Arya M. Sharma, MD

Earlier this week, Bill Colmers and I gave the inaugural Centennial Lecture for our Faculty of Medicine and Dentistry in anticipation of the upcoming 100 year anniversary of the University of Alberta medical school.

In this talk, we discussed why it is so difficult to keep weight off. I presented the clinical problem, and Colmers, the neuroscientist, presented an overview of how the brain affects eating behaviour and regulates body weight.

I was particularly impressed by how Colmers described the respective roles of the hedonic and homeostatic systems in human evolution.

While the hedonic (pleasure seeking) system evolved to help our hunter-gatherer ancestors seek out and take advantage of any highly palatable energy dense foods they happened to come upon, the homeostatic system evolved to protect from wasting away those extra calories that they did ingest.

Thus, according to Colmers, the hedonic system’s job was to make it hard to resist, in fact, make our ancestors to often go to considerable lengths to searching out those rare palatable energy dense foods and then to eat as much of them as possible, whether they were actually hungry or not. They could of course always store those extra calories as fat tissue for later use - a tremendous survival advantage.

In contrast, the job of the homeostatic system was to ‘defend’ those stored calories - in fact, it is designed to regard any accumulation of fat stores as the ‘new normal’ and from then on make sure that this increased level of fatness was maintained (or regained) ever after.

Indeed, the homeostatic system is ‘designed’ to readjust its set point of body weight - after all it has to do this starting from birth as body weight continues to increase as the baby grows into a toddler that grows into a kid and ultimately into an adult.

Unfortunately, the mechanisms that allow the set point to reset to ‘defend’ a progressively higher body weight - generally works in only one direction - after all that is all that is required by nature, where people do not naturally ’shrink’.

Colmers used the analogy of a ratchet to describe how the homeostatic system is designed to defend ever increasing body weights without having the ability to reset itself to a lower body weight even if the person now wants to lose weight.

Once set to a higher weight (e.g. resulting from ‘overindulgence’ driven by the hedonic system or other factors that may promote weight gain), the homeostatic system uses a wide range of mechanisms affecting hunger, satiety, appetite, metabolic rate, etc. to ‘defend’ this weight from then on.

A very helpful analogy I thought, nicely explaining why evolution has given us the mechanisms to gain weight but not to lose it.

AMS
Edmonton, Alberta

Hunger and satiety are mediated by a range of peripheral signals to the brain.

A new study by Akila de Silva and colleagues from Imperial College London, UK, published in Cell Metabolism, shows that infusion of two gut hormones can reduce food intake and mimic the central effects of a meal in humans.

Specifically, the researchers used functional magnetic resonance imaging (fMRI) to examine the effect of infusing the gut hormones PYY(3-36) and GLP-1(7-36 amide) on brain activation with presentation of food-salient images in six brain regions known to be involved in ingestive behaviour (amygdala, caudate, insula, nucleus accumbens, orbitofrontal cortex, and putamen) of 16 young normal-weight volunteers.

In addition, the researchers looked at the effect of these gut hormones on hunger and eating behaviour before and after a standardized breakfast and an ad libitum buffet lunch.

Combined infusion of these hormones not only led to similar activation/suppression of brain regions as seen after the standardized meal, but also reduced subsequent energy intake.

Not only does this study provide further insight into how the gut talks to the brain but also provides evidence for the involvement of these hormones in ingestive behaviour.

Whether or not such insights can be harnessed to provide better treatments for obesity remains to be seen.

AMS
San Francisco, CA

p.s. Hat tip to Bill Colmers for alerting me to this article

De Silva A, Salem V, Long CJ, Makwana A, Newbould RD, Rabiner EA, Ghatei MA, Bloom SR, Matthews PM, Beaver JD, & Dhillo WS (2011). The Gut Hormones PYY(3-36) and GLP-1(7-36 amide) Reduce Food Intake and Modulate Brain Activity in Appetite Centers in Humans. Cell metabolism, 14 (5), 700-6 PMID: 22000927

Anyone, who has ever experienced even a mild drop in blood glucose levels, understands the notion of hunger - a drive so powerful, that almost any food will taste good (energy-dense foods will taste even better!).

But whether or not elevated glucose levels can also suppress appetite is less well studied.

As study by Kathleen Page and colleagues from Yale University, just published in the Journal of Clinical Investigation, examines whether obese and nonobese individuals regulate their desire to consume high-calorie foods differently in response to changes in blood glucose levels.

Using functional MRI (fMRI) combined with a stepped hyperinsulinemic euglycemic-hypoglycemic clamp, that allows changing the blood glucose levels in a controlled fashion, the authors show that even modest reductions in blood glucose levels preferentially activate limbic-striatal brain regions in response to food cues to produce a greater desire for high-calorie foods.

In contrast, high-normal blood glucose levels preferentially activated the medial prefrontal cortex, an area of the brain involved in regulating impulse control and reducing motivation for rewarding stimuli such as food and drugs.

Interestingly, however, higher circulating glucose levels predicted greater medial prefrontal cortex activation only in lean but not in obese subjects.

As the authors discuss:

“These results are consistent with reports showing that high BMI is associated with decreased prefrontal activity at rest and after meal consumption and that obese subjects have an attenuated postprandial deactivation of the hypothalamus. These altered obesity-associated neural responses to food cues may contribute to overeating behavior, especially several hours after consumption of high-carbohydrate meals, a time when glucose often declines significantly below baseline levels.”

