Summary: Researchers report that a weight-loss medication reduces the brain’s response to food cues in regions tied to emotion and attention, and that these changes are associated with reductions in calorie intake, weight and BMI.
Source: Beth Israel Deaconess Medical Center.
Findings indicate the drug may be especially helpful for people who eat in response to emotions.
A randomized, double-blind clinical trial led by investigators at Beth Israel Deaconess Medical Center (BIDMC) found that the weight-loss drug lorcaserin reduced activity in brain regions linked to attention and emotion when study participants viewed images of appealing foods. These neural changes were associated with reduced caloric intake, weight loss and lower body mass index (BMI). The study, the first to examine lorcaserin’s action in the human brain, clarifies the drug’s mechanism and suggests which patients may benefit most. The paper was published in the journal Diabetes.
“Human eating behavior engages brain systems involved in cognitive control, attention and decision-making,” said Christos S. Mantzoros, MD, Director of the Human Nutrition Unit in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Professor of Medicine at Harvard Medical School. “We set out to determine whether lorcaserin acts on these brain regions and, if so, where and how. With one-third of the U.S. population obese and another third overweight, safe and effective treatments remain a public health priority.”
Approved by the U.S. Food and Drug Administration (FDA) in 2012, lorcaserin is prescribed for obese or overweight adults with weight-related health conditions such as diabetes. Clinical trials have shown that roughly half of people taking the drug lose at least 5 percent of their body weight within a year, but individual responses vary widely and the neural mechanisms were previously unexplored.
In the present study, researchers followed 48 obese adults for four weeks. Participants were randomly assigned to receive lorcaserin or a placebo. During the study they attended four clinic visits for blood tests, physical exams, body measurements and weight-loss counseling with a registered dietitian. They also kept food records throughout the trial.
On three visits—before medication (Week 0), after one week of treatment (Week 1) and after four weeks of treatment (Week 4)—participants underwent two functional magnetic resonance imaging (fMRI) sessions: one after fasting for at least 12 hours and one after consuming a standardized meal. During each scan they viewed 150 images including highly palatable foods (for example, cake and onion rings), less palatable foods (vegetables), and nonfood items (rocks, trees). fMRI measures changes in blood flow that reflect neural activation during these tasks.
After one week, fasting-state fMRI showed that participants taking lorcaserin had reduced activation in attention-related parietal and visual cortical regions when viewing highly desirable foods. By Week 4, in the fed state, the lorcaserin group showed lower activity in the parietal cortex across all food images. The study also observed attenuated limbic responses—including the insula and amygdala—by Week 4, regions involved in emotion and the salience of stimuli.
Importantly, the investigators found that participants with the strongest baseline brain responses to food cues—especially in emotion- and attention-related regions—experienced the greatest reductions in caloric intake, weight and BMI when treated with lorcaserin. This pattern suggests that lorcaserin may be particularly effective for individuals who eat in response to emotional or salient food cues, often described as “emotional eaters.”
Lorcaserin selectively targets the serotonin 5-HT2C receptor, which animal studies have implicated in abnormal food consumption. Earlier serotonergic weight-loss agents affected a broader range of 5-HT receptors and were associated with serious cardiac side effects. Because lorcaserin is more selective for 5-HT2C, the authors note it may provide anti-obesity effects without the same cardiac risks seen with previous, less selective drugs.
“The distinct mechanism of lorcaserin compared with other obesity medications also raises the possibility of combination therapies,” Mantzoros added. “Combining treatments with complementary mechanisms could produce stronger and more durable weight loss, and this is an avenue for future research.”
Funding: This work was supported by the Harvard Clinical and Translational Science Center Grant (UL1 RR025758) from the National Center for Research Resources. Eisai, Inc. provided an Investigator-Initiated Study grant and supplied study medication through Arena Pharmaceuticals GmbH. Eisai approved the study’s design but had no role in data collection, management, analysis, interpretation, or manuscript preparation. The study also received partial support from the National Institutes of Health (DK081913). Olivia M. Farr was supported by fellowship grant 5T32HD052961.
Source: Jacqueline Mitchell – Beth Israel Deaconess Medical Center
Image Source: Image used for illustrative purposes only.
Original Research: Abstract for “Lorcaserin administration decreases activation of brain centers in response to food cues and these emotion- and salience-related changes correlate with weight loss effects: a four week long randomized, placebo-controlled, double-blinded clinical trial” by Olivia M. Farr et al., published in Diabetes (September 2016), doi:10.2337/db16-0635
Beth Israel Deaconess Medical Center. “Study Reveals Weight Loss Drug’s Effect on Brain.” Neuroscience News. 12 September 2016.
Abstract
Lorcaserin administration decreases activation of brain centers in response to food cues and these emotion- and salience-related changes correlate with weight loss effects: a four week long randomized, placebo-controlled, double-blinded clinical trial
Lorcaserin is a serotonin 5-HT2C receptor agonist effective in treating obesity. Although rodent studies showed lorcaserin acts in the brain to reduce weight, its effects in humans were not previously characterized. In a randomized, placebo-controlled, double-blind trial of 48 obese participants, researchers used functional magnetic resonance imaging (fMRI) to examine lorcaserin’s impact on brain responses to food cues. Compared with placebo, lorcaserin reduced activations in attention-related parietal and visual cortices in response to highly palatable food cues at one week in the fasting state, and reduced parietal cortex responses to all food cues at four weeks in the fed state. Emotion- and salience-related limbic activity, including the insula and amygdala, was attenuated at four weeks. Baseline activations in the amygdala, parietal and visual cortices correlated with subsequent reductions in caloric intake, weight and BMI, suggesting higher baseline reactivity predicted greater treatment benefit. These findings support a model in which lorcaserin reduces attention-related and emotional neural responses to food cues, and indicate potential particular benefit for individuals whose eating is driven by emotional or highly salient food cues.
Previous serotonergic agents such as fenfluramine activated multiple 5-HT receptor subtypes and were linked to cardiac complications. Because the anti-obesity effects of fenfluramine were blocked by a 5-HT2C receptor antagonist, selective activation of 5-HT2C by lorcaserin may preserve weight-loss benefits while minimizing cardiac risk. Animal models lacking 5-HT2C receptors exhibit increased body weight and altered feeding behaviors, as well as metabolic disturbances including insulin and leptin resistance and impaired glucose tolerance, supporting a key role for this receptor in energy balance. Similar pathways may underlie improvements observed in fasting glucose, lipids and blood pressure in patients treated with lorcaserin.
“Lorcaserin administration decreases activation of brain centers in response to food cues and these emotion- and salience-related changes correlate with weight loss effects: a four week long randomized, placebo-controlled, double-blinded clinical trial” by Olivia M. Farr, Jagriti Upadhyay, Anna Gavrieli, Michelle Camp, Nikolaos Spyrou, Harper Kaye, Hannah Mathew, Maria Vamvini, Anastasia Koniaris, Holly Kilim, Alexandra Srnka, Alexandra Migdal, and Christos S. Mantzoros in Diabetes. Published online September 2016 doi:10.2337/db16-0635