Research Mentioning the Binge-Trigger Concept

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COMMENTS: This provides evidence for our theory of a binge cycle as described in our videos and articles. It appears that several mechanisms may initiate binging in food, and maybe sex, but chronic overconsumption leads the accumulation of DeltaFosB and addiction-reltaed brain changes.


Study Links Insulin Action On Brains Reward Circuitry To Obesity (2011)

Researchers reporting in the June issue of Cell Metabolism, a Cell Press publication, have what they say is some of the first solid proof that insulin has direct effects on the reward circuitry of the brain. Mice whose reward centers can no longer respond to insulin eat more and become obese, they show.

The findings suggest that insulin resistance might help to explain why those who are obese may find it so difficult to resist the temptation of food and take the weight back off.

"Once you become obese or slide into a positive energy balance, insulin resistance in [the brain's reward center] may drive a vicious cycle," said Jens Brüning of the Max Planck Institute for Neurological Research. "There is no evidence this is the beginning of the road to obesity, but it may be an important contributor to obesity and to the difficulty we have in dealing with it."

Previous studies had focused primarily on insulin's effect on the brain's hypothalamus, a region that controls feeding behavior in what Brüning describes as a basic stop and start "reflex." But, he says, we all know people overeat for reasons that have much more to do with neuropsychology than they do with hunger. We eat based on the company we keep, the smell of the food and our mood. "We may feel full but we keep eating," Brüning said.

His team wanted to better understand the rewarding aspects of food and specifically how insulin influences higher brain functions. They focused on key neurons of the midbrain that release dopamine, a chemical messenger in the brain involved in motivation, punishment and reward, among other functions. When insulin signaling was inactivated in those neurons, mice grew fatter and heavier as they ate too much.

They found that insulin normally causes those neurons to fire more frequently, a response that was lost in animals lacking insulin receptors. The mice also showed an altered response to cocaine and sugar when food was in short supply, further evidence that the reward centers of the brain depend on insulin to function normally.

If the findings hold in humans, they may have real clinical implications.

"Collectively, our study reveals a critical role for insulin action in catecholaminergic neurons in long-term control of feeding," the researchers wrote." The further elucidation of the exact neuronal subpopulation(s) and cellular mechanisms responsible for this effect may thus define potential targets for the treatment of obesity."

As a next step, Brüning said they plan to conduct functional magnetic resonance imaging (fMRI) studies in people who have had insulin artificially delivered to the brain to see how that may influence activity in the reward center.


Insulin action in the brain can lead to obesity (2011)

June 6th, 2011 in Neuroscience

Fat-rich food makes you fat. Behind this simple equation lie complex signalling pathways, through which the neurotransmitters in the brain control the body's energy balance. Scientists at the Cologne-based Max Planck Institute for Neurological Research and the Cluster of Excellence in Cellular Stress Responses in Ageing-associated Diseases (CECAD) at the University of Cologne have clarified an important step in this complex control circuit.

They have succeeded in showing how the hormone insulin acts in the part of the brain known as the ventromedial hypothalamus. The consumption of high-fat food causes more insulin to be released by the pancreas. This triggers a signalling cascade in special nerve cells in the brain, the SF-1 neurons, in which the enzyme P13-kinase plays an important role. Over the course of several intermediary steps, the insulin inhibits the transmission of nerve impulses in such a way that the feeling of satiety is suppressed and energy expenditure reduced. This promotes overweight and obesity.

The hypothalamus plays an important role in energy homeostasis: the regulation of the body's energy balance. Special neurons in this part of the brain, known as POMC cells, react to neurotransmitters and thus control eating behaviour and energy expenditure. The hormone insulin is an important messenger substance. Insulin causes the carbohydrate consumed in food to be transported to target cells (e.g. muscles) and is then available to these cells as an energy source. When high-fat food is consumed, more insulin is produced in the pancreas, and its concentration in the brain also increases. The interaction between the insulin and the target cells in the brain also plays a crucial role in the control of the body's energy balance. However, the precise molecular mechanisms that lie behind the control exercised by insulin remain largely unclear.

A research group led by Jens Brüning, Director of the Max Planck Institute for Neurological Research and scientific coordinator of the CECAD (Cellular Stress Responses in Aging-Associated Diseases) cluster of excellence at the University of Cologne has achieved an important step in the explanation of this complex regulatory process.

As the scientists have shown, insulin in the SF-1 neurons – another group of neurons in the hypothalamus – triggers a signalling cascade. Interestingly, however, these cells appear only to be regulated by insulin when high-fat food is consumed and in the case of overweight. The enzyme P13-kinase plays a central role in this cascade of messenger substances. In the course of the intermediary steps in the process, the enzyme activates ion channels and thereby prevents the transmission of nerve impulses. The researchers suspect that the SF-1 cells communicate in this way with the POMC cells.

