to peptide YY
and pancreatic polypeptide. Nature 296, 659-60 (1982).

5. Harris, J.I. & Lerner, A.B. Amino-acid sequence of the
alpha-melanocyte-stimulating hormone. Nature 179, 1346-7 (1957).

6. Carraway, R. & Leeman, S.E. The amino acid sequence of a
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(1975).

7. Patzelt, C. & Schiltz, E. Conversion of proglucagon in
pancreatic alpha cells: the major endproducts are glucagon and a
single peptide, the major proglucagon fragment, that contains
two glucagon-like sequences. Proc Natl Acad Sci U S A 81,
5007-11 (1984).

8. Jegou, S., Mounien, L., Boutelet, I. & Vaudry, H. [The YY3-36
peptide, a new therapeutic weapon against obesity?]. Med Sci
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9. Soucy, J. & Leblanc, J. Protein meals and postprandial
thermogenesis. Physiol Behav 65, 705-9 (1999).

10. Johnston, C.S., Day, C.S. & Swan, P.D. Postprandial
thermogenesis is increased 100% on a high-protein, low-fat diet
versus a high-carbohydrate, low-fat diet in healthy, young
women. J Am Coll Nutr 21, 55-61 (2002).

11. MacDougald, O.A., Hwang, C.S., Fan, H. & Lane, M.D.
Regulated expression of the obese gene product (leptin) in white
adipose tissue and 3T3-L1 adipocytes. Proc Natl Acad Sci U S A
92, 9034-7 (1995).

12. Mizuno, T.M., Makimura, H. & Mobbs, C.V. The physiological
function of the agouti-related peptide gene: the control of
weight and metabolic rate. Ann Med 35, 425-33 (2003).

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