The Mechanisms behind Weight Loss and Changes in Brain Regulation of Eating Behaviors and Food Choices after Bariatric Surgery

Principal Investigator: Claudia Sanmiguel, MD

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The purpose of this study is to assess changes in brain activity and structure associated with sensations of hunger and fullness, food preferences and eating habits after bariatric surgery. We are exploring the role of different signal pathways, including gut peptides, fat-related inflammatory markers, metabolites and gut-microbiome derived products in weight loss after bariatric surgery and their influence in brain regulation of body weight and eating behaviors. In addition we are exploring if parameters in brain activity/anatomy and/or metabolite profiles can be useful predictors of successful weight loss.

Background: Obesity has become a major health care problem. Despite considerable progress in understanding the regulation of ingestive behavior, the relative contribution of homeostatic and hedonic eating mechanisms in human obesity remains unknown. Bariatric surgery remains the only treatment resulting in sustained weight loss in humans, yet little is known about how weight loss surgery works, and who most benefits from it. Recent studies showed changes in appetite and food preferences following gastric bypass, yet data about the underlying changes in brain function is very limited. Importantly, there are no published data on the brain moderators of treatment outcomes following bariatric surgery.

Significance: If we identify brain and/or metabolomic/inflammatory mechanisms behind successful weight loss after bariatric surgery, we can target those mechanisms to produce innovative therapies for weight loss without requiring a surgical intervention. In addition, although many patients undergo bariatric surgery, one in every five to six patients will not achieve significant weight loss and we do not know how to predict weight loss response to bariatric procedures. The proposed studies have the potential to determine if brain activity patterns are useful predictors of bariatric surgery outcomes (moderators) and to identify changes in brain activity and evoked brain responses (mediators) which are associated with successful bariatric surgery. We could also use innovative therapeutic options to rescue failed bariatric procedures and/ or to maximize weight loss after surgery.

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Methods: This study recruits 50 obese women scheduled for gastric bypass or sleeve gastrectomy. Subjects will undergo structural and functional MRI scanning before surgery, and at 1-month, 6 months and 12-months after surgery. On the day of the MRI sessions, anthropometrics, demographic and clinical data, gut peptides, adipokines, questionnaires about hunger, food preferences and food intake and blood and stool samples will be obtained. Based on the excess weight loss (EWL) achieved after surgery, the study classifies subjects as responders and non-responders.

Other Investigators: Emeran Mayer: UCLA Medicine/Gastroenterology; Erik Dutson: UCLA Surgery; Yijun Chen: UCLA Surgery; Lisa Kilpatrick: UCLA Medicine/Gastroenterology; Jennifer Labus: UCLA, Medicine/Gastroenterology; Arpana Gupta: UCLA Medicine/Gastroenterology.

Funding: This research is funded in part by UCLA Clinical and Translational Science Institute Seed Grant, the Iris Cantor-Women’s Health Center Pilot Grant – CTSI Grant # UL1TR000124 and CURE:DDRC DK P30 41301 Pilot and Feasibility Award

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The Effect of Neuromodulation on Food Cravings Control in Overweight and Obese Women

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Principal Investigator: Claudia Sanmiguel, MD

The purpose of this study is to assess the effect of a non-invasive technique called tDCS (transcranial Direct Current Stimulaltion) vs. a sham stimulation on the control over food cravings and on brain function related to eating behaviors in overweight and obese women.

Background: Obesity, in some, is associated with altered control over impulse eating resulting in overconsumption of calories. Neuroplasticity is the brain’s ability to change its function to adapt to new experiences and to injury. We now know that neuroplasticity persists in adulthood. Therapies like tDCS may promote neuroplasticity. tDCS delivers small voltage electrical currents to the scalp to stimulate the brain. tDCS of the prefrontal cortex has shown to decrease cravings for psychotropic drugs and for preferred foods.

Hypotheses: We believe that the short-term tDCS will reduce food cravings and improve cognitive control of cravings and eating behaviors. Also tDCS will result in improved brain function, as measured by fMRI, in brain areas in charge of impulse control.

Significance: If we demonstrate that tDCS is a useful neuromodulatory therapy to enhance food cravings control and results in decreased food ingestion, we will open a door to study tDCS as a new modality for treatment or prevention of obesity. Also if we demonstrate that tDCS has and effect on brain function, and this effect is associated with changes in eating behaviors and scores of food addiction; we will open a door to understand the mechanisms behind this treatment effects and mechanisms behind food cravings/food addiction traits. We may also be able to explore if there are brain-related markers to response or lack-of-response to treatment with tDCS.

