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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 hypothalamic peptide, neurotensin. J Biol Chem 250, 1907-11 (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 (Paris) 19, 537-9 (2003).

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).

About the author:

Dr. Ekema is a biomedical scientist whose research includes the role of the brain in obesity and weitht loss. He is interested in the mechanisms involved in the brain's control of appetite, nutrient preference, satiety. He is involved in the discovery and development of drugs for obesity; however, he believes that proper dieting is exceedingly the safest and most efficient weight loss therapy. It is this belief that led to the brilliant research


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