Readers may be well aware that the use of cannabis or “hashish” can induce the “munchies”, an acute craving for highly palatable foods.

Now Garron Dodd and colleagues from the University of Manchester, UK, have identified a new brain peptide called hemopressin that acts through cannabinoid receptors to reduce food intake in rats and mice. Their findings are published in the latest edition of the Journal of Neuroscience.

Hemopressin is a short, nine amino acid peptide found in the rat brain that behaves as an inverse agonist at the cannabinoid receptor CB(1), where it inhibits agonist-induced receptor internalization.

In their studies, Dodd and colleagues found that this peptide dose-dependently decreases night-time food intake in normal male rats and mice, as well as in obese ob/ob male mice, when administered centrally or systemically, without any obvious adverse side effects.

Hemopressin specifically blocks the hyperphagic response to CB(1) receptor agonists, while having no effect on eating behaviour in CB(1) receptor null mutant male mice.

Obviously, the discovery of this peptide not only increases our understanding of the complex neurobiology of ingestive behaviour but may also lead the way to new treatments for obesity.

It should however be noted that we have already had potent inhibitors of the CB(1) receptor for the treatment of obesity (readers will recall rimonabant), which were withdrawn from the market due to increased incidence of depression.

Nevertheless, it may well be that endogenous inhibitors of the endocannabinoid system (like hemopressin) may well be better tolerated previous inhibitors of this system.

Perhaps we have not seen the last of our attempts to decrease appetite by blocking the endocannabinoid system just yet.

AMS
Edmonton, Alberta

p.s. You can now also follow me and post your comments on Facebook

Dodd GT, Mancini G, Lutz B, & Luckman SM (2010). The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice. The Journal of neuroscience : the official journal of the Society for Neuroscience, 30 (21), 7369-76 PMID: 20505104

An important aspect of enjoying food, in addition to the actual taste and mouth feel, is the complex sensory stimulation of the olfaction system. After the food enters the oral cavity, aroma molecules find their way to the sensitive olfactory nerve endings in the nose by making their way up the back of the throat into the nasal cavity (apparently the nose has a clever way of telling whether this aroma is coming from the food on your plate or from the food in your mouth).

This activation of specific brain areas by a retronasally sensed food odor is not only associated with the perception of the aroma of the food that is consumed but is also hypothesized to directly contribute to its satiating effect (sensory-related satiation).

A paper by Rianne Ruijschop and colleagues from The Netherlands, published in the Journal of Agricultural and Food Chemistry, provides a splendid overview of this fascinating area of research.

In this paper, Ruijschop and colleagues describe a series of experiments that examine a wide range of factors that can affect retronasal olfaction-related satiation.

Not surprisingly, solid and semisolid foods that required a greater amount of chewing and swallowing elicited a stronger and longer-lasting retronasal aroma release pattern than the rather short-lived spiked pattern observed with liquid foods. A higher extent of retronasal aroma release may therefore be one of the explanations why solid foods appear to be more satiating than liquid foods.

Indeed, the researchers did observe a negative trend between the extent of retronasal aroma release and the amount of ad libitum food intake. Subjects who had a higher extent of retronasal aroma release tended to consume less.

However, retronasal aroma release intensity and profile morphology appeared to be subject specific, which may support the hypothesis that subject differences in the extent of retronasal aroma release are linked to subject differences in sensory satiation and food intake behavior.

In further studies, the researchers found that certain aromas were better at eliciting a satiation response than others. Thus, aromas that suggest fat content (i.e., lactones) were less effective in creating a satiation response than aromas suggesting carbohydrate content (i.e., maltol) or the breakdown of protein (i.e., “animalic”). In a separate experiment, custard products with the addition of maltol or animalic at sensory detection threshold were able to increase subjects’ feeling of fullness significantly.

These results are in line with the observation that macronutrients have different satiating efficiencies, in which protein is more satiating, followed by carbohydrate and fat as least satiating.

Based on these studies, the authors suggest that these findings may provide the rational for developing strategies for prolonging the duration of retronasal aroma release during food consumption.

