Arya M. Sharma, MD

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

Hedonic hyperphagia (overeating controlled by reward rather than need for calories) often underlies excess caloric intake. As the reward centres that regulate drug and other forms of addiction are the same that are stimulated by highly palatable foods, it is not surprising that genes associated with substance and other addictions may also be linked with obesity.

This assumption finds new support in a study published this month in PLoS Genetics by Nancy Heard-Costa from Boston University School of Medicine on behalf of the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) consortium .

The researchers performed genetic analyses on more than 30,000 subjects participating in 8 large cohort studies, including the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES- Reykjavik Study), the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), the European Special Population Network consortium (EUROSPAN), the Family Heart Study, the Framingham Heart Study, Old Order Amish (OOA), and the Rotterdam Study (RS).

Genetic loci studied included those identified in previous studies as well as new candidate loci for abdominal fat deposition.

In addition to confirming significant associations with the previously reported FTO and MC4R genes, the researchers found a novel locus in the NRXN3 gene associated with waist circumference, BMI and obesity.

NRNX3 has previously been associated with addiction (alcohol dependence, cocaine addiction, and illegal substance abuse) and is part of a family of central nervous adhesion molecules, which are highly expressed in sub-cortical regions of the brain in involved with learning and reward training.

Although the odds ratio for obesity per copy of the implicated G Allele was only 1.13, this small effect at a population level can be substantial.

More importantly, this finding clearly supports the notion that some individuals may be more susceptible to obesity because of an increased genetic predisposition to reward-seeking behaviours, that obviously include seeking out highly-palatable (addictive) foods.

Punitive approaches to drug addictions have not worked - neither will punitive approaches to obesity resulting from hedonic overeating.

AMS
Edmonton, Alberta

Smoking cessation is one of the most common risk factors for weight gain and there is little doubt that in some people food activates exactly the same hedonic pathways as does nicotine and other drugs - this is why for some people, food is very much an addiction.

In fact, previous studies have shown that people who abstain from smoking, not only tend to give in to food cravings more often, but as cravings for cigarettes become more intensified, so do cravings for starchy carbohydrates and fats. These food are also well know to improve dysphoric moods (anxiety, depression, and irritability) that typically accompany nicotine withdrawal.

A new study published this month in OBESITY further illustrates these striking similiarities in food cravings and mood states between obese women and women who smoke tobacco.

In this study, Yanina Pepino and colleagues form the Monell Chemical Senses Center, Philadelphia, PA, USA, assessed food cravings in 229 women who differed in smoking history (i.e., never smoker, former smoker, and current smoker) and body weight (i.e., normal weight, overweight, and obese).

Each subject completed the Food Craving Inventory (FCI), which measures cravings for sweets, high fats, carbohydrates/starches, and fast-food fats, and the Profile of Mood States (POMS), which measures psychological distress.

Both smoking and obesity were found to be independently associated with specific food cravings and mood states (particularly depression and anger). Current smokers clearly craved high fats more frequently than former and never smokers. They also craved starches more frequently and felt more depressed and angry than never smokers, but not former smokers.

From these findings the authors conclude that while cravings for starchy foods and poor mood may be characteristic of women who are likely to smoke, more frequent cravings for fat among smokers is related to smoking per se.

Similarly, obese women craved high fats more frequently than nonobese women and depression symptoms were intensified with increasing body weights.

The overlapping neuroendocrine alterations associated with obesity and smoking and the remarkable similarities in food cravings and mood states between women who smoke and women who are obese suggest that common biological mechanisms modulate cravings for fat in these women.

Unfortunately, while smoking can be addressed by “smoking cessation” programs it is highly unlikely that we will be able to address the obesity epidemic with “eating cessation” programs.

Nevertheless, the recognition that smoking and food cravings interact with mood and involve the same hedonic neuronal pathways, may well lead to treatments that can target both nicotine and food addiction.

AMS
Edmonton, Alberta