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Cognitive And Autonomic Determinants of Energy Balance

Denis Richard, PhD, Professor, Université Laval, QC, Canada

Denis Richard, PhD, Professor, Université Laval, QC, Canada

While I’m here at the 10th Canadian Obesity Network Summer School (Boot Camp), in the Canadian Rockies, it is perhaps of interest to note that one of the founding faculty of this school, Denis Richard from Laval University, has just published a paper in Nature Reviews Endocrinology, which nicely reviews the complex neurobiology of energy balance.

The paper focuses largely on the “energy out” part of energy homeostasis, which is partly determined by the themogenesis of brown adipose tissue and mediated by the sympathetic nervous system.

Thus, several areas of the brain work together in complex neuronal networks involving a host of neuronal systems including the opioid, endocannabinoid and melanocortin systems, that not only control  appetite and eating behaviour but also thermogenesis.

These neuronal systems, in turn receive inputs from a wide range of peripheral organs including the gut, liver and adipose tissue via hormonal and neuronal pathways that signal energy stores and nutritional status.

The paper also discusses how some of these findings may be relevant to the development of novel treatments for obesity.

For researchers and students: the paper includes a number of excellent graphics that nicely illustrate these systems.

@DrSharma
Kananaskis, AB

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Limbic Effects On Physical Activity And Obesity

sharma-obesity-running-mouseThe amygdala is a part of the so-called limbic system that performs a primary role in the processing of memory, decision-making, and emotional reactions. The amygdala has also been implicated in a variety of mental health problems including anxiety, binge drinking and post-traumatic stress syndrome.

A study by Xu and colleagues, published in the Journal of Clinical Investigation now shows that in mice, activity of the estrogen receptor–α (ERα) in the medial amygdala may have a profound influence on the development of obesity – an effect, which appears to me largely mediated through effects on physical activity.

Building on previous work showing that ERα activity in the brain prevents obesity in both males and female rats, the researchers used a series of complex experiments to demonstrate that specific deletion of the ERα gene from SIM1 neurons, which are highly expressed in the medial amygdala, cause a marked decrease in physical activity and weight gain in both male and female mice fed with regular chow, without any increase in food intake. In addition, this deletion caused increased susceptibility to diet-induced obesity in males but not in females.

Deletion of the ERα receptor also blunted the body weight-lowering effects of a glucagon-like peptide-1-estrogen (GLP-1-estrogen) conjugate.

In contrast, over-expression or stimulation of SIM1 neurons increased physical activity in mice and protected them from diet-induced obesity.

These findings point to a novel mechanism of neuronal control of physical activity, which in turn appears to have important effects on the susceptibility to weight gain.

@DrSharma
Edmonton, AB

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Cognitive And Emotional Functioning In Binge Eating Sydrome

sharma-obesity-mental-health1As a clinician often dealing with patients presenting with binge-eating disorder (BED), I am quite aware of the often pathological cognitive and emotional relationship to food, eating, and body image presented by patients with this syndrome.

Whether or not this impairment in thinking and feeling also extends to other behavioural or emotional domains is the topic of a systematic review by Kittel and colleagues from the University of Leipzig, published in the International Journal of Eating Disorders.

The paper is based on the review of almost 60 studies and shows that, individuals with BED consistently demonstrate higher information processing biases compared to obese and normal-weight controls in the context of disorder-related stimuli (i.e., food and body cues) – in contrast, cognitive functioning in the context of neutral stimuli appear to be less affected.

With regard to emotional functioning, individuals with BED also report greater emotional deficits when compared to obese and normal-weight controls.

Thus, these findings confirm the clinical observation that patients with BED tend to have specific difficulties in cognitive and emotional functioning when it comes to food, eating or body image, however, appear to function adequately in other domains.

For clinicians these finding are relevant as they show that while people with BED may benefit from help in changing their cognitive and emotional response to food cues, such problems are indeed more often encountered in people with BED rather than in everyone living with obesity.

Screening for BED should be an essential element of workup in anyone presenting with excess weight gain.

@DrSharma
Vancouver, BC

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Health Benefits Of Fasting?

sharma-obesity-fat-dietingEven a cursory glance at popular media stories on diets and weight loss will lead you to countless posts on the supposed benefits of alternative-day, intermittent or other forms of fasting.

But just how much evidence is there that any of this is actually beneficial to your health (i.e. if you are not a mouse).

This question was addressed by Benjamin Horne and colleagues from Salt Lake City, Utah, in a paper published in the American Journal of Clinical Nutrition.

The researchers review the evidence on various forms of fasting from the published literature, which consists of a grand total of three randomised controlled trials, together involving about 100 participants, with durations ranging between 2 days to 12 weeks.

Although all three trials reported some benefits in terms of body weight, cholesterol and other surrogate markers, the authors failed to find any study that looked at actual clinical endpoints (e.g., diabetes or coronary artery disease].

To be fair the authors did find two observational studies in humans (both involving the first author of this study), where fasting was associated with a lower prevalence of heart disease or diabetes but, as readers should be well aware, these types of studies cannot prove causality.

I guess it would be fair to say that the popular enthusiasm about the health benefits of various forms of fasting, as far as their benefits for humans are considered, appear largely based on hope and hype – at least as far as clinically meaningful outcomes are concerned.

This is not to say that fasting, whether alternative day or otherwise, may not well have some medical benefits – fact is, we just don’t know.

Or rather, as the authors put it,

“whether fasting actually causes improvements in metabolic health, cognitive performance, and cardiovascular outcomes over the long term; how much fasting is actually beneficial; and where the threshold of hormesis resides (i.e., a balance between long-term benefit from fasting compared with harm from insufficient caloric intake) remain open questions….considerable additional clinical research of fasting is required before contemplating changes to dietary guidelines or practice.”

@DrSharma
Vancouver, BC

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Liraglutide 3 mg For Obesity: The SCALE Trial

saxendaThis week, the New England Journal of Medicine publishes the results of the SCALE Trial, a 56-week randomised controlled trial of liraglutide 3.0 mg vs. placebo (both groups got advice on diet and exercise), on weight loss and other metabolic variables.

The study, that enrolled about 3,700 subjects (70% of who completed the trial), showed greater clinically relevant weight loss in participants treated with liraglutide than with placebo.

Overall, at 56 weeks,

– 2 in 3 individuals on liraglutide achieved a 5% weight loss (compared to 1 in 4 on placebo).

– 1 in 3 individuals on liraglutide achieved a 10% weight loss (compared to 1 in 10 on placebo).

– 1 in 6 individuals on liraglutide achieved a 15% weight loss (compared to fewer than 1 in 20 on placebo).

The adverse effect profile was as expected from a GLP-1 analogue (mainly gastrointestinal and gall bladder related issues).

While liraglutide 3.o mg has now been approved as an anti-obesity agent in the US, Canada and Europe, its key downsides will likely be cost and the fact that it consists of a once-daily injection.

Obviously, as with any obesity treatment, discontinuation will likely result in weight regain (which is not unexpected, given that obesity, once established, becomes a chronic disease).

While in the US, where there are now 4 novel prescription medications for obesity, liraglutide 3.o mg will be the only novel anti-obesity drug available in Canada – a rather sorry state of affairs for those who need medical treatment for this condition.

Where exactly liraglutide will establish itself in the treatment of obesity in clinical practice remains to be seen (time will tell) – but for some patients at least (especially the high-responders), it will hopefully offer a useful adjunct to behavioural treatments.

@DrSharma
Edmonton, AB

Disclaimer: I have received honoraria for consulting and speaking from Novo Nordisk, the makers of liraglutide

 

 

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