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Neuromodulation of the Prefrontal Cortex Can Reduce Energy Intake

sharma-obesity-brainNeuroimaging studies have implicated the  left dorsolateral prefrontal cortex (LDLPFC), an area of the brain that plays an important role in the organization and planning of behavior including goal-oriented regulation of eating behavior and food choice, has been implicated in obesity.

Now Marci Gluck and colleagues, present a proof of concept study published in OBESITY, suggesting that effects of cathodal transcranial direct current stimulation (tDCS)aimed at the LDLPFC may reduce energy intake and promote weight loss in individuals with obesity.

The randomised sham-controlled study was conducted in 9 (3m, 6f) healthy volunteers with obesity, who were admitted as inpatients for 9 days to a metabolic ward.

In a first study, following 5 days of a weight-maintaining diet, participants received cathodal or sham tDCS (2 mA, 40 min) on three consecutive mornings and then ate ad libitum from a computerized vending machine, which recorded energy intake.

In a second study participants repeated the 1st study, maintaining original assignment to active (this time anodal) and sham.

In both studies, each stimulation session consisted of 40 min of anodal tDCS delivered with a neuroConn® DC-STIMULATOR device, at a constant current of 2  mA (with a 30-second ramp at on- and offset) using two 5 × 5 cm sponge electrodes soaked in a sterile 0.9% sodium chloride solution.

Participants who received active tDCS consumed about 700 fewer total kilocalories per day during anodal versus cathodal stimulation. This reduction in caloric intake was mainly a result of reduced fat and pop consumption.

In contrast, sham stimulation had no effect on energy intake.

As may be expected in this short term study, not much happened to body weight.

Regarding the mechanisms the authors speculate that,

“Our results, in combination with previous work, point to a role for the LDLPFC in energy intake and body weight regulation. However, the mechanisms that mediate this association are not clear. Capacity for self-control in reward-related decision-making tasks depends critically on the activity of the DLPFC, a region that is activated in response to cues that induce food craving…. Thus, anodal tDCS over the LDLPFC could have reduced food intake by simultaneously suppressing food cravings and facilitating choices requiring delayed gratification.”

As the authors optimistically conclude,

“In this proof of principle clinical trial, participants with obesity receiving anodal versus cathodal tDCS to the LDLPFC tended to have lower ad libitum energy intake, less fat and soda intake, and significant differences in weight change. “

Obviously, it will take longer term studies as well as further exploration of the type of patient who may benefit from this type of treatment, before we can judge whether this type of treatment (which appears to be otherwise safe) can play a role in obesity management.

Vienna, Austria

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Transcriptional Control of Energy Regulation

Screen Shot 2015-10-30 at 10.59.13 AMTo students of human physiology, the commonly held view that obesity is simply a matter of energy in and energy out is nothing short of laughable.

Indeed, there are perhaps no other biological functions of more importance for survival of an organism, than those that regulate energy uptake, storage and expenditure – functions, without any form of life would be impossible.

Thus, the finely tuned complex and often highly redundant pathways that have evolved to optimize energy metabolism have evolved to readily switch from states of feeding to starvation with shifts in substrate use (both qualitative and quantitative) – functions that are controlled by hundreds (if not thousands) of genes.

Getting these genes to work in concert, requires a complex system of gene regulation, by which individual genes are switched on an off (to allow or stop protein synthesis) in various tissues to just the right amount at just the right time – a process known as transcriptional control.

Now, a comprehensive review by Adelheid Lempradl and colleagues, published in Nature Genetics, summarizes the multitude of interlinked processes that control transcription of genes involved in energy homeostasis.

As the authors explain,

“Transcriptional control is the sum of the cellular events that select and dose gene transcription. In simple terms, these events converge on the regulation of gene locus accessibility and polymerase activity (including recruitment, pausing, processivity and termination).”

“Energy homeostasis requires multi-layered regulation via dynamic, often periodic, expression of metabolic pathways to properly anticipate and respond to shifts in energy state.”

“Transcription factors act by binding to specific regulatory DNA sequences, thus controlling the transcriptional output of defined target gene sets. They cooperate with co-regulators, which either promote (co-activators) or inhibit (co-repressors) transcription. Together, they build feedback networks and control the stability and responsiveness of energy homeostasis. Metabolic cells use receptors and metabolic machinery to generate specific signalling responses to endocrine inputs (for example, insulin, glucagon or leptin receptors) or metabolic inputs (for example, the primary energy metabolism machinery itself).”

The papers goes on to discuss at length the various regulator, co-regulators and the plethora of epigenetic modifiers that determine how these factors do their job of activating or deactivating relevant genes throughout the body.

Why is any of this important?

