a fix for both obesity and malnutrition?

research on obesity is really going places these days. a little while ago, i reported on the discovery of an obesity virus and an obesity molecule.

now, feifan guo and douglas cavener, two biologists at penn state university, have discovered an enzyme with the weighty name of GCN2 eIF2alpha kinase (let’s call it GAK, shall we?), which, among other things, has a profound impact on fat metabolism. they found when a single amino acid, leucine, is removed from the diet, GAK switches the body to a starvation response, resulting in rapid consumption of stored fat.

the major food sources of leucine are whole grains and milk products. eggs, pork, beef, chicken, pulses, soybeans, and leaf vegetables are good sources of leucine.

what is quite fascinating is that their research also applies to the opposite problem – malnutrition due to insufficient protein intake, which plagues the populations of the poorer nations of asia and africa. there, people often eat a diet with sufficient
calories but lacking in essential amino acids, which results in stunted growth, developmental disorders, and sometimes death. (go here for the whole story).

of course, i would be interested in other effects of a lack of leucine. for example, the article on cavener’s and guo’s research implies that a lack of leucine also means that the body attacks muscle tissue in its starvation response. that doesn’t sound like such a good thing. also, as someone who works with people with the whole spectrum of eating disorders – from overeating to anorexia, the idea of inducing the body to go into starvation mode makes me a little nervous.

let’s see if we can get some answers from people who just might know about these things – i’m going to ask daniel at migrations, larry moran from sandwalk, and keith robison at omics! omics! oh – and i might as well ask feifan guo, too.

isabella mori
counselling in vancouver

12 thoughts on “a fix for both obesity and malnutrition?

  1. Daniel

    Guo’s and Cavener’s findings, as I understand them, are indeed promising, but all that’s done thus far is the identification of a potential drug target. It might eventually lead to a useful pharmaceutical treatment for such conditions, but before that happens, the FDA will probably take into consideration your concerns.

    It might not lead to a basis for FDA-sanctioned drug intervention or dietary suggestions though. Maybe it will simply be the basis for diagnosing certain conditions. Or maybe it will lead to the discovery of a subtle and/or efficacious treatments.

    Either way – great blog post; very interesting!

  2. Daniel

    Guo’s and Cavener’s findings, as I understand them, are indeed promising, but all that’s done thus far is the identification of a potential drug target. It might eventually lead to a useful pharmaceutical treatment for such conditions, but before that happens, the FDA will probably take into consideration your concerns.

    It might not lead to a basis for FDA-sanctioned drug intervention or dietary suggestions though. Maybe it will simply be the basis for diagnosing certain conditions. Or maybe it will lead to the discovery of a subtle and/or efficacious treatments.

    Either way – great blog post; very interesting!

  3. Keith Robison

    Thank you for inviting me to comment.

    My first response is to agree with the above poster that this work represents the initial validation of a new drug target for metabolic research. There are some important caveats to even that statement (based on reading the abstract; Cell Metabolism is pricey). In particular, they have completely ablated the gene from the mice from the get go. It is possible that GAK deficiency early in life sets up the condition they observe, but eliminating its function solely in adult mice would not do so. I suspect they have good reasons, based on other work, to suspect this is not the case, but it would appear it was not ruled out. Furthermore, gene deletion mice eliminate the protein altogether, whereas drug treatment leaves the protein in place but inactivates it. This can again make a big difference, as an inactive protein can still tie up important partners.

    Target validation is a very early step in the process, so it is unlikely that this will lead to anything soon. However, there are both public efforts (The Broad Institutes’ Connectivity Map being the best known) and private companies trying to identify late stage or even marketed drugs which can recapitulate the effects seen in studies such as this. So there is an outside chance that something will be turned up which can be moved into the clinic quickly.

    One other thought: leucine deprivation is also relevant to the mTOR signalling axis, which is another key metabolic regulation circuit. A quick PubMed search suggests that links between the two pathways have been touched upon in yeast, but it didn’t look well explored in mammals.

  4. Keith Robison

    Thank you for inviting me to comment.

    My first response is to agree with the above poster that this work represents the initial validation of a new drug target for metabolic research. There are some important caveats to even that statement (based on reading the abstract; Cell Metabolism is pricey). In particular, they have completely ablated the gene from the mice from the get go. It is possible that GAK deficiency early in life sets up the condition they observe, but eliminating its function solely in adult mice would not do so. I suspect they have good reasons, based on other work, to suspect this is not the case, but it would appear it was not ruled out. Furthermore, gene deletion mice eliminate the protein altogether, whereas drug treatment leaves the protein in place but inactivates it. This can again make a big difference, as an inactive protein can still tie up important partners.

    Target validation is a very early step in the process, so it is unlikely that this will lead to anything soon. However, there are both public efforts (The Broad Institutes’ Connectivity Map being the best known) and private companies trying to identify late stage or even marketed drugs which can recapitulate the effects seen in studies such as this. So there is an outside chance that something will be turned up which can be moved into the clinic quickly.

    One other thought: leucine deprivation is also relevant to the mTOR signalling axis, which is another key metabolic regulation circuit. A quick PubMed search suggests that links between the two pathways have been touched upon in yeast, but it didn’t look well explored in mammals.