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Methods: 34 obese/overweight women will be randomly assigned to receive either sham-therapy or tDCS-therapy applied to scalp at the area overlying the prefrontal cortex. Each sham or tDCS therapy session will last 20 min, and subjects will receive the therapy every day for a total of 8 sessions. Brain MRI-MRS, food cravings and food addiction questionnaires as well as 3 day food dairy will be obtained before and after finishing the treatment. Stool samples will be obtained before and after treatment is completed. Changes in brain activity and metabolism will be compared before and after treatment and between treatments. Changes in food cravings and food addiction scales as well as in eating behaviors (food dairy) will be compared before and after treatment and between treatments and correlated with changes in brain activity and metabolism to find indicators of therapy response.

Other Investigators: Emeran Mayer: UCLA Medicine/Gastroenterology; Lisa Kilpatrick: UCLA Medicine/Gastroenterology; Jennifer Labus: UCLA, Medicine/Gastroenterology; Arpana Gupta: UCLA Medicine/Gastroenterology.

Funding: 2015 Oppenheimer Transcutaneous Electrical Nerve Stimulation (TENS) Research Award Program

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Influence of Brain-Gut Interactions Involved in the Regulation of Food Intake in Obesity

Principal Investigator: Arpana Gupta, PhD

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The purposes of this study are: 1. To identify brain signatures associated with hedonic eating behaviors and the role of the gut microbiome and inflammatory markers in shaping these brain signatures. 2. To investigate how adverse psychosocial environmental (adverse life events, stress, psychological symptoms, socioeconomic status, diet, physical activity, resilience) and biological (race, sex, genes, microbiome) factors mediate the brain-gut relationship in obesity. 3. To determine the extent to which a targeted intervention (Cognitive Behavioral Therapy [CBT]) counteracts the hypothesized alterations within the extended reward network in obese individuals.

Background: Obesity is a major worldwide health problem, with more than half (65%) of the U.S. population being overweight or obese. The economic burden related to obesity and its comorbid diseases continues to rise, with billions of dollars being spent on diet, exercise products, and bariatric surgeries. Despite various efforts directed towards understanding the mechanisms underlying obesity, few treatments and interventions have demonstrated lasting benefits. In fact, obesity is a multifactorial disease that affects several organs including the brain. There is evidence that there are obesity-related changes in the brain in both function and structure. Studies have identified similarities between brain mechanisms involved in maladaptive obesity-related ingestive behaviors and addictive behaviors, resulting in the concept of food addiction. These studies have demonstrated that alterations in key regions of an extended reward network are linked to increased food related behaviors in obesity.

Significance: This area of study is significant because increases in the hedonic component of food intake, which are no longer driven by homeostatic needs, are likely to play an important pathophysiological role in some obese individuals, but the mechanisms that bias the brain towards this alteration in ingestive behavior are incompletely understood. Here I will use peripheral gut markers (microbiome and inflammatory gene expression profiles) to show that adverse experiences alter brain signatures within the extended reward network through the process of alterations in the gut microbiome and through neuroinflammation.

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Methods: Using advanced automated and mathematical analytic techniques allows to integrate information from multimodal neuroimaging data and metadata sets (genomics, micobiota and metabolomics, inflammatory markers, clinical behaviors, psychosocial environmental factors), in order to provide a powerful and sensitive biomarker that will increase biological readouts of hedonic eating behaviors and thus bring to the forefront those disadvantaged groups and individuals who are at increased risk for this type of obesity.

In order for effective and personalized obesity treatments to be developed for hedonic ingestion, this project addresses a comprehensive biopsychosocial bidirectional brain-gut mechanistic model that characterizes the influence of adverse environment factors on prefrontal inhibitory control of brain signatures in the extended reward network, while accounting for sex and race differences.

Other Investigators: Emeran A. Mayer: UCLA Medicine/Gastroenterology; Jennifer S. Labus: UCLA, Medicine/Gastroenterology; Claudia P. Sanmiguel: UCLA Medicine/Gastroenterology; Lisa A. Kilpatrick: UCLA, Medicine/Gastroenterology.

Funding: This research was supported in part by grants from the National Institutes of Health: K23 DK106528 (AG), and American Psychological Foundation-Visionary Pilot Grant (AG).

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