The (NP)Y's and Wherefores of Stress and Obesity

When I find myself in times of trouble
Ben and Jerry's comes to me
Snarfing Chunky Monkey so sweetly, so sweetly.

When stressed, some folks barely eat and consequently lose weight. Others, including myself, reach for high-fat-high-sugar (HFS) foods in an attempt to ameliorate the angst. Although the connection between stress and overeating is not fully understood, the evidence until recently focused on centrally acting (brain & spinal cord) mechanisms, e.g., hypothalamic control of food consumption and metabolism.

However, Lydia Kuo et al. (1) reported recently in Nature Medicine that stress-triggered release of neuropeptide Y (NPY) can stimulate angiogeneis (formation of new blood vessels) in the periphery, i.e., other places in the body than the brain and spinal cord. The researchers also demonstrated that NPY stimulates creation and differentiation of new fat cells (adipogenesis). NPY evidently binds to its receptor (or one of its receptors), NYP2R - a G-protein coupled receptor, and gets the big fat ball rolling.

More below the corpulent fold...

NPY is a peptide comprised of 36 amino acid residues. It acts as a neurotransmitter in the brain where it is involved with memory, learning and energy balance. With regard to the latter, NPY is orexigenic, that is, it stimulates the appetite. Glucocorticoids that are produced in response to stressors affect the release and actions of NPY. For example, mice that are exposed to cold temperatures (a physical stressor) or to an aggressive-dominant mouse (emotional stressor) have elevated levels of NPY in their blood.

The researchers from Georgetown University Medical Center took a number of approaches to examine the connection of peripheral effects of NPY and stress-induced obesity.

Kuo and colleagues found that stress-activation of the NPY-NPY2R system, coupled with an undoubtedly delicious high-fat-high-sugar (HFHS) diet, gave the mice pot bellies . Increased abdominal fat deposition is the worst for one's health, whether mouse or man. The stress resulted in upregulation of genes for NPY, NPY2R, and dipeptidyl peptidase 4 (DPP4), an enzyme that forms a peptide which then binds to and stimulates (agonist) NPY2R in white fat.

The scientists demonstrated that in vitro exposure of NPY in cell culture stimulated adipocytes to increase endogenous production (upregulate) NPY and its receptor, NPY2R. Secretion of leptin and resistin, both peptidic hormones - adipocytokines - implicated in feeding and energy balance, increased, and the treated adipocytes got fatter by sucking up more lipids.

Mice that are genetically obese had high levels of NPY in their plasma and also increased NPY and NPYR2 expression in subcutaneous belly fat.

When both lean and fat mice were treated with slow release pellets of NPY inserted into fat deposits, the mice formed more white fat. Mice with human-fat xenografts (see glossary below) were also treated with the NPY-containing pellets. The human (foreign) fat had increased survival time, and its blood supply (vascularization) was also increased. In contrast, when an antagonist of NPY2R (chemical that binds to the NPY receptor and keeps its natural effectors from stimulating it) was injected into the fat deposits of the mice, vascularization decreased and the adipocytes and endotheial cells in the abdominal fat pads succumbed to programmed cell death (apoptosis).

The Georgetown Med researchers also observed that cold- or aggression-stressed mice, when fed a HFS diet, had increased vascularization in their belly WAT, growth of new adipocytes, and showed features of metabolic syndrome. Treatment of the stressed nice with an NPY2R antagonist decreased their belly WAT by 40%.

Mice that had their gene function of the NPY receptor modified were bred. The knockout mice, that is, those that were homozygous for ablation of the NPY2R gene, were resistant to stress-augmented and HFS-diet induced obesity. Likewise, heterozygous mice (one impaired NPY2R gene, one functional wild type NPY2R) showed resistance to stress-induced and HFS induced weight gain.

The aforementioned "knockouts," both homo- and heterozygous, are genetically modified and bred from the embryonic state to carry such genetic modifications. The researchers also studied genetically altered mice with a conditional knockout of the NPY2R gene. This means that the receptor gene is still intact, but it can be turned on and off by an exogenous stimulus. In this case, the cre-lox system (see Glossary) was used. Mice with NPY2R genes under lox control were injected with an adenovirus vector containing Cre recombinase; the injection was localized to their abdominal WAT. The introduction of Cre effectively shuts down the production of NPY2R in that region. This "local knockdown" of gene function resulted in an 80% decrease of NPY2R gene expression in the abdominal adipocytes, but not in skeletal muscles or in the brain. The local knockdown also reduced the stress-induced belly fat by 50%.