Kinases are enzymes that activate other molecules through phosphorylation – the addition of a phosphate group to a protein or other organic molecule. "If insulin binds to its receptor on the surface of the SF-1 cells, it triggers the activation of the PI3-kinase," explains Tim Klöckener, first author of the study. "The PI3-kinase, in turn, controls the formation of PIP3, another signalling molecule, through phosphorylation. PIP3 makes the corresponding channels in the cell wall permeable to potassium ions." Their influx causes the neuron to 'fire' more slowly and the transmission of electrical impulses is suppressed.

"Therefore, in overweight people, insulin probably indirectly inhibits the POMC neurons, which are responsible for the feeling of satiety, via the intermediary station of the SF-1 neurons," supposes the scientist. "At the same time, there is a further increase in food consumption." The direct proof that the two types of neurons communicate with each other in this way still remains to be found, however.

In order to find out how insulin acts in the brain, the Cologne-based scientists compared mice that lacked an insulin receptor on the SF-1 neurons with mice whose insulin receptors were intact. With normal food consumption, the researchers discovered no difference between the two groups. This would indicate that insulin does not exercise a key influence on the activity of these cells in slim individuals. However, when the rodents were fed high-fat food, those with the defective insulin receptor remained slim, while their counterparts with functional receptors rapidly gained weight. The weight gain was due to both an increase in appetite and reduced calorie expenditure. This effect of insulin could constitute an evolutionary adaptation by the body to an irregular food supply and extended periods of hunger: if an excess supply of high-fat food is temporarily available, the body can lay down energy reserves particularly effectively through the action of insulin.

It is not currently possible to say whether the findings of this research will eventually help to facilitate targeted intervention in the body's energy balance. "We are currently still very far away from a practical application," says Jens Brüning. "Our objective is to find out how hunger and the feeling of satiety arise. Only when we understand the entire system at work here, we will be able to start developing treatments."

More information: Tim Klöckener, Simon Hess, Bengt F. Belgardt, Lars Paeger, Linda A.W. Verhagen, Andreas Husch, Jong-Woo Sohn, Brigitte Hampel, Harveen Dhillon, Jeffrey M. Zigman, Bradford B. Lowell, Kevin W. Williams, Joel K. Elmquist, Tamas L. Horvath, Peter Kloppenburg, Jens C. Brüning, High-fat Feeding Promotes Obesity via Insulin Receptor/P13k-Dependent Inhibition of SF-1 VMH Neurons, Nature Neuroscience, June 5th 2011

Provided by Max-Planck-Gesellschaft


Binge Mechanism Triggered by Fat Within Intestines Stimulating Endocannabinoids (2011)

Study Finds Why We Crave Chips & Fries

Stephanie Pappas, LiveScience Senior Writer

Date: 04 July 2011

It's hard to eat just one potato chip, and a new study may explain why.

Fatty foods like chips and fries trigger the body to produce chemicals much like those found in marijuana, researchers report today in the journal Proceedings of the National Academy of Sciences (PNAS). These chemicals, called "endocannabinoids," are part of a cycle that keeps you coming back for just one more bite of cheese fries, the study found.

"This is the first demonstration that endocannabinoid signaling in the gut plays an important role in regulating fat intake," study researcher Daniele Piomelli, a professor of pharmacology at the University of California, Irvine, said in a statement.

Homemade marijuana chemicals

The study found that fat in the gut triggers the release of endocannabinoids in the brain, but the gray stuff between your ears isn't the only organ that makes natural marijuana-like chemicals. Human skin also makes the stuff. Skin cannabinoids may play the same role for us as they do for pot plants: Oily protection from the wind and sun.

Endocannabinoids are also known to influence appetite and the sense of taste, according to a 2009 study in PNAS, which explains the munchies people get when they smoke marijuana.

In the new study, Piomelli and her colleagues fitted rats with tubes that would drain the contents of their stomachs as they ate or drank. These stomach tubes allowed the researchers to tell whether fat was acting on the tongue, in which case they would see an

endocannabinoid release even with the tubes implanted, or in the gut, in which case they wouldn't see the effect.

The rats got to sip on a health shake (vanilla Ensure), a sugar solution, a protein-rich liquid called peptone, or a high-fat beverage made of corn oil. Then researchers anesthetized and dissected the rats, rapidly freezing their organs for analysis.