Thus, as the authors conclude:

“These findings demonstrate that circulating glucose modulates neural stimulatory and inhibitory control over food motivation and suggest that this glucose-linked restraining influence is lost in obesity.”

They also speculate that:

“Strategies that temper postprandial reductions in glucose levels might reduce the risk of overeating, particularly in environments inundated with visual cues of high-calorie foods.”

One strategy to avoid drops in blood glucose levels is not to allow yourself to go hungry by consuming smaller but more frequent meals. The other is perhaps to chose low-glycemic index foods in order to prevent the ‘crash-and-crave’ drive that follows rapid changes in blood glucose levels.

The study, certainly provides further evidence for important ‘biological’ differences between non-obese and obese people - while the former experience ‘natural’ appetite suppression with high-normal glucose levels, the
latter do not experience such a suppression of appetite and will need to resort to conscious restraint - a far more difficult undertaking.

AMS
Edmonton, Alberta

p.s. Hat tip to Bill Graber for pointing me to this study

Page KA, Seo D, Belfort-Deaguiar R, Lacadie C, Dzuira J, Naik S, Amarnath S, Constable RT, Sherwin RS, & Sinha R (2011). Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. The Journal of clinical investigation, 121 (10), 4161-9 PMID: 21926468

The melanocortin system is one of the key systems involved in the regulation of ingestive behaviour. Thus, for example, genetic variants of the melanocortin type 4 receptor (Mc4R), have been found to be among the most common mutations associated with severe obesity (in about 5% of cases).

Other studies have also suggested a role for the Mc3R in the regulation of weight gain and food intake, especially with regard to its relationship to circadian rhythms. This is perhaps not surprising, given that the ventromedial hypothalamus (VMH), a critical node in the neural networks regulating feeding-related behaviors and metabolic homeostasis, exhibits dense Mc3R expression relative to other brain regions. In addition, Mc3R is also expressed in the limbic system as well as in peripheral tissues.

A study by Karima Bergriche and colleagues from the Scripps Research Institute, just published in the Journal of Biological Chemistry, shows that the Mc3R may affect body fat and food intake through both central and peripheral mechanisms.

Using a combination of Mc3R knockout mice with neural specific Mc3R expression, the investigators were able to dissect the role of these receptors and brain regions in food intake and metabolism.

Thus, although the knockout animals displayed reduced lean mass, increased fat mass, and accelerated diet-induced obesity (DIO), the attempt to rescue these mice by Mc3R expression in their nervous systems only partially rescued obesity in chow-fed conditions, and had no impact on the accelerated DIO phenotype.

More specifically targeting Mc3R expression to the VMH, despite marked improvements in metabolism also had little impact on obesity.

The authors interpret this findings to indicate that MC3Rs affect energy homeostasis through both central (neuronal) and peripheral mechanisms and that the effects of these receptors on behavior and metabolism involve divergent pathways.

Or, as the authors put it:

“Our data suggests that actions of MC3R in these neurones significantly impacts on metabolic homeostasis, but is not sufficient restore body composition to normal or for regulating expression of complex behaviours associated with food anticipation.”

Clearly, better understanding the pathways and mechanisms involved in these effects may lead to drugs that can perhaps help target this system to improve metabolism and treat obesity.

As always, what works in animals, does not necessarily directly lead to effective and safe medications for humans. Nevertheless, identifying drugable targets is certainly the first first step towards hopefully finding better treatments for obesity and related metabolic problems.

AMS
Edmonton, Alberta

Begriche K, Levasseur PR, Zhang J, Rossi J, Skorupa D, Solt LA, Young B, Burris TP, Marks DL, Mynatt RL, & Butler AA (2011). Genetic dissection of melanocortin-3 receptor function suggests roles for central and peripheral receptors in energy homeostasis. The Journal of biological chemistry PMID: 21984834

Regular readers of these pages will be well aware of the recent slew of evidence suggesting that not getting enough sleep is an important risk factor for weight gain (as anyone who works shifts probably knows from their own experience).

But, as always, not everyone appears to be equally affected.

A paper by Jean-Philippe Chaput and colleagues from the University of Ottawa, just published in SLEEP, suggests that sleep deprivation may especially tend to promote weight gain in people who tend to be disinhibited eaters.

Based on the examination of 276 adults aged 21 to 64 years and followed for 6 years in the Quebec Family Study, Chaput and colleagues found that individuals having both short sleep duration (loss than 6 hours a night) and high disinhibition eating behaviour (as assessed by the three factor eating questionnaire) were more likely to gain weight and increase their abdominal circumference over time.

In contrast, short-duration sleepers with a low disinhibition eating behavior trait had the same weight trajectory as those with average sleep duration.

Over the 6-year follow-up period, the incidence of overweight/obesity for short-duration sleepers with a high disinhibition eating behavior trait was 2.5 times more frequent than for short-duration sleepers with a low disinhibition eating behavior trait.

This increased risk of high disinhibition in short-duration sleepers was largely explained by higher caloric intake.

For those of us still dealing with leftovers from yesterday’s turkey, getting enough sleep may help with any ‘disinhibition’ we may experience when opening the refrigerator.

AMS
Edmonton, Alberta

Chaput JP, Després JP, Bouchard C, & Tremblay A (2011). The Association between Short Sleep Duration and Weight Gain Is Dependent on Disinhibited Eating Behavior in Adults. Sleep, 34 (10), 1291-7 PMID: 21966060