Brain changes responsible for the appetite effects of cannabis are identified in animal studies
New research on how cannabis use alters eating behavior could lead to treatments for appetite loss in chronic illness, according to experts at Washington State University. Using a new procedure to dose lab rats with cannabis vapor, the researchers found how the drug triggers hunger hormones. They also identified specific brain regions that shift to ‘hungry’ mode while under the influence, according to a report they shared this week at the Society for the Study of Ingestive Behavior, an international meeting of scientific experts on eating.
“We all know cannabis use affects appetite, but until recently we’ve actually understood very little about how or why,” explained Jon Davis, Ph.D., researcher in the Department of Integrative Physiology and Neurosciences at Washington State. “By studying exposure to cannabis plant matter, the most widely consumed form, we’re finding genetic and physiological events in the body that allow cannabis to turn eating behavior on or off.”
A recent wave of cannabis legalization for both medical and recreational purposes has stimulated research on its therapeutic potential. A family of compounds called cannabinoids, particularly delta-9 tetrahydrocannabinol (THC), are responsible for its psychological effects. The ability of THC to stimulate appetite is valuable since many illnesses cause extreme appetite loss which reduces quality of life and slows recovery.
For these new studies the scientists designed a vapor exposure system to mimic how people often consume cannabis. This allowed precise control of dosage while rats’ meals were closely monitored throughout the day. Brief exposure to cannabis vapor stimulated a meal even when rats had recently eaten, suggesting that inhaling cannabis tricks appetite circuits in the brain into hunger mode.
“We found that cannabis exposure caused more frequent, small meals,” stated Davis. “But there’s a delay before it takes effect.” That delay provided a clue to how the drug may act. Ordinarily, when the stomach is empty it releases a hormone called ghrelin, a message to the brain that it’s time to look for food. The researchers found that the cannabis dose triggered a ghrelin surge. When they gave a second drug which prevented the ghrelin surge, cannabis no longer triggered eating. They also found changes in how the brain responds to the message. In small region of the hypothalamus responsible for sensing ghrelin, cannabis changed the genetic activity of brain cells that respond to the hormone.
The researchers are optimistic that deciphering that ways cannabis acts in the body to alter appetite can lead to new treatments for illness-induced anorexia. Severe appetite loss is a common symptom of many chronic illnesses, and is especially problematic in cancer, HIV/AIDS, heart disease, and some metabolic disorders. A targeted treatment that offers the beneficial effects on appetite without the broader effects on the mind and body could increase quality of life and speed recovery.
Investigating the Neuroendocrine and Behavioral Controls of Cannabis-Induced Feeding Behavior. JF Davis, PQ Choi, J Kunze, P Wahl, Washington State University Pullman, WA, USA. Presented July 2018, Society for the Study of Ingestive Behavior, Bonita Springs, FL.
Jon Davis, Ph.D. Assistant Professor, Integrative Psychology and Neurosciences
Washington State University, Pullman, WA
Mindset during meal planning changes food choices and brain responses to food
A simple instruction to change your thinking as mealtime approaches can help cut calories, according to new research from the University of Tübingen, Germany. By encouraging study participants to concentrate on different types of information when planning their meal, the experimenters saw portion sizes shift. Adopting a health-focused mindset produced better outcomes than focusing on pleasure or the desire to fill up. These new findings were presented this week at the annual meeting of the Society for the Study of Ingestive Behavior, an international conference of experts on eating research.
“Daily food intake is highly dependent on the portion sizes we select,” explained Stephanie Kullmann, lead investigator on the project. “The rise in obesity since the 1950s has directly paralleled increasing portion sizes. We are finding that switching an individual’s mindset during pre-meal planning has the potential to improve portion control.” In recent experiment, the researchers learned that lean individuals can be encouraged to make healthier food choices by adopting a ‘health-focused mindset’. Brain scans showed how this approach can trigger activity in the prefrontal cortex, which is linked to self-control and future meal planning. Their latest study demonstrates how a shift in mindset might assist individuals who are overweight or obese.
Study participants ranged from normal weight to obese. They were told to focus their mindset on either the health effects of food, expected pleasure, or their intention to stay full until dinner time, while choosing their portion size for lunch. Additionally, in a control condition they chose their actual portion size for lunch without any mindset instruction. Compared to the control condition (no mindset instruction), participants in all weight categories selected smaller portions when prompted to think about health. By contrast, those who adopted the fullness mindset took larger portions. In pleasure mindset condition, obese participants selected larger portions than normal-weight participants. This tendency correlated with a heightened response in a taste-processing region of the brain. In the fullness mindset, obese persons showed blunted brain responses in regions for reward and physiological regulation.
