. Mammals have an adaptive advantage in seeking palatable fat-rich foods, which are nutritionally essential but scarce in most natural habitats. In modern societies, where fatty foods are readily available and the energy necessary to find them is minimal, this innate drive can become maladaptive and is considered a primary contributing factor for obesity, cardiovascular disease, and diabetes. Despite its theoretical and practical significance, the neural mechanisms controlling fat preference and compulsive eating are largely unknown. The endocannabinoid (eCB) system, in particular, has gained attention for its key roles in the acquisition and sensory evaluation of natural (e.g., food) and non-natural (e.g., drugs of abuse) reinforcers. The eCBs are endogenous lipids that bind to and activate the same receptors as ?9-THC, the psychoactive component in cannabis. Recent data from our laboratory indicate that oral exposure to dietary fat stimulates eCB mobilization in the rat small intestine, and localized blockade of this signaling event suppresses fat sham feeding. These results suggest that the intestinal eCB system exerts a powerful regulatory control over fat intake, and provide novel insights into physiological mechanisms that govern preference for fats, which are posited to possess addictive-like properties. The long-term goal of this research program is to utilize state-of- the-art experimental tools to probe the interface of food intake and reward, and thus, elucidate the biological substrates of fat preference and compulsive eating. The central hypothesis of this proposal is that the mobilization of eCBs in the small intestine, elicited by orosensory stimulation by fat-rich foods, contributes to the physiological control of fat intake and the pathophysiological state of obesity. We have three specific aims and unique approaches pertinent to a test of this hypothesis: (i) to identify lipid classes that stimulate intestinal eCB mobilization and promote dietary fat intake by utilizing a combination of surgical, biochemical, and pharmacological tools to identify select lipid classes responsible for driving intestinal eCB signaling and its role in fat preference; (ii) to define changes in intestinal eCB-metabolizing enzymes involved in cephalic-phase fat intake by characterizing modifications to intestinal gene transcripts and proteins involved in eCB metabolism; (iii) to identify oral fatty-acid receptors and neural pathways that maintain intestinal eCB mobilization and fat intake by investigating the ability for fat sham feeding to enhance intestinal eCB signaling in animals that lack the putative fat receptors, and identify the neural pathways that normally transmit this information to the gut. Collectively, the proposed plan will identify physiological mechanisms that control the positive feedback obtained from a fatty meal based on its orosensory properties. Furthermore, the proposal is highly novel because it focuses on an eCB signal in the gut, discovered in our preliminary work, that drives fat intake. Thus, these studies will provide support for the development of anti-obesity drugs that target the eCB system in the periphery, without disrupting central mechanisms that may lead to psychiatric side effects.

Public Health Relevance

. The overarching goal of the proposed research program is to elucidate the biological substrates of fat preference and compulsive eating, and posits that biological mechanisms supporting hedonically-driven feeding behaviors can become detrimental to health in modern environments, which consist of readily accessible calories and minimal energy requirements necessary to obtain them. This work addresses a critical barrier in the understanding of the oral mechanisms contributing to dietary fat preference, and will provide support for the development of therapeutic strategies for the safe treatment of obesity, cardiovascular disease, and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Transition Award (R00)
Project #
5R00DA034009-04
Application #
9064739
Study Section
Special Emphasis Panel (NSS)
Program Officer
Purohit, Vishnudutt
Project Start
2013-05-01
Project End
2018-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Type
Schools of Medicine
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Perez, Pedro A; DiPatrizio, Nicholas V (2018) Impact of maternal western diet-induced obesity on offspring mortality and peripheral endocannabinoid system in mice. PLoS One 13:e0205021
Little, Tanya J; Cvijanovic, Nada; DiPatrizio, Nicholas V et al. (2018) Plasma endocannabinoid levels in lean, overweight, and obese humans: relationships to intestinal permeability markers, inflammation, and incretin secretion. Am J Physiol Endocrinol Metab 315:E489-E495
Batugedara, Hashini M; Argueta, Donovan; Jang, Jessica C et al. (2018) Host- and Helminth-Derived Endocannabinoids That Have Effects on Host Immunity Are Generated during Infection. Infect Immun 86:
Price, Candice Allister; Argueta, Donovan A; Medici, Valentina et al. (2018) Plasma fatty acid ethanolamides are associated with postprandial triglycerides, ApoCIII, and ApoE in humans consuming a high-fructose corn syrup-sweetened beverage. Am J Physiol Endocrinol Metab 315:E141-E149
Dotsey, Emmanuel; Ushach, Irina; Pone, Egest et al. (2017) Transient Cannabinoid Receptor 2 Blockade during Immunization Heightens Intensity and Breadth of Antigen-specific Antibody Responses in Young and Aged mice. Sci Rep 7:42584
Argueta, Donovan A; DiPatrizio, Nicholas V (2017) Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity. Physiol Behav 171:32-39
Thompson, Zoe; Argueta, Donovan; Garland Jr, Theodore et al. (2017) Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes. Physiol Behav 170:141-150
Angelini, Roberto; Argueta, Donovan A; Piomelli, Daniele et al. (2017) Identification of a Widespread Palmitoylethanolamide Contamination in Standard Laboratory Glassware. Cannabis Cannabinoid Res 2:123-132
Wang, Hong; Taussig, Matthew D; DiPatrizio, Nicholas V et al. (2016) Obesity development in neuron-specific lipoprotein lipase deficient mice is not responsive to increased dietary fat content or change in fat composition. Metabolism 65:987-97
DiPatrizio, Nicholas V (2016) Endocannabinoids in the Gut. Cannabis Cannabinoid Res 1:67-77

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