Tuesday, July 3, 2007

Scientists Stressed About Weight Loss

Do researchers really think neuropeptide Y can sculpt the perfect body?


Every few years, researchers challenge Jenny Craig's and the late Dr. Atkins' stranglehold on the weight loss industry. (Honestly, I don't know what they are thinking. I wouldn't take Kirstie Alley on.)

I remember back around 2001 when a biotech company, Regeneron, was developing a drug trademarked as Axokine (it was actually ciliary neurotrophic factor, or CNTF) in hopes of manipulating the leptin "hunger" pathway. At the time, it was suggested that both leptin and Axokine worked in large part by inhibiting the activity of neuropeptide Y in neurons. Neuropeptide Y (NPY) was reputed to increase appetite in small animals when small doses were delivered directly to their brains. Additionally, when NPY receptor positive neurons are selectively destroyed, experimental animals eat much less. Regeneron generated data that showed that CNTF, like leptin, suppressed activity of NPY receptor positive neurons in the hypothalamus. Unfortunately for Regeneron and its stockholders in March of 2003, Phase III clinical trial results for Axokine indicated that the weight loss in the treatment group was a marginal 6.2 lbs loss. Additionally, a subset of Axokine treated patients developed antibodies to the drug which neutralized its effects. While leptin and NPY were still obvious players in appetite and weight gain/loss, it had become clear that manipulating the pathway would not be a trivial effort.

Now 4 years later, leptin and NPY are back in the news because of work published in Nature Medicine by researchers at Georgetown University Medical Center. As usual, the media has produced article titles like "Scientists Find Way to Block Weight Gain in Stressed People". (I often hate the news media, particularly FOXNews). These titles imply that overworked fat people will be able to take a pill that makes them lose weight within the next year. While there are a couple of clinical trials tied to the freshly reported research, we're going to have to wait for a little while before knowing how it will all play out. Not all of the current reports are promising. Well, let me put it this way, the research that is currently making news is right about where Regeneron was with Axokine circa 2000; and we all know how far that got.

With silly media coverage aside, the research conclusions by scientists at Georgetown University Medical Center are very interesting. It seems that NPY does not only work via appetite mediation in the brain signaling pathway. Rather, their data in mice suggest that when animals become stressed by aggression or temperature changes, their sympathetic nerves generate more NPY and NPY receptors in abdominal fat. This upregulation is concurrent with increased growth of new fat cells and in fat tissue angiogenesis . Fat tissue, just like any other tissue, needs blood supply to grow and sustain itself. The researchers backed up their conclusions further by suppressing the abdominal fat growth in stressed animals using a NPY blocker injected directly into the abdominal fat of stressed animals.

Aside from having discovered a potential way of reducing fat in the abdomen, there are other implications to this research:

1. Could anti-anxiety medications reduce this stress signaling pathway that causes weight gain?
2. Could NPY be injected to increase fat where desired? More natural looking breast implants?
3. Can increasing peripheral (outside of the brain) levels of NPY increase appetite while decreasing weight?


Major questions still remain, however. First and foremost, do human really work the same way as rodents in this case. Secondly, would this be a safe therapeutics. And, thirdly, most obviously to me, why do most of the stressed out people who I know appear emaciated. Personally, I lose weight when I get stressed. My guess is that, as usual, the physiology and molecular biology of this is far more nuanced than the current story allows. Time will tell.

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