“Rapid progress is currently being made in research on chromatin-based regulation of gene expression. Particular unknowns include the mechanisms that establish long-term set points or priming of gene expression. Identifying the processes that establish activation thresholds and maximal output set points, as well as their self-organizing principles is currently an intriguing area of research, and is important in understanding susceptibility to complex trait disorders, including metabolic and autoimmune diseases. For example, many intergenerational and developmental reprogramming paradigms elicit metabolic disease susceptibility. They highlight the potential impact of subtly divergent transcriptional profiles in any given genetic context.” 

In other words, understanding these processes are fundamental for our understanding of everything from the body’s weight set point (and how this is altered) to intergenerational transmission of obesity risk from one generation to the next (perhaps the most important driver of the current obesity epidemic).

But the complexity of these processes also raise important issues for clinicians,

“The seemingly exponential growth in this complexity now poses a major challenge for translational researchers in need of simplified but accurate paradigms for clinical use.”

The least we can do is to stop pretending that there is anything easy about energy in and energy out.

Berlin, Germany

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The Biology Of The Food Coma

sharma-obesity-sleep-deprivationFeeling ready for a nap after a meal is part of normal human physiology – but how exactly does this happen?

Now, Christophe Varin and colleagues from the Centre National de la Recherche Scientifique, Paris, France, in a paper published in the Journal of Neuroscience describe how glucose regulates key neurones in the brain to induce sleepiness.

Their studies in mice focussed on sleep-active neurons located in the ventrolateral preoptic nucleus (VLPO), critical in the induction and maintenance of slow-wave sleep (SWS).

Using both in vivo and ex vivo patch clamp studies, the researchers show that a rise in extracellular glucose concentration in the VLPO can promote sleep by increasing the activity of sleep-promoting VLPO neurons.

As the researchers note,

“The extracellular glucose concentration monitors the gating of KATP channels of sleep-promoting neurons, highlighting that these neurons can adapt their excitability according to the extracellular energy status… Glucose-induced excitation of sleep-promoting VLPO neurons should therefore be involved in the drowsiness that one feels after a high-sugar meal. This novel mechanism regulating the activity of VLPO neurons reinforces the fundamental and intimate link between sleep and metabolism.”

Apart from helping unravel the biology of a phenomenon that every parent of a young child is well aware of, this research raises a number of interesting clinical questions.

Does overconsumption of high-sugar foods necessitate counteracting these effects with caffeine? Is this why sugar-sweetened pop generally contains caffeine (to not put you to sleep)?

Does this also explain the practice of eating a bedtime snack to fight insomnia?

And what does this mean for people with poorly controlled diabetes: do they need to drink more coffee than people without diabetes to get through their day? (not something I’ve heard of).

Interesting stuff…

Berlin, Germany

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Unravelling The Biology Of The Body Weight Set Point

sharma-obesity-balanceEvery dieter’s dilemma is the simple fact that our bodies can harness complex neurohormonal circuitry to counteract our volitional attempts at weight loss.

Short of starving yourself, there is a limit to the amount of weight you can lose (everyone eventually hits a weight loss plateau) and keeping it off is a lifelong battle as the body strives to return its weight back to the “setpoint” (usually the highest weight you’ve ever been).

But how exactly does this setpoint work and why can some people eat whatever they want – and even gain weight – without resetting to a higher weight?

We don’t know the mechanism in humans, but a study by Dirk Luchtman working in William Colmer’s lab here at the University of Alberta, published in PLOS provides intriguing insights into how this works in rats.

Their research used rats that were either sensitive or resistant to weight-gain induces by feeding them a high-energy diet (HED). Thus, they defined two groups of animals – those that fail to gain weight on HED (designated dietary resistant or DR) and those, who gain weight and then defend their higher body weight when put on a calorie-restricted diet (Defenders).

In their series of elegant experiments, the researchers were able to clearly show that even after prolonged exposure to a calorie-restricted diet, neurohormonal changes (such as the  GABA inputs to PVN neurons) in the Defenders maintained highly attenuated responses to hunger reducing signals (e.g. MTII) compared to diet resistant (DR) or normal weight rats.

This diminished response was only restored to “normal” after the Defenders regained the lost weight.

Thus, the authors note that,

“The loss of melanocortin sensitivity restricted to PVN of Defender animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint.”


Clearly, further understanding exactly why some animals (or people) find it easier to gain and maintain (defend) their higher weight is one of the key areas of interest in finding solutions to better prevent and treat obesity.

At least this much is clear – the reason why most rats (and people) fail at permanently losing excess weight is because of these complex neurohormonal mechanisms that will go to great lengths to ensure that you will eventually put the weight back on.

Simply put – this is exactly the biological mechanism that (if nothing else) argues in favour of considering obesity (once established) a chronic disease.

Berlin, Germany

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Always Hungry? Blame It On Food Porn

sharma-obesity-fmri-brain1There is no doubt that living in a society in which we are constantly surrounded by highly palatable foods makes not overeating a challenge for most of us.

Now, an interesting paper by Charles Spence and colleagues from Oxford University, published in Brain and Cognition, makes a strong case for how exposure to images of desirable foods (which they label ‘food porn’, or ‘gastroporn’) via digital interfaces might be inadvertently exacerbating our desire for food (what they call ‘visual hunger’).

