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

Soda Pop and Video Games Adding to Childhood Obesity

If you’re a teenager and trying to lose weight, where do you go for advice?

Soda pop, video games and teenage obesityReportedly, 75% of obese teenagers are trying to lose weight, but when their methods were analyzed by researchers, it was found that certain habits and behaviors are holding them back.

These findings come from a study out of Philadelphia, where 14% of high-school students are overweight. This analysis from the Philadelphia Youth Risk Behavioral Survey, looked at about 44,000 high-schoolers to determine what kind of efforts are being made to help with weight loss and what kind of behaviors are lingering that prevent them reaching their goals.

Such behaviors as smoking, regular exercise, video game playing and the consumption of junk food were all taken into account.

Sadly, the obese weight group of female teenagers were also more likely to be smokers and even though most of these females were committed to 60 minutes of aerobic activity a day, their subsequent consumption of soda pop was standing in their way of success.

You need to exercise for 30 minutes of cardio to burn one soda pop.

Their male counterparts were less likely to exercise on a daily basis, giving up aerobic activity for video games – an average of three hours a day is spent on playing video games.

“From a health education standpoint, finding out that three-quarters of students who are obese want to lose weight is exactly what we want,” said lead researcher Clare Lenhart. “But the behavior they’re engaging in is puzzling; it’s counterproductive to what they’re trying to do.”

The researchers believe there is a lack of education amongst these teens and there needs to be a better system for raising awareness to help break bad habits causing weight gain.

“For example, among the girls who are exercising, they may not realize that one soda could undo that 30-minute walk they just took.”

Health-care providers can also do a better job at evaluating teen health with more accurate follow-up questions about their activity levels and nutritional habits.

“If a child is going to their pediatrician, and he asks them if they’re losing weight, an appropriate follow-up question might be, ‘How are you doing that?'” said Lenhart. “It could help guide those teens to more productive weight loss activities.”


Temple University. “Overweight teens want to lose weight, going about it the wrong way.”ScienceDaily, 1 Nov. 2011. Web. 5 Dec. 2011.

Using Brown Fat as a Treatment for Obesity and Diabetes

Obesity and diabetes are often linked in what is becoming one of the deadliest combinations in the obesity epidemic hitting America and indeed the rest of the world.

brown fatTo get to the bottom of the rise in this epidemic, researchers at the Joslin Diabetes Center conducted a study on brown fat found in mice. Brown fat is unlike common white fat as it burns energy rather than storing it and discovering a pathway to stimulate it into action could be instrumental in fighting obesity and weight-related diseases.

This study identified two molecular pathways that cause brown fat cells to grow:

“We used different drugs to stimulate or block the signaling pathways that we thought were important. The result was that we defined the two pathways. We found what goes to what to cause something to happen to the cells.” ~  Dr Aaron Cypress, October issue of Endicronology.

Previous studies have also identified these two molecular pathways as an important piece of the puzzle.

“With a more detailed description of the pathways leading to (brown fat tissue), there can be more focused attempts to develop interventions using brown fat as a treatment for obesity and diabetes.”

One intervention could be to grow brown fat in a laboratory and transplant it into the bodies of people who need it. Another could be the development of drugs to stimulate brown fat growth.

Over the years, the two lead researchers involved in this study have shown that brown fat is more abundant in children and especially those who are thin and closer to puberty. They have also proven that brown fat in adults, while not as abundant, is active and could be stimulated into action.

Remember: brown fat burns energy, so the more you have, the more calories you burn.

“Brown fat burns energy. It is a special tissue. These studies have opened up a new avenue for the treatment of obesity and its related disorders. This study will help us deepen our understanding of brown fat formation and could in the future, combined with other information that we have learned, be used to develop drugs or other interventions for obesity.”


Joslin Diabetes Center. “Combating obesity and diabetes: Researchers identify pathways leading to activation of ‘good’ fat.” ScienceDaily, 23 Sep. 2011. Web. 20 Oct. 2011.

Another Clue to How Obesity Works

With obesity gaining momentum, scientists are getting closer to understanding how the disease progresses, providing clues for future treatments.

Another clue into how obesity worksIn one study published in the journal Cell Metabolism, researchers examined the hormone leptin and how a resistance to it can develop. Leptin is a key hormone in the cause of obesity.

Lead author Professor Tony Tiganis, of the Monash Obesity and Diabetes Institute and Monash University’s Department of Biochemistry and Molecular Biology, said our bodies produce leptin in response to increasing fat deposits.