“This influence of pre-meal mindset on food choices may contribute to the vicious cycle we observe in obesity,” said Kullmann. “Focusing on food for pleasure leads to bigger servings and increased brain responses to food reward, whilst the sensation of fullness is perceived as less satisfying.”
The encouraging message from this study is people of all weights responded positively to a healthy mindset instruction, suggesting that this approach should be considered in strategies for healthy weight management. The findings also suggest that advertising healthy food options as “tasty” might be counterproductive because this has the potential to induce a pleasure mindset, which leads to the selection of larger serving sizes in individuals who are struggling with their weight.
Mindsets influence brain response and behavior during pre-meal planning in overweight and obese adults. Ralf Veit1, Lisa I. Horstman1, Maike A. Hege1, Martin Heni1, Peter J. Rogers2, Jeff M. Brunstrom2, Andreas Fritsche2, Hubert Preissl1, Stephanie Kullmann1
1Institute for Diabetes Research and Metabolic Diseases, University of Tübingen, Germany
2Nutrition and Behaviour Unit, University of Bristol, United Kingdom.
Presented at the Society for the Study of Ingestive Behavior, July 2018, Bonita Springs, FL.
Stephanie Kullmann, Ph.D
Researchers identify brain area linked to motivational disruptions in binge eating
Scientists at Rutgers Brain Health Institute have discovered that a small group of brain cells in the hypothalamus called ‘orexin’ neurons could be a promising target for medications for controlling binge eating episodes in individuals with obesity. These neurons, named for the chemical messenger they use to communicate with other brain cells, have previously been shown to be important for addiction to several drugs, including cocaine.
“Several key symptoms of eating disorders, such as the sense of losing control, overlap with what we know about the driven nature of drug addiction,” said Dr. Gary Aston-Jones, director of the Brain Health Institute at Rutgers, The State University of New Jersey, and one of the senior authors of the study. “Since the orexin system has been implicated in addiction to drugs of abuse, we targeted it to understand the change in food motivation caused by repeated episodes of binge eating.”
The researchers studied female rats fed a control diet or a sugary, high-fat diet that causes weight gain and binge eating patterns. Then they set up a task where rats could work to earn sweet treats. As the work required increased, persistent motivation to earn the treat was seen only in the binge-eaters who had previously gained weight on a high-fat diet. Notably, this enhanced motivation was reversed by treatment with a compound that blocks orexin signals in the brain.
“This study was really a proof-of concept for using orexin blockers to reduce binge-like eating in rodents,” said the lead study author Dr. Morgan James, post-doctoral research fellow at the Rutgers Brain Health Institute. “Currently there are several orexin-targeting medications in clinical trials or already FDA-approved, so we have begun testing whether these compounds would produce similar results in our rodent model of binge eating.” The study team reported their findings this week at the annual meeting of the Society for the Study of Ingestive Behavior (SSIB), an international group of scientific experts on eating behavior.
The researchers also found that the orexin blocker reduced the amount of food consumed during the binge eating episodes, where rats were given unrestricted access to a sweetened fat mixture over a 30 minute period. “Pharmacological treatments are currently limited for patients with eating disorders, so it is really exciting if a novel therapy could expand treatment options for obese individuals with binge eating disorder,” said Dr. Nicholas Bello, associate professor of animal sciences in the School of Environmental and Biological Sciences at Rutgers University and a senior author of the study.
The authors will continue their research by investigating how the size and number of orexin neurons in the brain might be altered following changes to dietary habits or weight or their combination. Funding for this research was provided the Rutgers One Nutrition Pilot Grant program and Rutgers Brain Health Institute.
Orexin/hypocretin system preferentially drives food motivation in female rats experienced with excessive weight gain and binge-like eating. Presented July, 2018 at the Society for the Study of Ingestive Behavior, Bonita Springs, FL.
Authors: MH James1, S Liu1, S Walsh2, BL Yeomans2, HE Bowrey1, G Aston-Jones1, NT Bello1,2
Affiliations: 1 Rutgers Brain Health Institute, Rutgers, The State University of New Jersey.
2 Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey
Nicholas T. Bello, Ph.D.
Anti-obesity drug derived from chili peppers shows promise in animal trials
A novel drug based on capsaicin, the compound that gives chili peppers their spicy burn, caused long term weight loss and improved metabolic health in mice eating a high fat diet, in new studies from the University of Wyoming School of Pharmacy. The drug, Metabocin, was designed to slowly release capsaicin throughout the day so it can exert its anti-obesity effect without producing inflammation or adverse side effects.
“We observed marked improvements in blood sugar and cholesterol levels, insulin response, and symptoms of fatty liver disease,” reported Dr. Baskaran Thyagarajan, lead investigator, describing how Metabocin reversed many damaging effects of the high fat diet. He presented the results this week at the annual meeting of the Society for the Study of Ingestive Behavior, the leading international conference of experts on food and fluid intake.
