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Grant Details

Grant Number: 4R01CA180030-04 Interpret this number
Primary Investigator: De Araujo, Ivan
Organization: John B. Pierce Laboratory, Inc.
Project Title: (PQA3) the Gut-Brain Axis: a Novel Target for Treating Behavioral Alterations in
Fiscal Year: 2016


Abstract

DESCRIPTION (provided by applicant): Our proposal addresses NCI's Provocative Question #3 (Group A): We designed a strategy to change cancer- inducing dietary habits, which is based on rescuing normal neural activity in brain circuits of overweight/obese individuals. The relevance of our proposal to cancer prevention is demonstrated by epidemiological studies establishing that several forms of cancer could be prevented by the adoption of healthier dietary habits, with up to 20% of cancer-related deaths being potentially attributable to obesity alone. In both rodents and humans, excessive intake of dietary fats leads to dysregulated neuronal function in dorsal striatum. This diet-derived striatal deficiency leads to an impaired ability to learn about the negative outcomes of one's actions which, in turn, results in the expression of impulsive behaviors such as excessive caloric intake. Our strategy builds on previous animal studies demonstrating that prolonged exposure to a high-fat diet substantially reduces the intestinal synthesis of appetite-regulating lipid messengers. Since our previous work had established that gut- brain signals regulate neurochemical activity in dorsal striatum, we set fort the central hypothesis that rescuing gut-brain communication will restore striatal function. As a corollary, we predict that rescuing gut-brain communication will enhance the ability to learn about negative outcomes, thereby reducing impulsivity behavioral scores and increasing compliance with a low-calorie diet. Accordingly, our Specific Aims are as follows: Specific Aim 1 (Mechanistic studies): To identify which gut N-acylethanolamines rescue striatal function and reduce impulsivity in high-fat fed mice, and to determine the neural and molecular mechanisms of their action; Specific Aim 2 (Translational studies): To determine whether gut N-Acylethanolamines precursors rescue striatal function and reduce impulsivity scores in overweight/obese human subjects. We thus propose that the gut-brain axis is a novel target for treating behavioral alterations in the obese, the normalization of which may greatly contribute to reducing cancer-related dietary habits.



Publications

Identification of a brain fingerprint for overweight and obesity.
Authors: Farruggia M.C. , van Kooten M.J. , Perszyk E.E. , Burke M.V. , Scheinost D. , Constable R.T. , Small D.M. .
Source: Physiology & behavior, 2020-08-01; 222, p. 112940.
EPub date: 2020-05-14.
PMID: 32417645
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No evidence for an association between obesity and milkshake liking.
Authors: Wall K.M. , Farruggia M.C. , Perszyk E.E. , Kanyamibwa A. , Fromm S. , Davis X.S. , Dalenberg J.R. , DiFeliceantonio A.G. , Small D.M. .
Source: International journal of obesity (2005), 2020 08; 44(8), p. 1668-1677.
EPub date: 2020-05-12.
PMID: 32398755
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A Neural Circuit for Gut-Induced Reward.
Authors: Han W. , Tellez L.A. , Perkins M.H. , Perez I.O. , Qu T. , Ferreira J. , Ferreira T.L. , Quinn D. , Liu Z.W. , Gao X.B. , et al. .
Source: Cell, 2018-10-18; 175(3), p. 665-678.e23.
EPub date: 2018-09-20.
PMID: 30245012
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DRD2: Bridging the Genome and Ingestive Behavior.
Authors: Sun X. , Luquet S. , Small D.M. .
Source: Trends in cognitive sciences, 2017 05; 21(5), p. 372-384.
EPub date: 2017-03-31.
PMID: 28372879
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Integrated Control of Predatory Hunting by the Central Nucleus of the Amygdala.
Authors: Han W. , Tellez L.A. , Rangel M.J. , Motta S.C. , Zhang X. , Perez I.O. , Canteras N.S. , Shammah-Lagnado S.J. , van den Pol A.N. , de Araujo I.E. .
Source: Cell, 2017-01-12; 168(1-2), p. 311-324.e18.
EPub date: 2017-01-12.
PMID: 28086095
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Circuit organization of sugar reinforcement.
Authors: de Araujo I.E. .
Source: Physiology & behavior, 2016-10-01; 164(Pt B), p. 473-477.
EPub date: 2016-04-26.
PMID: 27126968
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Effects of the modern food environment on striatal function, cognition and regulation of ingestive behavior.
Authors: Burke M.V. , Small D.M. .
Source: Current opinion in behavioral sciences, 2016 Jun; 9, p. 97-105.
EPub date: 2016-03-09.
PMID: 29619405
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Separate circuitries encode the hedonic and nutritional values of sugar.
Authors: Tellez L.A. , Han W. , Zhang X. , Ferreira T.L. , Perez I.O. , Shammah-Lagnado S.J. , van den Pol A.N. , de Araujo I.E. .
Source: Nature neuroscience, 2016 Mar; 19(3), p. 465-70.
EPub date: 2016-01-25.
PMID: 26807950
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Striatal Dopamine Links Gastrointestinal Rerouting to Altered Sweet Appetite.
Authors: Han W. , Tellez L.A. , Niu J. , Medina S. , Ferreira T.L. , Zhang X. , Su J. , Tong J. , Schwartz G.J. , van den Pol A. , et al. .
Source: Cell metabolism, 2016-01-12; 23(1), p. 103-12.
EPub date: 2015-11-19.
PMID: 26698915
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Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction.
Authors: Stoeckel L.E. , Arvanitakis Z. , Gandy S. , Small D. , Kahn C.R. , Pascual-Leone A. , Pawlyk A. , Sherwin R. , Smith P. .
Source: F1000Research, 2016; 5, p. 353.
EPub date: 2016-03-15.
PMID: 27303627
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Physiological mechanisms by which non-nutritive sweeteners may impact body weight and metabolism.
Authors: Burke M.V. , Small D.M. .
Source: Physiology & behavior, 2015-12-01; 152(Pt B), p. 381-8.
EPub date: 2015-06-03.
PMID: 26048305
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Sensing of triacylglycerol in the gut: different mechanisms for fatty acids and 2-monoacylglycerol.
Authors: Kleberg K. , Jacobsen A.K. , Ferreira J.G. , Windeløv J.A. , Rehfeld J.F. , Holst J.J. , de Araujo I.E. , Hansen H.S. .
Source: The Journal of physiology, 2015-04-15; 593(8), p. 2097-109.
EPub date: 2015-02-09.
PMID: 25639597
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