For the love of fat

Tasting sugars and proteins didn't affect the release of the body's natural marijuana chemicals, the researchers found. But supping on fat did. The results showed that fat on the tongue triggers a signal to the brain, which then relays a message down to the gut via a nerve bundle called the vagus nerve. This message commands the production of endocannabinoids in the gut, which in turn drives a cascade of other signals all pushing the same message: Eat, eat, eat!

This message would have been helpful in the evolutionary history of mammals, Piomelli said. Fats are crucial to survival, and they were once hard to come by in the mammalian diet. But in today's world, where a convenience store full of junk food sits on every corner, our evolutionary love of fat easily backfires.

The findings suggest that by blocking the reception of endocannabinoid signals, medical researchers might be able to break the cycle that drives people to overeat fatty food. Blocking endocannabinoid receptors in the brain can cause anxiety and depression, Piomelli said, but a drug designed to target the gut might not trigger those negative side effects.


How junk food primes the brain's food-seeking behavior (2015)

February 23, 2016 by Christopher Packham

(Medical Xpress)—The current epidemic of obesity in developed countries should be a warning for health officials in the developing world with newly opened markets. Food manufacturers, restaurant franchising companies, food supply chains and advertisers collaborate to create environments in which extremely palatable, energy-dense foods and their related cues are readily available; however, people still have adaptive neural architecture best suited for an environment of food scarcity. In other words, the brain's programming may make it difficult to handle the modern food ecosystem in a metabolically healthy way.

Humans, like all animals, have ancient genetic programming adapted specifically to ensure food intake and food-seeking survival behaviors. Environmental cues strongly influence these behaviors by altering neural architecture, and corporations have refined the science of leveraging human pleasure response and perhaps inadvertently reprogramming people's brains to seek surplus calories. In an environment that is rich in highly palatable, energy-dense foods, the pervasiveness of food-related cues can lead to food seeking and overeating regardless of satiety, a likely driver of obesity.

A group of Canadian researchers at the University of Calgary and the University of British Columbia recently published the results of a mouse study in the Proceedings of the National Academy of Sciences in which they explored the neural mechanisms behind these changes in food-seeking behavior.

Programming future food approach behaviors

They report that the short-term consumption of extremely palatable food—specifically, sweetened high-fat food—actually primes future food approach behaviors. They found that the effect is mediated by the strengthening of of excitatory synaptic transmission onto dopamine neurons, and lasts for days after initial 24-hour exposure to sweetened high-fat foods.

These changes occur in the brain's ventral tegmental area (VTA) and its mesolimbic projections, an area involved in adapting to environmental cues used for predicting motivationally relevant outcomes—in other words, the VTA is responsible for creating cravings for stimuli found to be rewarding in some way.

The researchers write, "Because enhanced excitatory synaptic transmission onto dopamine neurons is thought to transform neutral stimuli to salient information, these changes in excitatory synaptic transmission may underlie the increased food-approach behavior observed days after exposure to sweetened high-fat foods and potentially prime increased food consumption."

Possible therapeutic approaches to obesity

The enhanced synaptic strength lasts for days after exposure to high-energy-density food, and is mediated by increased excitatory synaptic density. The researchers found that introducing insulin directly to the VTA suppresses excitatory synaptic transmission onto dopamine neurons and completely suppresses food-seeking behaviors observed after 24-hour access to sweetened high-fat food.

During that period of food access, the number of glutamate release sites onto dopamine neurons increases. Insulin acts to block those sites, competing with glutamate. Noting that this suggests a possible therapeutic approach to obesity, the authors write, "Thus, future work should determine whether intranasal insulin can decrease overeating due to food priming induced by palatable food consumption or food-related cues."

More information: Consumption of palatable food primes food approach behavior by rapidly increasing synaptic density in the VTA. PNAS 2016 ; published ahead of print February 16, 2016, DOI: 10.1073/pnas.1515724113


In an environment with easy access to highly palatable and energydense food, food-related cues drive food-seeking regardless of satiety, an effect that can lead to obesity. The ventral tegmental area (VTA) and its mesolimbic projections are critical structures involved in the learning of environmental cues used to predict motivationally relevant outcomes. Priming effects of food-related advertising and consumption of palatable food can drive food intake. However, the mechanism by which this effect occurs, and whether these priming effects last days after consumption, is unknown. Here, we demonstrate that short-term consumption of palatable food can prime future food approach behaviors and food intake. This effect is mediated by the strengthening of excitatory synaptic transmission onto dopamine neurons that is initially offset by a transient increase in endocannabinoid tone, but lasts days after an initial 24-h exposure to sweetened high-fat food (SHF). This enhanced synaptic strength is mediated by a long-lasting increase in excitatory synaptic density onto VTA dopamine neurons. Administration of insulin into the VTA, which suppresses excitatory synaptic transmission onto dopamine neurons, can abolish food approach behaviors and food intake observed days after 24-h access to SHF. These results suggest that even a short-term exposure to palatable foods can drive future feeding behavior by "rewiring" mesolimbic dopamine neurons.