The research team developed Metabocin, which can be taken orally, to target receptors called TRPV1 (transient receptor potential vanilloid subfamily 1) that are found in high numbers in fat cells. Stimulating the TRPV1 receptors causes white fat cells to start burning energy instead of storing it, which, in theory, should cause weight loss. An important question for the researchers was whether the drug remains effective when used long term, and whether adverse effects would outweigh its benefits. The mice in this experiment remained on the drug for 8 months, maintaining the weight loss with no evidence of safety problems. Additional ongoing experiments will see how long that can be maintained.
“It proved safe and was well tolerated by the mice,” Thyagarajan concluded. “Developing Metabocin as a potent anti-obesity treatment shows promise as part of a robust strategy for helping people struggling with obesity.”
Although these results may give some people the idea to eat more spicy food to lose weight, that would not work as intended. Most of the capsaicin in spicy food is not well absorbed into the body so it would not produce these effects. The researchers specifically modified the capsaicin in Metabocin for proper absorption and sustained release.
Obesity is a growing public health concern, resulting in metabolic diseases including type 2 diabetes, hypertension, atherosclerosis and heart diseases. Currently one in three individuals world-wide is either overweight or obese. Exercise and diet are the standard recommendation, but those are difficult for most people to maintain in the long term, and rebound weight gain usually occurs. The Wyoming researchers advocated for continuing to pursue medical options that stay effective in the long term to counter obesity and its metabolic impacts, to assist people seeking to maintain a healthier weight.
Pharmacological and Safety Analyses of Subchronic Oral MetabocinTM Feeding in Mice,
P Baskaran1, L Markert1, J Bennis1, L Zimmerman1, J Fox
1University of Wyoming School of Pharmacy Laramie, WY, USA
2University of Wyoming, Dept. of Veterinary Sciences Laramie, WY, USA
Presented at the Society for the Study of Ingestive Behavior, July 2018, Bonita Springs, FL.
Researchers find that hunger hormones offer promising avenue for addiction treatment
Hormones that signal the body’s state of hunger and fullness could be the key to new treatments for drug and alcohol addiction. That is the consensus of an expert panel convened this week at the annual meeting of the Society for the Study Ingestive Behavior, the leading international research conference on food and fluid intake. Gut hormones have received considerable attention from scientists seeking to understand overeating and obesity, which led the panelists to discover that those hormones are also involved in addiction. They expressed optimism about the potential for rapid progress toward new addiction treatments, since several drugs that affect these hormones are already approved or in the FDA pipeline.
“Hormones from the gut act in the brain to modulate dopamine signaling, which controls decisions to seek out rewards,” explained Dr. Mitchell Roitman, University of Illinois-Chicago neuroscientist. That explains how food and water become more or less rewarding based on a person’s state of hunger, fullness, or thirst. Since drugs like cocaine and alcohol act on those same dopamine circuits in the brain, gut hormones could potentially turn their rewarding effects up or down in the same fashion.
Ghrelin, a hunger hormone released by the stomach, can influence the reward value of alcohol much like it increases the reward value of food, according to new data shared by panelist Dr. Lorenzo Leggio, leader of a joint team from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). The NIAAA/NIDA team has demonstrated that ghrelin promotes alcohol seeking in people with alcohol use disorder. More recently, they have also studied rats genetically insensitive to ghrelin, an approach that further supports a role of the ghrelin system in alcohol seeking.
Other gut hormones like GLP-1 and amylin are released during eating to tell the brain when a person has had enough. In animal studies reported by several of the panelists, medications that enhance the action of those hormones reduce the rewarding effects of drugs and alcohol. In one study led by Dr. Elisabet Jerlhag of the University of Gothenberg in Sweden, treating rats with a compound that mimics amylin significantly reduced alcohol-seeking, even in rats selectively bred for excess alcohol consumption. Dr. Heath Schmidt of the University of Pennsylvania’s Perelman Medical School, reported similar effects of GLP-1 analogs in reducing rats’ cocaine seeking.
All members of the panel were optimistic about the potential for new therapies to help people battling addiction. “These results provide strong rationale for clinical trials of GLP-1 analogs for people seeking addiction treatment,” said Schmidt. “Medications affecting GLP-1 and amylin are already FDA approved for Type II diabetes and obesity. These drugs could be re-purposed for treating drug craving and relapse.”