In their paper, the authors review the growing body of cognitive neuroscience research demonstrating the profound effect that viewing such images can have on neural activity, physiological and psychological responses, and visual attention, especially in the ‘hungry’ brain.

Beginning with a brief discussion of evolutionary aspects of vision and food, the authors remind us that,

“Foraging – the search for nutritious foods – is one of the brain’s most important functions. In humans, this activity relies primarily on vision, especially when it comes to finding those foods that we are already familiar with. In fact, it has been suggested that trichromatic colour vision may originally have developed in primates as an adaptation that facilitated the selection of more energy-rich (and likely red) fruits from in-amongst the dark green forest canopy.”

“The brain is the body’s most energy-consuming organ, accounting for somewhere in the region of 25% of blood flow, or rather, 25% of the available consumed energy. Note that this figure is even higher in the newborn human, where the brain absorbs up to two thirds of the energy that is consumed by the developing organism. As Brown notes: “In embryos, the first part of the neocortex to develop is the part which will represent the mouth and tongue…” As the brain grew in size over the course of human evolution, the demands on the visual system to efficiently locate nutrients in the environment would likely also have increased.”

This notion is not trivial given our current environmental exposure to a multitude of food images:

“Our brains learnt to enjoy seeing food, since it would likely precede consumption. The automatic reward associated with the sight of food likely meant another day of sufficient nutrients for survival, and at the same time, the physiological responses would prepare our bodies to receive that food. Our suggestion here is that the regular exposure to virtual foods nowadays, and the array of neural, physiological, and behavioural responses linked to it, might be exacerbating our physiological hunger way too often. Such visual hunger is presumably also part of the reason why various food media have become increasingly successful in this, the digital age.”

And the influence of food media is widespread:

“Every day, it feels as though we are being exposed to ever more appetizing (and typically high calorie) images of food, what some (perhaps pejoratively) call ‘gastroporn’ or ‘food porn’. Moreover, the shelves of the bookstores are increasingly sagging under the weight of all those cookbooks filled with high-definition and digitally-enhanced food images. It has been suggested that those of us currently living in the Western world are watching more cookery shows on TV than ever before. Such food shows often glamorize food without necessarily telling a balanced story when it comes to the societal, health, and environmental consequences of excess consumption.”

And let’s not forget facebook and Instagram:

“At the same time, the last few years have seen a dramatic rise in the dining public’s obsession with taking images of the foods that they are about to eat, often sharing those images via their social media networks. The situation has reached the point now that some chefs are considering whether to limit, or even, on occasion, to ban their customers from taking photographs of the dishes when they emerge from the kitchen. However, one restaurant consultant and publisher has recently suggested that the way food looks is perhaps more important than ever: “I’m sure some restaurants are preparing food now that is going to look good on Instagram”.

The paper goes on to discuss at length the evidence that exposure to images of foods can alter cognitive responses and create the need for constant dietary restraint, which may be more difficult for some than others.

But not all images of food have these effects:

These results support the view that people rapidly process (i.e. within a few hundred milliseconds) the fat/carbohydrate/energy value or, perhaps more generally, the pleasantness of food. Potentially as a result of high fat/high carbohydrate food items being more pleasant and thus having a higher incentive value, it seems as though seeing these foods results in a response readiness, or an overall alerting effect, in the human brain.

As for the parts of the brain that are stimulated by exposure to food images – pretty much all of it. Thus, in one study:

“…the results revealed that obese individuals exhibited a greater increase in neural activation in response to food as compared to non-food images, especially for high-calorie foods, in those brain regions that are associated with reward processing (e.g., the insula and OFC), reinforcement and adaptive learning (the amygdala, putamen, and OFC), emotional processing (the insula, amygdala, and cingulate gyrus), recollective and working memory (the amygdala, hippocampus, thalamus, posterior cingulate cortex, and caudate), executive functioning (the prefrontal cortex (PFC), caudate, and cingulate gyrus), decision making (the OFC, PFC, and thalamus), visual processing (the thalamus and fusiform gyrus), and motor learning and coordination, such as hand-to-mouth movements and swallowing (the insula, putamen, thalamus, and caudate).”

But this knowledge is not all bad. There is also some evidence that digital manipulation of images of vegetables and other healthy foods can make them more attractive and thus hopefully increase their consumption. Whether or not this would actually work in practice remains to be seen.


“Given the essential role that food plays in helping us to live long and healthy lives, one of the key challenges outlined here concerns the extent to which our food-seeking sensory systems/biology, which evolved in pre-technological and food-scarce environments, are capable of adapting to a rapidly-changing (sometimes abundant) food landscape, in which technology plays a crucial role in informing our (conscious and automatic) decisions.”

Are you affected by exposure to foodporn? Is this really a problem?

Edmonton, AM

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