Decoding Neural Circuits that Control Compulsive Sucrose Seeking (2015)


  • •LH-VTA neurons encode reward-seeking actions after they transition to habits
  • •A subset of LH neurons downstream of VTA encode reward expectation
  • •LH-VTA projections provide bidirectional control over compulsive sucrose seeking
  • •Activating LH-VTA GABAergic projections increases maladaptive gnawing behavior


The lateral hypothalamic (LH) projection to the ventral tegmental area (VTA) has been linked to reward processing, but the computations within the LH-VTA loop that give rise to specific aspects of behavior have been difficult to isolate. We show that LH-VTA neurons encode the learned action of seeking a reward, independent of reward availability. In contrast, LH neurons downstream of VTA encode reward-predictive cues and unexpected reward omission. We show that inhibiting the LH-VTA pathway reduces “compulsive” sucrose seeking but not food consumption in hungry mice. We reveal that the LH sends excitatory and inhibitory input onto VTA dopamine (DA) and GABA neurons, and that the GABAergic projection drives feeding-related behavior. Our study overlays information about the type, function, and connectivity of LH neurons and identifies a neural circuit that selectively controls compulsive sugar consumption, without preventing feeding necessary for survival, providing a potential target for therapeutic interventions for compulsive-overeating disorder.


Do Orexins contribute to impulsivity-driven binge consumption of rewarding stimulus and transition to drug/food dependence? (2015)

Pharmacol Biochem Behav. 2015 Apr 28.

Alcaraz-Iborra M1, Cubero I2.


Orexins (OX) are neuropeptides synthesized in the lateral hypothalamic region which play a fundamental role in a wide range of physiological and psychological functions including arousal, stress, motivation or eating behaviors. This paper reviews under the addiction cycle framework (Koob, 2010), the role of the OX system as a key modulator in compulsivity-driven consumption of rewarding stimulus including ethanol, palatable food and drugs and their role in impulsivity and binge-like consumption in non dependent organisms as well.

We propose here that drug/food binge-like consumption in vulnerable organisms increases OX activity which, in turn, elicits enhanced impulsivity and further impulsivity-driven binge consumption in a positive loop that would promote compulsive-driven binge-consumption and the transition to drug/food disorders over time.


Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling (2015)

Psychoneuroendocrinology. 2015 Oct;60:206-16.

Valdivia S1, Cornejo MP1, Reynaldo M1, De Francesco PN1, Perello M2.


Binge eating is a behavior observed in a variety of human eating disorders. Ad libitum fed rodents daily and time-limited exposed to a high-fat diet (HFD) display robust binge eating events that gradually escalate over the initial accesses. Intake escalation is proposed to be part of the transition from a controlled to a compulsive or loss of control behavior. Here, we used a combination of behavioral and neuroanatomical studies in mice daily and time-limited exposed to HFD to determine the neuronal brain targets that are activated - as indicated by the marker of cellular activation c-Fos - under these circumstances. Also, we used pharmacologically or genetically manipulated mice to study the role of orexin or ghrelin signaling, respectively, in the modulation of this behavior.

We found that four daily and time-limited accesses to HFD induce: (i) a robust hyperphagia with an escalating profile, (ii) an activation of different sub-populations of the ventral tegmental area dopamine neurons and accumbens neurons that is, in general, more pronounced than the activation observed after a single HFD consumption event, and (iii) an activation of the hypothalamic orexin neurons, although orexin signaling blockage fails to affect escalation of HFD intake. In addition, we found that ghrelin receptor-deficient mice fail to both escalate the HFD consumption over the successive days of exposure and fully induce activation of the mesolimbic pathway in response to HFD consumption. Current data suggest that the escalation in high fat intake during repeated accesses differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling.


Opioid system in the medial prefrontal cortex mediates binge-like eating (2013)

Addict Biol. 2013 Jan 24. doi: 10.1111/adb.12033.

Blasio A, Steardo L, Sabino V, Cottone P.


Binge eating disorder is an addiction-like disorder characterized by excessive food consumption within discrete periods of time.

This study was aimed at understanding the role of the opioid system within the medial prefrontal cortex (mPFC) in the consummatory and motivational aspects of binge-like eating. For this purpose, we trained male rats to obtain either a sugary, highly palatable diet (Palatable rats) or a chow diet (Chow rats) for 1 hour/day.

