The main theme of this proposal is the identification of brain signatures associated with hedonic eating behaviors (HEB) and the role of inflammatory mediators in shaping these brain signatures. I will also evaluate the feasibility of using a targeted intervention (Cognitive Behavioral Therapy [CBT]) to counteract the hypothesized alterations within the extended reward network in this subgroup of obese subjects. 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 inflammatory gene expression profiles to show that adverse experiences alter brain signatures within the extended reward network through the process of neuroinflammation. The proposal begins by characterizing brain signatures related to HEB. Then gene expression profiles as measured by peripheral blood mononuclear cells and plasma cytokines are identified and correlated with brain signatures and HEB. CBT will be used to investigate the therapeutic effect linked to strengthening inhibitory influences of prefrontal regions within the extended reward network, and reducing increased sympathetic nervous system modulation of the immune system, thereby offering a cost effective way of counteracting HEB. Advanced and sophisticated multivariate analytic techniques will be used to integrate the data from multiple neuroimaging sources, gene profiles, and behavioral data in order to determine the unique variance of adverse environmental factors in determining signatures associated with HEB. This may serve as a sensitive measure of central biomarkers in obesity related to HEB. A model that accounts for sex and race differences will increase the validity of the model, and will help identify disadvantaged groups who are at increased risk for obesity associated with HEB. I have a background in psychology and seek the following training goals from this award: (1) knowledge in the pathophysiology of obesity; (2) genomic analysis techniques including bioinformatics techniques; (3) knowledge and expertise in metabolomics data analysis; (4) specific expertise in diffusion tensor MRI analysis; (5) advanced data driven multivariate techniques using topological network and system biological analytical techniques (e.g. cluster and classification analysis); and (6) expertise in applying behavioral therapy to obesity. The work environment at the Center for Neurobiology of Stress provides an excellent infrastructure for training in neuro-genetic investigations of obesity. I will attend courses, workshops, and meetings in order to obtain a comprehensive understanding of the underlying biological sequelae of obesity. Regular individual and group meetings with mentors (Mayer [primary], Pisegna, Li, Cole, Labus, Naliboff [co-mentors]) have been set up. I plan to apply for a R03 grant by Year 3 and a R01 grant by Year 5. Long term, I plan to establish an independent research career in brain-gut interactions associated with health disparities in obesity.

Public Health Relevance

With obesity becoming a major health epidemic in the United States, and with concerns being raised about the validity and effectiveness of obesity treatments, this project investigates increases in the hedonic related food addiction component of food intake which are no longer driven by homeostatic needs, and are thus likely to play an important pathophysiological role in some obese individuals. In order for effective and personalized obesity treatments to be developed for hedonic ingestion, this project addresses a comprehensive biopsychosocial bidirectional brain-immune 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. Using advanced automated and mathematical analytic techniques allows to integrate information from multimodal neuroimaging data and metadata sets (genomics, 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

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK106528-03
Application #
9456759
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Spain, Lisa M
Project Start
2016-05-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Gupta, Arpana; Mayer, Emeran A; Labus, Jennifer S et al. (2018) Sex Commonalities and Differences in Obesity-Related Alterations in Intrinsic Brain Activity and Connectivity. Obesity (Silver Spring) 26:340-350
Tillisch, Kirsten; Mayer, Emeran A; Gupta, Arpana et al. (2017) Brain Structure and Response to Emotional Stimuli as Related to Gut Microbial Profiles in Healthy Women. Psychosom Med 79:905-913
Sanmiguel, Claudia P; Jacobs, Jonathan; Gupta, Arpana et al. (2017) Surgically Induced Changes in Gut Microbiome and Hedonic Eating as Related to Weight Loss: Preliminary Findings in Obese Women Undergoing Bariatric Surgery. Psychosom Med 79:880-887
Gupta, Arpana; Mayer, Emeran A; Acosta, Jonathan R et al. (2017) Early adverse life events are associated with altered brain network architecture in a sex- dependent manner. Neurobiol Stress 7:16-26
Coveleskie, K; Kilpatrick, L A; Gupta, A et al. (2017) The effect of the GLP-1 analogue Exenatide on functional connectivity within an NTS-based network in women with and without obesity. Obes Sci Pract 3:434-445
Gupta, Arpana; Love, Aubrey; Kilpatrick, Lisa A et al. (2017) Morphological brain measures of cortico-limbic inhibition related to resilience. J Neurosci Res 95:1760-1775
Gupta, Arpana; Mayer, Emeran A; Fling, Connor et al. (2017) Sex-based differences in brain alterations across chronic pain conditions. J Neurosci Res 95:604-616
Gupta, A; Cole, S; Labus, J S et al. (2017) Gene expression profiles in peripheral blood mononuclear cells correlate with salience network activity in chronic visceral pain: A pilot study. Neurogastroenterol Motil 29:
Gupta, A; Mayer, E A; Hamadani, K et al. (2017) Sex differences in the influence of body mass index on anatomical architecture of brain networks. Int J Obes (Lond) 41:1185-1195
Latorre, Rocco; Huynh, Jennifer; Mazzoni, Maurizio et al. (2016) Expression of the Bitter Taste Receptor, T2R38, in Enteroendocrine Cells of the Colonic Mucosa of Overweight/Obese vs. Lean Subjects. PLoS One 11:e0147468

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