Examples could include food products with an increase of aftertaste or an increased or lingering aroma release via flavor delivery systems or encapsulation technology or the development of long-chewable food structures in beverages that evoke substantially more oral processing and an increase in transit time in the oral cavity.

Furthermore, a reduction in bite size by tailored packaging may support the “right” oral processing behavior in food products. Interestingly, as blogged previously, eating too fast has been previously associated with increased risk for obesity.

Differences in the extent of retronasal aroma release during consumption may be one of the reasons that people vary in their satiation characteristics, which may prevent them from overeating or not. Whether or not there is a difference in this effect between normal weight and obese people is not known.

As the authors point out, integration of these findings into novel food products may provide a new way to reduce food consumption.

While we wait for these new foods here are my retronasal olfaction-based satiation tips:

1) Take small bites
2) Chew your food thoroughly
3) Don’t drink your calories

Remember, the main problem with fast food is not the “food” - it’s the “fast”.

Happy Holidays,

AMS

p.s. As I am planning to take it easy for the next couple of days you are likely to see sporadic posts till the new year.

One of the best ways to increase your hunger, slow down metabolism and increases spontaneous physical search activity is to simply stop eating or to even just reduce caloric intake. This is called the adaptive response to fasting and it is of course this hyopthalamic response that limits the long-term effectiveness of weight loss strategies.

A new study by Jose Silva and colleagues from New York’s Rockefeller University, published this week in NATURE identifies forkhead box transcription factor (Fox-a2) as a key molecule in the regulation of this response.

Using mice models, the researchers now showed that the stimulation of the lateral hypothalamic area (the main ‘feeding centre’ that regulates food intake, arousal and motivated behaviour) through the actions of orexin and melanin-concentrating hormone (MCH), neuropeptides that are released during fasting, are regulated by Fox-a2. This transcription factor incidentally is also a target of insulin signaling.

During fasting, Fox-a2 binds to MCH and orexin promoters and stimulates their expression thereby increasing hunger and increasing spontaneous activity.

In fed and in hyperinsulinemic obese mice, insulin signalling leads to nuclear exclusion of Foxa2 and reduced expression of MCH and orexin, thereby decreasing hunger and increasing activity.

Activation of Fox-a2 increases orexin and MCH production leading to mice that eat more, are more physically active and have improved insulin sensitivity. Turning on Foxa2 in obese mice also increases lean body mass and reduces their fat content. 

Thus, the researchers appear to have identified a key molecule that may prove to be a useful pharmacological target for medications that can help increase spontaneous physical activity and improve health.

AMS
Edmonton, Alberta

Regular readers of this blog may recall previous surprising and seemingly counterintuitive reports like the one that messages telling you to move more will only promote snacking, marking healthy “choices” on menus virtually guarantees that these will be the least popular items, and the even more astonishing findings that putting calories on menu boards may actually make you eat more (at home).

If you are wondering why all of these well-meant policies so regularly backfire, you may want to pick up (or borrow) marketing Guru Martin Lindstrom’s book called Buy-ology, or how everything we believe about why we buy is wrong.

The basic thesis is that we all use emotional parts of our brains (and not just the rational parts) when making decisions. Unfortunately, it seem that in the long run, the emotional parts always win hands down. Lindstom’s book backs what some marketers have perhaps always known with cutting edge findings from the latest in neuroscience research.

Based on some of his own studies using sophisticated functional MRI and steady-state topographic (SST) electroencephalographic studies on thousands of volunteers, Lindstrom helped turn simple time-old marketing techniques largely based on brand recognition and market research into a whole new field of neuromarketing.

To be fair, Lindstrom is himself not a neuroscientist, but did recruit the services of at least two renowned experts in the field: Gemma Calvert, Chair in Applied Neuroimaging and Director of the fMRI Centre at the Warwick Manufacturing Group at the University of Warwick and co-founder of Neurosense in Oxford, UK and Richard Silberstein, Chair in Cognitive Neuroscience and CEO of Neuro-Insight, a market research company based in Melbourne, Australia.