We then evaluated the effects of the opioid receptor antagonist, naltrexone, given either systemically or site-specifically into the nucleus accumbens (NAcc) or the mPFC on a fixed ratio 1 (FR1) and a progressive ratio schedule of reinforcement for food.

Finally, we assessed the expression of the genes proopiomelanocortin (POMC), pro-dynorphin (PDyn) and pro-enkephalin (PEnk), coding for the opioids peptides in the NAcc and the mPFC in both groups.

Palatable rats rapidly escalated their intake by four times. Naltrexone, when administered systemically and into the NAcc, reduced FR1 responding for food and motivation to eat under a progressive ratio in both Chow and Palatable rats; conversely, when administered into the mPFC, the effects were highly selective for binge eating rats. Furthermore, we found a twofold increase in POMC and a ∼50% reduction in PDyn gene expression in the mPFC of Palatable rats, when compared to control rats; however, no changes were observed in the NAcc.

Our data suggest that neuroadaptations of the opioid system in the mPFC occur following intermittent access to highly palatable food, which may be responsible for the development of binge-like eating.


Researchers unlock mechanisms in the brain that separate food consumption from craving (2016)

March 8, 2016

Researchers investigating eating disorders often study chemical and neurological functions in the brain to discover clues to overeating. Understanding non-homeostatic eating—or eating that is driven more by palatability, habit and food cues—and how it works in the brain may help neuroscientists determine how to control cravings, maintain healthier weights and promote healthier lifestyles. Scientists at the University of Missouri recently discovered the chemical circuits and mechanisms in the brain that separate food consumption from cravings. Knowing more about these mechanisms could help researchers develop drugs that reduce overeating.

"Non-homeostatic eating can be thought of as eating dessert after you've eaten an entire meal," said Kyle Parker, a former grad student and investigator in the MU Bond Life Sciences Center. "I may know that I'm not hungry, but this dessert is delicious so I'm going to eat it anyway. We're looking at what neural circuitry is involved in driving that behavior."

Matthew J. Will, an associate professor of psychological sciences in the MU College of Arts and Science, a research investigator in the Bond Life Sciences Center and Parker's adviser, says for behavior scientists, eating is described as a two-step process called the appetitive and consummatory phases.

"I think of the neon sign for a donut shop—the logo and the aroma of warm glazed donuts are the environmental cues that kick start the craving, or appetitive, phase," Will said. "The consummatory phase is after you have that donut in hand and eat it."

Parker studied the behavior patterns of laboratory rats by activating the brain's pleasure center, a hotspot in the brain that processes and reinforces messages related to reward and pleasure. He then fed the rats a cookie dough-like diet to exaggerate their feeding behaviors and found that the rats ate twice as much as usual. When he simultaneously inactivated another part of the brain called the basolateral amygdala, the rats stopped binge eating. They kept returning to their food baskets in search of more, but only consumed a normal amount.

"It seemed as if the rats still craved the dough," Will said. "They kept going back for food but simply didn't eat. We found that we had interrupted the part of the brain that's specific to feeding—the circuit attached to actual eating—but not the craving. In essence, we left that craving intact."

To find out what was happening in the brain during cravings, Parker set up a spin-off experiment. Like before, he switched on the region of the brain associated with reward and pleasure and inactivated the basolateral amygdala in one group of rats but not the other. This time, however, he limited the amount of the high fat diet the rats had access to so that both groups ate the same amount.

Outwardly, both groups of rats displayed the same feeding behaviors. They ate a portion of food, but kept going back and forth to their food baskets. However, inside the brain, Parker saw clear differences. Rats with activated nucleus accumbens showed increased dopamine neuron activity, which is associated with motivated approach behavior.

The team also found that the state of the basolateral amygdala had no effect on dopamine signaling levels. However, in a region of the brain called the hypothalamus, Parker saw elevated levels of orexin-A, a molecule associated with appetite, only in rats with activated basolateral amygdala.

"We showed that what could be blocking the consumption behavior is this block of the orexin behavior," Parker said.

"The results reinforced the idea that dopamine is involved in the approach—or the craving phase—and orexin-A in the consumption," Will said.

The team believes that these findings could lead to a better understanding of the different aspects of overeating and drug addiction. By revealing the independent circuitry of craving vs. the actual consumption or drug taking, this could lead to potential drug treatments that are more specific and have less unwanted side effects.

Parker and Will's study, "Neural activation patterns underlying basolateral amygdala influence on intra-accumbens opioid-driven consummatory versus appetitive high-fat feeding behaviors in the rat," recently was published in Behavioral Neuroscience. Research was funded in part by the National Institute of Drug Abuse (DA024829).