Currently substance abuse disorders are one of most common and expensive chronic health problems. In just the United States, more than 21 million adults require treatment for alcohol or illicit drug abuse, according to government statistics. Behavioral therapy is the standard treatment approach, but persistent cravings lead to high relapse rates. There are at present only a few medications approved to help manage cravings, and they are not effective for all people. The panelists concluded that data from animal experiments and preliminary trials in humans all support the gut hormone system as a prime target for novel treatments.
Contact for More information:Dr. Elisabeth Jerlhag, University of Gothenberg, [email protected]
Dr. Lorenzo Leggio, National Institutes of Health, [email protected]
Dr. Mitchell Roitman, University of Illinois-Chicago, [email protected]
Dr. Heath Schmidt, University of Pennsylvania, [email protected]
Based on the symposium “Gut Hormones As Novel Targets For Addiction Treatment” convened at the annual meeting of the Society for the Study of Ingestive Behavior, July 2018, Bonita Springs, FL. http://www.ssib.org/2018/
Diabetes drug with better side-effect tolerance could improve treatmentImproved medications for Type 2 diabetes are one step closer thanks to a new discovery reported this week by researchers at the University of Pennsylvania and Syracuse University. By modifying the key ingredient in current diabetes drugs, the researchers produced a compound that was effective for hyperglycemia in animal trials, yet without the most problematic side effects of current drugs.
“Drug regimens often have long lists of side effects which negatively impact treatment,” said Dr. Bart De Jonghe of University of Pennsylvania School of Nursing, one of the study leaders. “In Type 2 diabetes, nausea and vomiting top that list. It’s the main reason people stop taking their diabetes medications, and diminishes quality of life for millions who do take them.” De Jonghe and his collaborators presented their findings this week at the annual meeting of the Society for the Study of Ingestive Behavior, a leading international research conference for experts on eating behavior.
The rate of Type 2 diabetes, which is linked to obesity, has increased dramatically in recent decades. One widely prescribed class of drugs mimics the hormone glucagon-like peptide-1 (GLP-1) and is effective for controlling hyperglycemia. Yet all FDA-approved GLP-1 based drugs cause nausea and vomiting in between 20-50% of patients. The Penn-Syracuse team modified the active ingredient in current drugs, a compound called exendin-4. By attaching each molecule of exendin-4 to vitamin B-12, they produced a compound that is less absorbed into regions of the brain that trigger nausea and vomiting.
Having recently published that their exendin-4/B-12 conjugate improves blood sugar levels, the team’s newest research addressed the issue of side effects. Measuring that in animal trials proved challenging, since lab rats and mice are unable to vomit. The researchers turned their attention to the musk shrew (Suncus murinus), a mouse-sized mammal with a vomiting reflex similar to humans. Their modifications made a striking difference in the shrews’ response. Both versions of the drug showed equal benefits for controlling blood sugar, yet vomiting occurred in almost 90% of shrews dosed with ordinary exendin-4 and only 12% of shrews treated with the modified version.
“The vomiting results are striking and very encouraging,” says De Jonghe. “It’s rare to see such positive results with a new drug compared to the standard. It’s hard to not be optimistic when you observe a complete flip in the side effect prevalence in favor of vastly improved tolerance.”
Dr. Tito Borner a postdoctoral fellow in De Jonghe’s group, performed additional experiments that explain the improvements in vomiting. The modified drug shows decreased activation of a brain area called the dorsal vagal complex. This primitive brain region is located in the hindbrain and is thought to coordinate many ingestive behaviors, including responses like vomiting to ensure survival.
Type 2 diabetes is the most common form of diabetes, affecting more than 25 million Americans. It occurs when the body stops responding properly to insulin, resulting in chronically high blood sugar. It is most common in people who are overweight or obese, and prevalence is highest in people of Native American, African-American, and Hispanic heritage. Left untreated, consequences of diabetes include circulatory damage, kidney disease, high blood pressure, and stroke. In addition to diet and exercise, physicians often recommend medication for its ability to quickly stabilize blood sugar. The Penn-Syracuse team’s discovery could improve diabetes management by leading to a next generation of the FDA-approved medications that are better tolerated, reducing the number of people who cease medication due to adverse side effects.
Exendin-4 conjugated to vitamin B12 improves glucose tolerance in mice and shrews without inducing vomiting or hypophagia
T Borner1, E Shaulson1, LM Stein2, JL Workinger3, RB Jaime-Lara1, CG Liberini2, RP Doyle3,4, MR Hayes1,2, BC De Jonghe1
1Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania Philadelphia, PA, USA,
2Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA,
3Department of Chemistry, Syracuse University Syracuse, NY, USA, 4Department of Medicine, Upstate Medical University, State University of New York Syracuse, NY, USA
Presented July 2018 at the Society for the Study of Ingestive Behavior, Bonita Springs, FL
Bart De Jonghe, PhD