  5. isabella mori

    thank you for your comments, daniel and keith.

    and thanks for making it abundantly clear that this research does not mean there will be an obesity drug in the next three months!

    i think it’s very important that the general public become more savvy in understanding science. for example, it was interesting to read that working on cell metabolism is costly.

    also, “gene deletion mice” – that’s not a phrase that generally runs in my vocabulary (or that of my readers, if i’m not mistaken). of course it makes sense that mice who do not have this gene at all are different from mice (or humans, for that matter!) for whom leucine is simply inactive.

    and what’s mTOR? mTOR regulates translation and cell division. it belongs to a protein complex that is used by cells to sense nutrients in the environment. nutrient availability influences mTOR so that when cells are not able to grow to normal size they will not undergo cell division. (at least that’s what i gathered from google definition).

    all this leads me to confirm my belief that the equation of “calories in, calories out” which claims that weight is solely dependent on how many calories we ingest is a ridiculous oversimplification. the human body is an immensely complex interplay of chemicals, and simplistic formulae like that just won’t do.

  6. isabella mori

    thank you for your comments, daniel and keith.

    and thanks for making it abundantly clear that this research does not mean there will be an obesity drug in the next three months!

    i think it’s very important that the general public become more savvy in understanding science. for example, it was interesting to read that working on cell metabolism is costly.

    also, “gene deletion mice” – that’s not a phrase that generally runs in my vocabulary (or that of my readers, if i’m not mistaken). of course it makes sense that mice who do not have this gene at all are different from mice (or humans, for that matter!) for whom leucine is simply inactive.

    and what’s mTOR? mTOR regulates translation and cell division. it belongs to a protein complex that is used by cells to sense nutrients in the environment. nutrient availability influences mTOR so that when cells are not able to grow to normal size they will not undergo cell division. (at least that’s what i gathered from google definition).

    all this leads me to confirm my belief that the equation of “calories in, calories out” which claims that weight is solely dependent on how many calories we ingest is a ridiculous oversimplification. the human body is an immensely complex interplay of chemicals, and simplistic formulae like that just won’t do.

  7. Keith Robison

    One other thought: even if a drug was waiting in the wings for this indication, trials in metabolic disorders are going to be very large sets of participants over many years. Since obesity is a chronic disease affecting a very broad population, the safety bar is going to be very high (previous fiascos such as fen/phen also contribute to this).
    So any approved indication (i.e. it’s on the label, high likelihood of insurance reimbursement, etc) is a long way off — if there was a drug already approved or near approval for another indication. A ballpark estimate is that for a from-scratch drug this target _might_ yield an obesity drug in a decade-and-a-half but more likely two decades — since it will probably be 7-10 years of trials to prove the thing is safe (throwing in some trial misfires & delays and such). A more avid watcher of clinical trials could probably give a better estimate, but in general it suggests don’t hold your breath.

  8. Keith Robison

    One other thought: even if a drug was waiting in the wings for this indication, trials in metabolic disorders are going to be very large sets of participants over many years. Since obesity is a chronic disease affecting a very broad population, the safety bar is going to be very high (previous fiascos such as fen/phen also contribute to this).
    So any approved indication (i.e. it’s on the label, high likelihood of insurance reimbursement, etc) is a long way off — if there was a drug already approved or near approval for another indication. A ballpark estimate is that for a from-scratch drug this target _might_ yield an obesity drug in a decade-and-a-half but more likely two decades — since it will probably be 7-10 years of trials to prove the thing is safe (throwing in some trial misfires & delays and such). A more avid watcher of clinical trials could probably give a better estimate, but in general it suggests don’t hold your breath.

  9. Pingback: A Link Between Obesity and Malnutrition « Migrations

  10. Pingback: A Link Between Obesity and Malnutrition « Migrations

  11. Harold Mounce

    You right on about obeseity and malnutrition. Our food supply is highly suspect in being as nutritious as it once was. Food producers looking to the bottom line are wearing out the soil. They do not rotate or let land rest. Thank you for your good work…keep it up.

  12. Harold Mounce

    You right on about obeseity and malnutrition. Our food supply is highly suspect in being as nutritious as it once was. Food producers looking to the bottom line are wearing out the soil. They do not rotate or let land rest. Thank you for your good work…keep it up.

  13. isabella mori

    thanks for the comment, harold.

    you have a good point there. i often wonder, when we are given the nutritional contents of foods, how are they measured? i have a hard time believing that a canned pea, a pea that was harvested 4 weeks ago from a heavily fertilized soil, and a pea taken off the vine from an organic garden have exactly the same nutritional content.

  14. isabella mori

    thanks for the comment, harold.

    you have a good point there. i often wonder, when we are given the nutritional contents of foods, how are they measured? i have a hard time believing that a canned pea, a pea that was harvested 4 weeks ago from a heavily fertilized soil, and a pea taken off the vine from an organic garden have exactly the same nutritional content.

  15. mili

    How To Combine diet pills With Your Health Routine
    To avoid any sort of side effect you must combine your diet pills intake with a healthy diet and routine exercising. Doing the trio of actions – diet pill consumption, healthful eating and regular activity – will yield you the best and safest results. In terms of your diet, you must eat well, and in substantial amounts as to promote definite weight loss. And note, to please, not starve yourself – this will not help you to lose weight in the slightest bit. And as far as exercise goes you should, in the least, workout 3-5 times a week to keep metabolism levels racing and your body tuned for energy utilization and overall weight loss。

  16. Lorqess

    Sounds very interesting, perhaps the next generation of weight loss medication will be based on such research, but I still think we will be years away from a complete side effects free method, but I do think we are getting there.

  17. Jon

    Makes sense, obese people are not healthy eaters. People get fat as a result of sugar addiction, and sugar has no nutritional benefit, just pure energy.

    Of course, rather than use the drug to combat fat, you could eat the foods in which the chemical appears naturally.

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