A fascinating (and quick) read, the book explains why putting “horror” pictures and health warnings on cigarette packages and even banning cigarette advertising actually promotes their sales (it was only the prohibition of smoking in public places, which was vehemently demanded by non-smokers in response to the discovery of the harms of “passive smoking” that finally made a noticeable dent in tobacco sales).

At least according to Lindstrom, the banning of tobacco advertising was the best thing that ever happened to the tobacco industry in terms of promoting “neuroscience-based” advertising, which helped push tobacco advertising almost entirely under the radar of our consciousness and thus now makes it virtually impossible to regulate while at the same time making it more enticing than ever.

Great for folks like LIndstrom, who can now jet around the globe and make gazillions (which I assume he makes) by helping companies make sure they can continue selling whatever they have to sell to customers who continue faithfully buying their stuff without any idea of why or what they are actually buying.

While I have personally always suspected much of what I read in the book, I did not know that there was actually that much neuroscience (rather than just market research and psychology) to back it up (I should have known!).

I guess while obesity researchers are using sophisticated brain imaging to study ingestive behaviour, marketers are using the very same sophisticated equipment (and I bet their gadgets are way fancier than ours!) to discover how to make folks consume even more.

In fact, after reading Lindstrom’s book, I would guess that the brain imaging research budget of major corporations now exceeds by an order of magnitude the total budget for brain imaging of all “medical” neuroscience brain imaging research facilities around the world – probably no surprise there.

Anyone wanting to learn more about this stuff (but is too cheap to buy the book) can simply visit Martin Lindstrom’s website for a fun and enlightening read.

AMS
Edmonton, Alberta

Orexigen Therapeutics, yesterday anounced that all three remaining trials in their Contrave Obesity Research Phase 3 Program succesfully meet critical FDA benchmarks and that it hopes to file a New Drug Application (NDA) with the US Food and Drug Administration (FDA) in the first half of 2010.

As blogged before, Contrave is a combination of bupropion SR/naltrexone SR for the treatment of obesity and food cravings.

Orexigen summarizes the key findings of the three trials as follows

- 48.0% and 56.3% of patients on Contrave32(1) in COR-I (NB-301) and COR-II (NB-303) lost at least 5% of their body weight after 56 weeks, approximately three times the placebo categorical response rates of 16.4% and 17.1%, respectively (ITT, p<0.001).

- Contrave patients in COR-I and COR-II on Contrave32 had mean weight loss of 6.1% and 6.4% after 56 weeks, compared to 1.3% and 1.2% on placebo, respectively (ITT, p<0.001).

- In the COR-Diabetes (NB-304) trial, 44.5% of patients on Contrave32 lost greater than or equal to 5% of their body weight after 56 weeks, more than double the 18.9% of patients on placebo (p<0.001). Contrave patients also showed a 0.6% reduction in HbA1c from baseline, compared to a 0.1% reduction in placebo. This difference of 0.5% is clinically and statistically significant (ITT, p<0.001).

- Key secondary endpoints met across the entire COR Phase 3 program included significant improvements in cardiovascular and metabolic risk factors such as waist circumference, visceral fat, HDL cholesterol and triglycerides.

- Additional analyses indicate that Contrave patients experienced reductions in the frequency and strength of food cravings and an increased ability to control their eating compared to placebo.

A full copy of the Orexigen press release with additioal information regarding trial desigs and outcomes is available here.

While Contrave is certainly not a new magic bullet for obesity, I can well imagine that this drug will be particularly helpful in obese patients stuggling with hedonic hyperphagia, addictive eating and mood disorders.

Given our limitations to effectively manage obesity by behavioural changes alone (leaving many patients with no alternative but to eventually get bariatric surgery), any safe and effective addition to the pharmacological armamentum for obesity is only too welcome.

Obviously, both buproprion and naltrexone have well-known side effects, and as with any medical treatment, a careful assessment of risk-benefit ratios will be required. Nevertheless, for patients who respond well and tolerate the combination of these compounds, Contrave, in addition to behavioural treatments, may well provide an important aid in weight management and preventing the many complications of obesity.

AMS
Berlin, Germany