GDF15 gene related protein reduces weight in animals and is promising human obesity treatment

Researchers have created engineered proteins that lowered body weight, bloodstream insulin, and cholesterol levels in obese mice, rats, and primates.

The delivery of the GDF15 gene reduced body weights, food intake, and serum insulin levels in the animals.

The GDF15 regimen altered food preferences in mice — leading the animals to opt for lower calorie chow when offered a choice between standard food and an extra-rich condensed-milk diet (untreated mice gorged themselves on the high-calorie eats).

The authors determined that GDF15 activated a population of nerve cells called AP neurons that make up a portion of the gut-brain axis, yet note that further studies to identify the protein’s cellular receptor are needed as potential therapeutics make their way to the clinic.

Science Translational Medicine – Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys

A bigger molecule to help slim down

Obesity is becoming increasingly common worldwide, and the available interventions do not fully address this problem. Surgery is currently the most effective intervention, especially for severe obesity, but it carries more risks than noninvasive treatments and produces permanent side effects. Xiong et al. searched for metabolically regulated proteins and identified the growth differentiation factor 15 (GDF15) pathway as a potential target for intervention. The loss of this protein in mice is associated with weight gain and worsened metabolic parameters. Conversely, the authors showed that treating with GDF15 improved metabolic health in mice, rats, and monkeys. They also designed a modified version of GDF15 (GDF15-Fc fusion) that has a longer half-life and would thus be a better candidate for clinical testing.

Abstract

In search of metabolically regulated secreted proteins, we conducted a microarray study comparing gene expression in major metabolic tissues of fed and fasted ob/ob mice and C57BL/6 mice. The array used in this study included probes for ~4000 genes annotated as potential secreted proteins. Circulating macrophage inhibitory cytokine 1 (MIC-1)/growth differentiation factor 15 (GDF15) concentrations were increased in obese mice, rats, and humans in comparison to age-matched lean controls. Adeno-associated virus–mediated overexpression of GDF15 and recombinant GDF15 treatments reduced food intake and body weight and improved metabolic profiles in various metabolic disease models in mice, rats, and obese cynomolgus monkeys. Analysis of the GDF15 crystal structure suggested that the protein is not suitable for conventional Fc fusion at the carboxyl terminus of the protein. Thus, we used a structure-guided approach to design and successfully generate several Fc fusion molecules with extended half-life and potent efficacy. Furthermore, we discovered that GDF15 delayed gastric emptying, changed food preference, and activated area postrema neurons, confirming a role for GDF15 in the gut-brain axis responsible for the regulation of body energy intake. Our work provides evidence that GDF15 Fc fusion proteins could be potential therapeutic agents for the treatment of obesity and related comorbidities.

6 thoughts on “GDF15 gene related protein reduces weight in animals and is promising human obesity treatment”

  1. This is truly uncharted territory, but we are entering the Genetic Age… These things are coming, and people are going to gulp when they see what is possible. Already, I have had one friend’s life saved by a genetically engineered drug. I believe in the next five years we will see solutions for obesity, baldness, cancer, diabetes, and other autoimmune conditions. Certainly, the elimination of the worst parts of ageing would be a blessing to humanity. In the long run, we will see age-reversal, organ regeneration, and in the far future – possibly even sex reassignment. Being a believer in God, I am all for most of these things, but can only hope no applications arise that would contravene His law. I do not believe any of the aforementioned would, but say, if they were to begin working on creating life; or immortality; or creating hybrid abominations; or reanimating the recently deceased… I believe those efforts would simply prove futile.

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    • Most new tech gives people the opportunity for doing something bad. Of all the techs in world history, the only one I can think of that was truly abandoned for moral/religious reasons was castrati.
      https://en.wikipedia.org/wiki/Castrato

      Though, given the huge prestige given in today’s society to top musical performers, combined with a social movement to drive children to castrate themselves, we may see their return.

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  2. To expand on my earlier point a bit… it seems fairly doomed to fail given that human populations respond differently to dietary makeup..and that is just the within-species variation..there is variation when it comes to age…gender…fitness….microbiome… something that simply flips a switch into healthier eating…even if it was just say…lower calorie eating (a difficult claim to lay at the feet of genetics in the first place)

    sounds too good to be true..at least for populations whose reactions’ to different diets are greatly different. It might even kill populations that have subsisted mainly on high calorie high fat, animal protien diets as the reaction between calories and fat production are not explicitly always negative…even in the modern setting.

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    • Actually I think that an obesity treatment that only works for a subset of the population could be valid. Providing you can tell ahead of time which people are suitable.

      The first thing to check is whether this really does make you eat more healthfully, or whether it just makes you dislike extra-rick condensed milk. In the second case it would work well if you are in a cage where the only options are balance nutrient meal or condensed milk. In the real world of humans they’ll just move on to some other food and overeat that.

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  3. I wish them luck, but they are going to need it.
    1. There is ~ 4 billion years of evolution driving organisms to eat, while assuming that food is in limited supply. Trying to interupt that level of deep core code is liable to be risky.
    2. Even if you get the biology sorted, you still have to deal with psychology. Or rather psychiatry. If an effective diet drug hits the market, it will be eagerly sort out by two types of people. Those desperate to drop their weight below 100 kg, and those desperate to drop their weight below 100 pounds. The second group will take 5 times the recommended dose and… oops… their parents are crying on TV asking how the evil pharmaceutical corporation can be allowed to make a profit on other people’s death and please give us $50 million in compensation…

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    • It sounds like you’re saying there will be people who understand the metric system and then people who think its equivalent to the Imperial system..

      though that may not have been your intent…I don’t think Pharmacology will settle this schism any time soon.

      That said…I don’t see how genetics are responsible for dietary choice..or at least…if they are…what conditions are they promoting that makes mice choose lower calorie foods.. There are many avenues to healthy calorie consumption…and some of them include fatty foods to boot..sometimes at the exclusion of other not-unhealthy foods….so the question becomes one of….if the medication does in fact support the conclusion of the study which has the subject choose the lower calorie option…what is the condition underlying mechanism that has you subjectively choose a lower calorie but still healthy (very, incredibly subjective…certainly nothing to do with genetics) and not say…0 calorie dirt… causing some sort of brain altering suicidal change to how a human would normally logically process a problem caused by genetics.

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