This is the third submission of an RO1 grant application to study the functions of the endogenous lipid amide oleoylethanolamide (OEA) in the control of food intake. The increasing prevalence of obesity in industrialized countries underscores the need to understand the physiological mechanisms that control energy homeostasis and to develop effective anti-obesity therapies. We have shown that the endogenous lipid amide OEA reduces food intake in rodents. This effect requires intact peripheral sensory fibers and results from the ability of OEA to prolong feeding latency and intermeal interval without altering meal size or causing visceral illness. We have also found that fasting decreases intestinal OEA levels, while feeding increases them. Based on these results, we hypothesize that feeding-dependent OEA mobilization in the proximal small intestine contributes to the physiological induction of satiety. The present proposal has two goals pertinent to a test of this hypothesis: 1. To identify physiological signals that control feeding-induced OEA mobilization. If our hypothesis is correct, then physiological signals involved in the induction of satiety should initiate OEA mobilization in the small intestine. We will use a combination of surgical and pharmacological approaches to identify the mechanisms governing intestinal OEA mobilization. Specifically, we will examine the contribution of four candidate signals: (/) cephalic stimuli; (//) intestinal fat digestion and absorption; (///) intrinsic and extrinsic neural innervation; and (iv) post-absorptive processes. 2. To determine the role of feeding-induced OEA mobilization in the control of satiety. Another corollary of our hypothesis is that experimental interventions that alter intestinal OEA mobilization should influence feeding behavior. To test this prediction, we will conduct two complementary series of experiments.
In Aim 2. 1 we will test whether genetic and pharmacological interventions that enhance intestinal OEA mobilization also induce satiety. We will utilize three complementary strategies: (/) viral- mediated overexpression of the OEA-synthesizing enzyme NAPE-PLD (A/-phosphatidylethanolamine- specific phospholipase D); (if) selective pharmacological inhibition of the OEA-degrading enzyme FAAH (fatty-acid amide hydrolase); (iii) constitutive genetic deletion of the FAAH gene.
In Aim 2. 2 we will test whether genetic interventions that decrease intestinal OEA mobilization also reduce satiety. We will use two strategies: (/) constitutive genetic deletion of the NAPE-PLD gene; (if) local NAPE-PLD knockdown by viral- mediated RNA interference. By identifying OEA as a novel satiety factor, our studies will provide new insights into the regulation of feeding behavior and facilitate the development of novel therapeutic strategies for the treatment of obesity and other feeding disorders. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK073955-01A2
Application #
7258464
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Yanovski, Susan Z
Project Start
2007-04-01
Project End
2011-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$324,706
Indirect Cost
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Keereetaweep, Jantana; Chapman, Kent D (2016) Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification. Neural Plast 2016:2426398
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
Yu, Tian; Taussig, Matthew D; DiPatrizio, Nicholas V et al. (2015) Deficiency of Lipoprotein Lipase in Neurons Decreases AMPA Receptor Phosphorylation and Leads to Neurobehavioral Abnormalities in Mice. PLoS One 10:e0135113
Basit, Abdul; Piomelli, Daniele; Armirotti, Andrea (2015) Rapid evaluation of 25 key sphingolipids and phosphosphingolipids in human plasma by LC-MS/MS. Anal Bioanal Chem 407:5189-98
DiPatrizio, Nicholas V; Piomelli, Daniele (2015) Intestinal lipid-derived signals that sense dietary fat. J Clin Invest 125:891-8
Igarashi, Miki; DiPatrizio, Nicholas V; Narayanaswami, Vidya et al. (2015) Feeding-induced oleoylethanolamide mobilization is disrupted in the gut of diet-induced obese rodents. Biochim Biophys Acta 1851:1218-26
DiPatrizio, Nicholas V; Igarashi, Miki; Narayanaswami, Vidya et al. (2015) Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways. Am J Physiol Regul Integr Comp Physiol 309:R805-13
Magotti, Paola; Bauer, Inga; Igarashi, Miki et al. (2015) Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids. Structure 23:598-604
Holman, E Alison; Guijarro, Ana; Lim, James et al. (2014) Effects of acute stress on cardiac endocannabinoids, lipogenesis, and inflammation in rats. Psychosom Med 76:20-28

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