“Acting on a part of the brain called the hypothalamus, leptin instructs the body to increase energy expenditure and decrease food intake, and so helps us maintain a healthy body weight,” said Professor Tiganis.

“The body’s response to leptin is diminished in overweight and obese individuals, giving rise to the concept of ‘leptin-resistance’. We’ve discovered more about how ‘leptin-resistance’ develops, providing new directions for research into possible treatments.”

Previous studies have revealed two proteins that inhibit leptin in the brain and Professor Tiganis’ team have discovered a third.

Tests performed on mice revealed this third protein as more abundant with weight-gain, exacerbating leptin-resistance and hastening progression to morbid obesity. The study showed that the three negative regulators of leptin take effect at different stages, shedding light on how obesity progresses.

“Drugs targeting one of the negative regulators are already in clinical trials for Type 2 Diabetes; however, our research shows that in terms of increasing leptin-sensitivity in obesity, targeting only one of these won’t be enough. All three regulators might need to be switched off,” said Professor Tiganis.

When two of the negative regulators were removed from the test mice, weight gain from a high fat diet was largely prevented.

“We now have to determine what happens when all three negative regulators are neutralised. Do we prevent high fat diet-induced obesity?”

Professor Tiganis said the more that is known about obesity, the better-equipped scientists are to develop drugs to support good diet and exercise choices.

“Humans have a deep-seated attraction to overeating and nutrient-rich food, inherited from our hunter-gatherer ancestors. Now that food is more readily available and our lifestyles are less active, our evolutionary drive to overeat is becoming problematic.”

“Simply telling people to eat less and exercise more is not going to be sufficient to reverse the obesity trend. There is a pressing need to develop novel drugs that complement diet and exercise to both prevent and treat this disease,” said Professor Tiganis.


Monash University. “Another clue to how obesity works.” ScienceDaily, 14 Oct. 2011. Web. 18 Oct. 2011.

Is your Neighborhood Unhealthy?

With obesity affecting more and more teens these days, parents need to take a look at their nutritional habits and their neighborhoods.

Is your Neighborhood Unhealthy?The more junk food options available in your neighborhood, the more likely your teenagers will visit these places for meals.

“You are what you eat. You are, also, where you live,” said Susan Babey from the UCLA Center for Health Policy, “and if you live in a place where there’s a fast food restaurant or convenience store on every block, with few healthier alternatives, you are likely to eat more junk.”

It’s not just fast food outlets like burger joints but other retail outlets like convenience stores, dollar stores, pharmacies and liquor stores that dominate most neighborhoods over healthier outlets.

Babey is senior research scientist at the center and co-authored the most recent study proving this theory, using two databases – the 2007 California Health Interview Survey and InfoUSA – that measured the relationship between the number of unhealthy and healthy outlets and the teens’ eating habits and from these findings created the Home and School Retail Food Environment Index.

“Research has shown that the consumption of fast food and soda has been linked to taking in excess calories and can contribute to diabetes and obesity.”

The results showed that the average California teen lives in a neighborhood with a saturation level of unhealthy outlets of seven times the number of healthy ones and these teens are 17% more likely to drink soda every day and 18% more likely to eat fast food at least twice a week than their peers who live in healthy neighborhoods.

“It is a travesty that our kids have better access to liquor stores and other unhealthy food outlets than a grocery store,” said Robert K. Ross, M.D., president and CEO of the California Endowment, which funded the study. “We have put our children and youth in harm’s way, and they are paying the price for our carelessness. If nothing is done, this will be the first generation to live shorter lives than their parents.”

These results spread over both rural and urban communities:

  • More than 70% of teens drink soda every day in San Benito, Sutter, Merced and Fresno counties
  • More than 55% of teens eat fast food at least twice a week in Tulare, Riverside, Ventura and Kern counties
  • A total of 13 counties across California had Home and School Retail Food Environment Index scores of more than 8 points and rates as an unhealthy food environment

The researchers recommended of policies that would help improve these unhealthy environments:

  • Better zoning, especially around schools
  • Farm-to-school programs that bring fresh produce into school cafeterias
  • Better incentives were needed to bring healthy food outlets, such as farmers markets and grocery stores, into underserved neighborhoods

“The research shows that how we plan and zone our communities has a real impact on our health and quality of life,” Babey said. “Policymakers need to take this into account when deciding whether to zone a new grocery store or a fast food restaurant. Hopefully, they will make the healthy choice.”


University of California – Los Angeles. “As unhealthy food outlets multiply, teens eat more junk.” ScienceDaily, 27 Jul. 2011. Web. 27 Jul. 2011.

Originally published @ FITLODE.COM