Bending the Brain to Find the Roots of Hunger and Eating

Bending the Brain to Find the Roots of Hunger and EatingSynaptic plasticity – the ability of the synaptic connections between the brain’s neurons to change and modify over time — has been shown to be a key to memory formation and the acquisition of new learning behaviours. Now research led by a scientific team at Beth Israel Deaconess Medical Center (BIDMC) reveals that the neural circuits controlling hunger and eating behaviours are also controlled by plasticity.

Described in the February 9, 2012 issue of the journal Neuron, the findings show that during fasting, the AgRP neurons that drive feeding behaviours actually undergo anatomical changes that cause them to become more active, which results in their “learning” to be more responsive to hunger-promoting neural stimuli.

“The role of plasticity has generally not been evaluated in neuronal circuits that control feeding behaviour and with this new discovery we can start to unravel the basic mechanisms underpinning hunger and gain a greater understanding of the factors that influence weight gain and obesity,” explains senior author Bradford Lowell, MD, PhD, an investigator in BIDMC’s Division of Endocrinology, Diabetes and Metabolism and Professor of Medicine at Harvard Medical School (HMS).

Adds BIDMC Chairman of Neurology Clifford Saper, MD, PhD, “For most animals, finding enough food to survive is their biggest daily challenge, and so the brain’s increase in feeding drive may be adaptive. But, for humans who are overweight, reducing this drive to the AgRP neurons may prove to be a path to future weight loss therapies.”

The roots of hunger, eating, and weight are based in the brain’s complex and rapid-fire neurocircuitry. Over the years, nerve cells containing agouti-related peptide (AgRP) protein and pro-opiomelanocortin (POMC) protein have emerged as critical players in feeding behaviors. Located in the hypothalamus, the brain area that controls automatic body functions, AgRP neurons have been shown to drive eating and weight gain while POMC neurons inhibit feeding behaviours, causing satiety and weight loss.

Previous work by the Lowell lab and others had demonstrated that when AgRP neurons in mice are artificially switched on, the animals eat voraciously, consuming four times more than control animals. “The ‘switched-on’ animals search in an unrelenting fashion for food, and when given a task to obtain pellets, will work five times harder to get them,” Lowell explains. “Given the important role played by AgRP neurons, we had a great interest in understanding the factors that regulate their activity.” While much focus had centered on hormones, including leptin, insulin and ghrelin, the Lowell team hypothesized that other nerve cells might be the mechanisms that were regulating neuronal activity.

Neurons communicate with one another via neurotransmitters, chemical messengers that traverse synapses, the specialized junctions between upstream and downstream neurons. Glutamate is one such excitatory neurotransmitter.

“Studies in other regions of the brain [for example those controlling learning and reward and addiction behaviours] have demonstrated that glutamate synapses are highly plastic, changing in their strength and sometimes even in their number,” explains Lowell. Shown to exert powerful control over behaviour, synaptic plasticity is brought about when glutamate binds to NMDA receptors on downstream neurons.

“NMDA receptors are unusual and really interesting,” he adds. “When glutamate gets released by upstream neurons and binds to NMDA receptors, calcium enters the downstream neuron. This, in turn, engages signal transduction pathways that cause synaptic plasticity. In other parts of the brain, such as the hippocampus, NMDA receptors drive plasticity which serves to encode memories.”

Led by co-first authors Tiemin Liu, PhD, Dong Kong, PhD, Bhavik P. Shah, PhD, and Chianping Ye, PhD, the investigators created and studied mice genetically engineered to lack glutamate-binding NMDA receptors on the AgRP neurons. For the sake of comparison, they also created mice genetically engineered to lack NMDA receptors on POMC neurons.

They found that while mice lacking NMDA receptors on POMC neurons showed no change in feeding behaviour, the situation was dramatically different in the mice lacking NMDA receptors on AgRP neurons. “These mice ate a lot less and were much skinnier than a group of control mice,” explains Lowell. Furthermore, the scientists found that a 24-hour period of fasting — which causes intense hunger in the control mice — was associated with a 67 percent increase in the number of dendritic spines on the AgRP neurons.

“Dendritic spines are tiny structures attached to the neuron’s dendrites, the tree-like branches that receive incoming signals from upstream neurons,” explains Lowell. “These structures are the physical site, the subcellular communication hub, where synaptic input from upstream glutamate-releasing neurons is received, typically one synaptic input per spine.”

“I’ve been studying spines for a long time and I’ve never before seen a manipulation that triggered such rapid and robust changes in spine number,” says coauthor Bernardo Sabatini, MD, PhD, a Howard Hughes Medical Institute investigator in the Department of Neurobiology at Harvard Medical School. “Clearly, feeding is plugging in to the most basic mechanisms that control synapse and spine number in these cells. This may be a great system to understand not only feeding behaviour, but also to understand the cell biology behind dynamic synapse formation and retraction.”

When the control mice were refed — and their hunger alleviated — the number of spines dropped back to normal. (In contrast, fasting had no effect on spine number in the mutant mice lacking NMDA receptors on AgRP neurons.) These dramatic changes in spine number and their tight association with states of hunger and satiety in control mice — and the absence of changes in spine number in mice lacking NMDA receptors on the downstream AgRP neurons- strongly suggests that structural plasticity of excitatory glutamate synapses on AgRP neurons is an important regulator of feeding behaviour, says Lowell.

“Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, and certain types of cancer,” he adds. “By understanding the neurobiological mechanisms underlying feeding behaviours, we can work on treatments for a problem that has now become a global epidemic. These findings move us closer to a mechanistic understanding of how various factors controlling hunger might work.”

This study was supported by grants from the National Institutes of Health and the American Diabetes Association, as well as support from the Shapiro Predoctoral Fellowship and the Parkinson’s Disease Foundation Postdoctoral fellowship programs.

In addition to Lowell, Sabatini and the paper’s first authors, other coauthors include BIDMC investigators Shuichi Koda and Zongfang Yang and HMS investigators Arpiar Saunders and Jun B. Ding.

Journal Reference:

  1. Matthew R. Banghart, Bernardo L. Sabatini.Photoactivatable Neuropeptides for Spatiotemporally Precise Delivery of Opioids in Neural TissueNeuron, 2012; 73 (2): 249 DOI: 10.1016/j.neuron.2011.11.016


Beth Israel Deaconess Medical Center (2012, February 8). Roots of hunger and eating: Plasticity in the brain’s wiring controls feeding behavior in mice. ScienceDaily. Retrieved February 21, 2012, from­/releases/2012/02/120208132253.htm

How Not to Overeat

To find out how effective the traditional method of diet and exercise is in losing weight, scientists studied children to get their reaction.

How not to overeatOvereating is something we all do, whether we are young or old and even if we’re not hungry. Changing this repetitive and destructive habit requires a lifestyle change and some serious behavioral therapy.

A recent study out of the University of California, published in the Journal of Consulting and Clinical Psychology looked at a couple of different methods to help overeating.

These studies focused on reprogramming natural responses to satiety and internal hunger cues. Scientists also brought cognitive therapy into the mix by working on the psychological and physiological response to foods in any given situation.

The first method was called Appetite Awareness Training that focused on learning the difference between being full and actual hunger. The second method was called Cue Exposure Training that focused on resisting temptation – something like that old dog trick, where you sit your dog down in front of a delicious treat and he sits there and drools, not touching the food until he’s given the command.

“We teach children and parents how the environment tricks us into eating foods even when we’re not hungry,” said Kerri Boutelle, PhD and lead study author, citing examples of food triggers such as TV commercials, the abundance of easy-to-eat and high-calories snacks, and the use of food as a reward.

This study lasted eight weeks and provided the participants with coping skills and ideas to help resist temptation and the urge to overeat. Test subjects were also taught how to manage their overeating and listen to their body’s hunger cues and food-related moods.

The results were recorded for body weight, overeating, binge eating and caloric intake.

“While this was a pilot study, our initial results suggest that the ‘cue exposure’ approach might be very helpful in reduction of eating in the absence of hunger,” said Boutelle. She added that significant reduction in such overeating was found in the cue-exposure group, even six months post-treatment, though there was very little long-term impact on overeating in the appetite awareness group. There was only a small effect on body weight and no effect on reported calories eaten in either group; however, both approaches resulted in decreased binge eating in children and their parents

“These findings are exciting because they offer a completely new paradigm for controlling overeating and binge eating,” Boutelle said. “By reducing overeating and binge eating, we hope to provide a new way of preventing weight gain and providing children with a sense of control over what they chose to eat. This is really important, because a loss of control can lead to depression and other psychiatric problems, and of course childhood obesity.”


University of California – San Diego. “New approach to management of overeating in children.” ScienceDaily, 7 Dec. 2011. Web. 20 Dec. 2011

Tapping into our Sense of Smell to Combat Overeating

Fruit flies are probably the last thing you think of when you think of dieting and overcoming cravings, but scientists use these pesky creatures regularly to tap deeper into the mystery of human biological mechanisms.

smell_weightlossWhen you feel hungry or when your blood sugar is low, the body produces neuropeptides that enhance your reaction to food odors, tempting you to eat. Scientists are working with these neuropeptides in fruit flies to develop a solution to helping obese people from overeating and conversely, those who are underweight to eat more.

“Olfaction makes important contributions to the perception of food quality and profoundly influences our dietary choices,” said Jing Wang, head researcher at the University of California, San Diego.

This research hopes to develop drugs that will bypass insulin in regulating hunger and satiety levels by tapping into these neuropeptides.

“Our studies in Drosophila address an important question – how starvation modulates olfactory processing. We were surprised to find that starvation modulation of smell happens at the periphery, because most of the literature on feeding regulations is about the function of the hypothalamus. There are hints to suggest that this kind of starvation modulation in the peripheral olfactory system is present in vertebrate systems as well.”

This study looks at the relationship between insulin sensitivity and our sense of smell when it comes to hunger and satiety. When insulin levels are low and the body is in a starved state, the olfactory senses kick into high gear in an attempt to seek out food.

“The notion that starvation modulation at the peripheral olfactory system is linked to insulin signaling has potential implications for the therapeutic intervention of the seemingly unstoppable obesity epidemic trend in a large percentage of the population. Learning how olfactory neural circuits impact dietary choices is relevant towards better understanding factors that contribute to obesity and eating disorders.”

Plans to create this new drug are already underway.


University of California – San Diego. “Fruit fly’s response to starvation could help control human appetites.” ScienceDaily 31 Mar. 2011. Web. 8 Apr. 2011.