This proposal is based on extensive preclinical and clinical evidence supporting complex interactions between alterations in the stress response system reactivity, visceral adipose tissue (VAT), and brain structural and functional changes that might be related to gastrointestinal symptoms and IBS pathophysiology. Using an interdisciplinary translational approach, we will test the hypothesis that increased VAT related to hyperactivity of the HPA axis, is associated with changes in brain morphometry with sex related differences in these alterations. We will adress the following specific aims:
Aim A will correlate changes between visceral adiposity, HPA axis activity and regional brain morphology in a rodent model of chronic unpredictable stress in adult male and female rats.
Aim B will characterize the role of visceral fat products in stress-induced changes in the HPA axis and brain structural and functional changes in male and female rodents.
Aim C will study sex differences in the correlation between HPA overactivity, VAT and adipokines in CRF-OE mice as a model of chronic alterations of stress, genetically driven by CRF since early life, Aim D will correlate HPA axis with VAT accumulation and circulating adipokines to regional brain structural and resting state functional changes in male and female IBS patients. We will employ several novel methodologies and state-of-the-art technologies in many aspects of this application, including rodent brain MRI, multimodal brain imaging in humans, and quantitative MRI-or CT based VAT assessment methods in rodents and humans. Transgenic animals will be used to test the specific role of adipokines and of the CRF/CRFR1 signaling pathways in this system. The use of rodent models and human studies in this project are complementary and related to project 1 which characterizes HPA axis dysregulation in IBS patients and to Project 3 which uses multimodal brain imaging, advanced mathematical modeling/systems biological approaches to identify IBS patients subtypes based on distinct endophenotype clusters. The results of the proposed preclinical and clinical studies should be able to unequivocally address the main hypotheses on the pathophysiological role of excessive VAT accumulation and brain changes and relationship to IBS.

Public Health Relevance

Understanding the pathophysiological role of excessive VAT accumulation and brain changes in IBS patients would fundamentally change current concepts about proinflammatory mechanisms and their relationship to stress in IBS pathophysiology and therapy. VAT accumulation associated with chronic psychological stress, and its risk factors, could become a major target for novel therapeutic interventions in IBS and other FGIDs.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Los Angeles
United States
Zip Code
Hoffman, Jill M; Baritaki, Stavroula; Ruiz, Jonathan J et al. (2016) Corticotropin-Releasing Hormone Receptor 2 Signaling Promotes Mucosal Repair Responses after Colitis. Am J Pathol 186:134-44
Gupta, Arpana; Labus, Jennifer; Kilpatrick, Lisa A et al. (2016) Interactions of early adversity with stress-related gene polymorphisms impact regional brain structure in females. Brain Struct Funct 221:1667-79
Moussaoui, Nabila; Larauche, Muriel; Biraud, Mandy et al. (2016) Limited Nesting Stress Alters Maternal Behavior and In Vivo Intestinal Permeability in Male Wistar Pup Rats. PLoS One 11:e0155037
Hong, J-Y; Naliboff, B; Labus, J S et al. (2016) Altered brain responses in subjects with irritable bowel syndrome during cued and uncued pain expectation. Neurogastroenterol Motil 28:127-38
Padua, David; Pothoulakis, Charalabos (2016) Novel approaches to treating Clostridium difficile-associated colitis. Expert Rev Gastroenterol Hepatol 10:193-204
Videlock, Elizabeth J; Shih, Wendy; Adeyemo, Mopelola et al. (2016) The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression. Psychoneuroendocrinology 69:67-76
Law, Ivy Ka Man; Jensen, Dane; Bunnett, Nigel W et al. (2016) Neurotensin-induced miR-133α expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin. Sci Rep 6:22195
Park, S H; Videlock, E J; Shih, W et al. (2016) Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity. Neurogastroenterol Motil 28:1252-60
Duboc, H; Tolstanova, G; Yuan, P-Q et al. (2016) Reduction of epithelial secretion in male rat distal colonic mucosa by bile acid receptor TGR5 agonist, INT-777: role of submucosal neurons. Neurogastroenterol Motil 28:1663-1676
Million, M; Larauche, M (2016) Stress, sex, and the enteric nervous system. Neurogastroenterol Motil 28:1283-9

Showing the most recent 10 out of 190 publications