Now how does this relate to humans? There are implications that NPY2R plays a similar role. Some people have a variant of NPY2R that is silent. The variant does not ablate the function of the receptor, but its effect is enough to attenuate it and protect the people carrying the silent variant from obesity. In contrast, people who have gain-of-function mutations in their NPY2R gene are prone to obesity, atherosclerosis and diabetes.

Based on the evidence derived from their studies, the Georgetown Med researchers posit that increased NPY levels as the result of stress or genetically modulated increase the risk of diet-induced obesity by further upregulatng NPY and its receptor in abdominal fat. Their research findings are interesting from a number of angles, notably by revealing a coordinated connection between adipogenesis and angiogenesis that occurs during fat remodeling that is stimulated by stress.

The proposed pathway is complex, as shown by the diagram below from the Kuo et al. paper. Chronic stimulation of the NPY pathway that occurs during prolonged exposure to stress may lead to obesity and its concomitant pathologies.


That NPY acts peripherally is a tantalizing finding for Big (and Medium and Small) Pharma's efforts to discover anti-obesity meds. Such a mechanism may allow for fewer adverse effects if a drug that does not cross the blood-brain barrier can be developed.

As I have stated in the past, I have great reservations about pursuing obesity targets in pharma (biting the hand that feeds me again), but Kuo et al.'s findings are fascinating in an ain't it cool kind of fashion. It also says that it isn't "just in my head" when I reach for the Ben and Jerry's or Cape Cod potato chips under prolonged periods of stress. Of course, a brisk walk, a jog, or a half hour on a rowing machine are sound alternatives for alleviating such stress. However, none of those are as sensually tasty and satisfying.


Adipocytes: fat cells

Cre-lox: For a nice explanation (with pictures!) of the cre-lox system, check out this site from Davidson College.

Xenograft: graft of tissue or cells from one species transplanted to another; strains of mouse with impaired host-graft responses are used for experiments to study human tissue responses.


Lydia E. Kuo, Joanna B. Kitlinska, Jason U. Tilan, Lijun Li, Stephen B. Baker, Michael D. Johnson, Edward W. Lee, Mary Susan Burnett, Stanley T. Fricke, Richard Kvetnansky, Herbert Herzog, Zofia Zukowska. (2007) "Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome," Nature Medicine 13: 803-811.

Alexandra Fleming (Sept. 2007)"Stress and obesity connect at NPY" Nature Reviews: Drug Discovery 6:

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Excellent post, and fascinating topic! Now I am off to track down the original article. Thanks for your fine summary.

By ctenotrish, FCD (not verified) on 20 Sep 2007 #permalink

I love ice cream, especially chocolate, mint chocolate chip, and heavenly hash (clearly a fat+sugar combo, although it is one of the few fat+sugar combos that I really, really go after). Yet, if I am injured, a bowl of ice cream in no way even approaches being as satisfying as knocking back several miles running. I would gladly give up several months worth of "ice cream rights" to have the injury resolved overnight! There are few things which stress me more than having an injury that prevents me from running (as it is a major stress reducer to begin with, so we have a positive feedback loop).

Consequently, I find that food in general doesn't do much for me stress-wise, at least not over the long haul. I certainly don't stop eating, either, so perhaps I'm just an outlier.

ctenotrish, thanks so much for the accolade! I'm glad to hear you liked my summary well enough to find the original article, which is a good read.

C'mon, Fiore. I know you're a mutant.

As a little aside, I enjoyed writing this entry, largely because I find the subject interesting and because I Learned Something in the process. But on the old Sitemeter? Take a guess at which of my recent posts got more reads. Far more reads. Fortunately, comments like ctenotrish's keep me coming back to more hardcore stuff.

Thank you for this very good post although I read it several days late.
By the way ... 'it's just in your head' about a mental or self-control issue is really no different than saying diabetes is 'just in your pancreas' .
As for ice cream - once I spent 6 months eating 1-3 pints of ice cream a day in addition to a normal 3 meals a day. I wasn't weighing myself, so I don't know how much weight I gained - but all my clothes still fit (both the 28-inch and 30-inch waist pants). So while I do tend to gravitate toward ice cream at times (I don't know why stopped eating so much ice cream - now its like 1-2 pints a month), its effect on my weight seems modest.

Another thank you for the post.

I find it more helpful to know that there are physiological reasons for my obesity problem than to be bombarded with "it's all in your head" messages. The former gives me tools I can use - when I'm stressed, go for walk instead of going for the HFS - while the latter just contributes to negative mental images that ultimately only cause more stress.

llewlly - pardon a bit of snark, but I've noticed that as men get fatter, they don't buy bigger pants, they just wear them lower.

After looking at many articles on the fat reducing of NYP2R antagonist, I can't find the name of the antagonist used by Zofia Zukowska and colleagues in their experiments on mice. Can anyone tell me what they used.