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"Thin gene" discovered and scientists already know how to target it

"Thin gene" discovered and sci...
"Thin" gene variants discovered are linked to a gene already linked to cancer
"Thin" gene variants discovered are linked to a gene already linked to cancer
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"Thin" gene variants discovered are linked to a gene already linked to cancer
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"Thin" gene variants discovered are linked to a gene already linked to cancer

Great insights have been gathered over recent years into the genetic drivers underpinning obesity, but little study has focused on the genes that could be related to thinness. A comprehensive new study investigating potential "thin" genes has identified one gene in particular that seems to play a major role in promoting thinness in both humans and animals.

“We all know these people, who can eat whatever they want, they don’t exercise, but they just don’t gain weight,” says Josef Penninger, senior author on the new study. “They make up around one per cent of the population. We wanted to understand why. Most researchers study obesity and the genetics of obesity. We just turned it around and studied thinness, thereby starting a new field of research.”

The research began by conducting a large genome-wide association study comprising nearly 50,000 subjects from Estonian biobank data. Instead of comparing thin and obese subjects, the profile looked at the genetic differences between healthy, thin individuals and normal weight individuals.

Two particular variants in the ALK gene quickly stood out to the researchers. Initial tests in animals revealed entirely blocking activity of the gene conferred a resistance to diet-induced obesity. Mice deficient in the ALK gene seemed to burn more calories and break down fat more rapidly.

“By using a technique called indirect calorimetry, we could show that ALK deficient mice exhibit increased energy expenditure,” says Michael Orthofer, first author on the study. “This means that they burn more calories than normal mice and explains why they remain thin even if they eat the same amount of food. In addition to that, these animals also show improved glucose tolerance.”

Zooming in even further, to understand exactly what mechanisms were at play, the researchers found ALK to be highly expressed in a particular brain region in the hypothalamus known as the paraventricular nucleus (PVN). When ALK was blocked in this single brain region only, the researchers saw the same body weight reductions and general metabolic effects as detected in the full ALK knockout animals.

What makes this discovery a little more exciting than other gene discoveries is that there is a volume of research already accumulated surrounding ALK inhibition in humans. For several years ALK has been investigated as a major driver of cancer development. In fact, several ALK inhibitors have already been developed, initially targeting non-small cell lung carcinomas.

A variety of ALK inhibitors have already been approved by the FDA for clinical uses, plus an assortment more are at different trial stages. So, as Penninger suggests, not only has ALK already been shown to be therapeutically targetable, many drugs currently exist to do the job.

"If you think about it, it's realistic that we could shut down ALK and reduce ALK function to see if we did stay skinny," he says. "ALK inhibitors are used in cancer treatments already. It's targetable. We could possibly inhibit ALK, and we actually will try to do this in the future."

The new study was published in the journal Cell.

Sources: Austrian Academy of Sciences, University of British Columbia

7 comments
Wombat56
". . . not only has ALK already been shown to be therapeutically targetable, many drugs currently exist to do the job."

Um, yeah. But if you look up these drugs on Wikipedia they all seem to have nasty side effects, up to and including death (2.8% in one case I read).
Karmudjun
Beware of limiting your medical research to Wikipedia. PF-06463922, an ALK inhibitor in use now against NSCLC shows some CNS penetration - which would or could provide penetration into the PVN - but as far as I know there have been no human studies on tolerance or selectivity in the PVN, especially for weight management.

Non Small Cell Lung Cancer diagnosis has been a fairly rapid death sentence even with 'complete' surgical resections. ALK inhibitors yield a few more moths of life, they give a cancer patient a taste of remission and there are many reasons why someone in long term terminal therapy experiences the side effects of these drugs. Now I haven't gotten my medical knowledge from wikipedia although I have corrected some misleading wikipedia posts, but I can tell you several reasons why the various formulations of ALK inhibitors produce nasty side effects in the terminal cancer patients. 1) the tumor genetics change - when one aberrant expression is blocked, the same genetic machinery that failed to catch the first mutation fail to catch another ALK mutation and - like antibiotic resistance, the surviving tumor grows exponentially again. A weakened cancer survivor asks for 'all you can do' and more or a new variation of ALK inhibitors are added. We call this polypharmacology and the side effects - of whatever drugs are in the mix - are reported in order of their appearance with whatever drugs are being administered. Yep - nasty side effects and possibly 4 -6 more months of viable - not robust - life extension.

What are the side effects of these drugs on an obese individual without cancer, without a cours
Karmudjun
course of surgery and chemotherapy? I don't know and I doubt I will find it on wikipedia.

Thanks Rich, I had not heard that one of our higher priced new medications that give our non-smoker and smoker patients a few more months of life might give our obese patients an improvement in insulin resistance and improve other factors that weight loss usually improves - blood pressure, cardiac function, pulmonary function, and even sleep quality. But beware - if ALK inhibitors may work in the PVN, what is to stop the rapid mutation of the receptors in the healthy PVN if par
guzmanchinky
Wombat answered my question, ALK inhibitors must have some side effects or they would already be on the market as an obesity fighter, wouldn't they?
Wombat56
Karmudjun, there's a big difference about prescribing a drug for a terminal cancer where you may be able to eke out a couple of extra months of life for the patient, and prescribing it for excess weight which is not likely to be immediately critical or fatal and there may be less dangerous treatments available.
aksdad
guzmanchinky, FDA approves drugs and therapies for specific uses. If it's discovered that a drug may help a different condition, they still have to go through the approval process. Because it's already been found safe (enough) for humans, it makes it easier to start a human clinical trial for a different purpose.
christopher
So skinny people think differently to fat people? I note that this study is not specifically talking about curing the fat - it looks more like curing the skinny in fact. Anyhow - the PVN might be affecting eating choices just as much. " The paraventricular nucleus of the hypothalamus (PVN) has emerged as one of the most important autonomic control centers in the brain, with neurons playing essential roles in controlling stress, metabolism, growth, reproduction, immune, and other more traditional autonomic functions (gastrointestinal, renal and cardiovascular). "