2013 — 2017 |
Dipatrizio, Nicholas Vincent |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
A Role For Endocannabinoids in the Control of Dietary Fat Intake @ University of California-Irvine
DESCRIPTION (provided by applicant): 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 an 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 an 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.
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2018 — 2019 |
Dipatrizio, Nicholas Vincent Nair, Meera Goh |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Endocannabinoid Regulation of Host-Helminth Interaction @ University of California Riverside
Parasitic helminths exhibit the remarkable ability to establish chronic, often lifelong, infections by triggering multiple mechanisms to regulate the host immune response. In turn, the host induces a balanced immune response that mediates helminth killing while limiting tissue damage. In this multi-PI exploratory proposal, we identify the endocannabinoid (eCB) system as a previously unrecognized contributor to this dynamic host-helminth interaction. The lipid signaling molecules eCBs are the body?s natural cannabis-like molecules that regulate neural behaviors such as addiction and feeding. Receptors for eCBs are expressed throughout the body, including by immune cells, where eCB-mediated signaling can dampen inflammation. Following Nippostrongylus brasiliensis (Nb) infection as a mouse model of geohelminth infection, we observed significant eCB production and eCB receptor expression in the infected tissue that functionally impacted the host immune response and helminth egg burden. Moreover, we show that Nb produces eCBs at every life cycle stage, and identify putative genes for eCB synthetic and degradative enzymes in genome of Nb and parasitic nematodes that infect humans. Our central hypothesis is that eCBs mediate bi-directional communication between the host and helminth that dictates host physiology, immune response and helminth parasitism. In Aim 1 we will investigate how helminth infection-induced endocannabinoids affect the host by (i) quantifying eCB levels and eCB signaling following Nb infection; (ii) abrogating eCB receptor signaling by pharmacologic reagents or eCBR deficient mice; (iii) integrating the datasets to identify functional interactions with statistical models. In Aim 2 we will use molecular tools and high throughput microscopy to delineate the endocannabinoid pathway in the parasitic helminth. We will (i) evaluate Nb-derived eCBs and eCB signaling utilizing pharmacologic tools to promote or abrogate eCB signaling in Nb; and (ii) examine the role of eCBs in Nb-host immune cell interaction utilizing a novel co-culture system.
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2019 — 2020 |
Dipatrizio, Nicholas Vincent |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gut-Brain Endocannabinoid Signaling in Feeding Behavior and Obesity @ University of California Riverside
PROJECT SUMMARY/ABSTRACT Food intake and energy balance are controlled by a dynamic interplay of gut-brain signaling pathways; however, the molecular underpinnings in these processes and their dysregulation in obesity remain poorly understood. Recent work from the DiPatrizio lab suggests that our bodies? cannabis-like signaling molecules, the endocannabinoids (eCBs), are critical mediators of gut-brain signaling important for food intake, and are upregulated in the gut in diet-induced obesity (DIO). These seminal studies suggest that eCB signaling in the gut is an orexigenic signal that is activated under several behavioral and metabolic conditions, and may become dysregulated in obesity. The mechanism(s) of gut-brain eCB control of food intake and reorganization of these pathways in DIO is unknown. Preliminary data, however, suggests that in DIO, increased eCB signaling in the intestinal epithelium inhibits nutrient-induced release of satiation peptides, which increases meal size and delays satiation. We propose the central hypothesis that the eCB system in the gut plays a critical role in nutrient sensing and gut-brain satiation signaling, which is remodeled after chronic exposure to high-energy nutrients and contributes to overeating in DIO. We propose the following specific aims to test this hypothesis: SA1. To determine if CB1Rs in the gut control gut-brain satiation signaling. Based on preliminary data, we hypothesize that CB1Rs in the intestinal epithelium control nutrient sensing and gut-brain satiation signaling that become dysregulated in DIO. To test this hypothesis, we will examine the role for CB1Rs in controlling feeding behavior by evaluating nutrient-induced release of satiation peptides in vivo and in vitro using our first-of-kind mouse model that conditionally lacks CB1Rs in intestinal epithelium in combination with peripherally-restricted CB1R antagonists, and enteroendocrine cell lines. This aim will provide evidence of a previously unidentified control mechanism of nutrient-induced gut-brain satiation signaling. SA2. To determine the mechanism of eCB system remodeling in DIO, and impact of dietary intervention on these pathways. The molecular underpinnings of eCB system remodeling in DIO, specific dietary components that drive this process, as well as the impact of dietary intervention on these pathways and behavioral outcomes are unknown. We hypothesize that chronic exposure to WD leads to remodeling of the eCB system in the gut, which promotes overeating and DIO. To test this hypothesis, we will use our intestinal epithelial CB1R-null mice in combination with targeted lipidomics and advanced UPLC/MS/MS-based assays of eCB system function to identify specific dietary components that drive heightened eCB system activity and overeating, and the mechanism of remodeling that occurs in DIO. Furthermore, weight loss following dieting is all-too-often met with high levels of recidivism to overeating and obesity; thus, we will assess the ability for low-calorie dietary intervention to normalize gut-brain eCB signaling in DIO.
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