Optimal digestion and absorption of fat depend on regulated presentation of this nutrient to the absorptive sites of the small intestine. Intestinal transit is inhibited by fat in a load-dependent fashion to provide this controlled nutrient delivery whether the region of exposure to fat is limited to the proximal gut (jejunal brake) or extended to the distal gut (ileal brake). In order for the small bowel to respond appropriately to the fat entered, the presence of fat in the lumen must be detected. Afferent nerves that fire specifically in response to luminal fat (fat chemoreceptors) have been found in the lamina propria. Since the terminal ends of these nerves are not in contact with the lumen, a gut endocrine cell in contact with the lumen may serve as a """"""""taste bud"""""""" for the small intestine and act on the afferent pathways by releasing a peptide product. Our preliminary data showed that PYY, a peptide that inhibits intestinal transit, is the preabsorptive signal transducer and chylomicron (or its apoprotein component, apo A-IV) is the postabsorptive signal transducer. Since PYY cells are principally found in the distal gut, PYY may be released by fat in the proximal gut via a neurally dependent, CCK-stimulated release mechanism (jejunal brake) but fat in the distal gut may release PYY via a neurally independent, non CCK-stimulated mechanism (ileal brake). In Phase I of the project, we will examine the effect of fat load, the region of fat exposure (proximal vs. distal gut) and the hypothesized mediators on intestinal transit and the release of PYY. In Phase II of the project, we will further examine the conditions for PYY release in a short term culture of ileal PYY cells. This proposal will provide the fundamental physiologic as well as mechanistic information to explain the control of intestinal transit by luminal fat. Such information is needed to develop novel, nutrient-based treatments for patients who are symptomatic from rapid transit including those with dumping syndrome, short bowel syndrome, postvagotomy diarrhea, enteral feeding related diarrhea, gastrectomy, or ileo-anal anastomosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK046459-02
Application #
2377805
Study Section
Special Emphasis Panel (ZRG4-GMA-1 (01))
Project Start
1996-03-15
Project End
2001-02-28
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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Lin, H C; Chen, J H (2003) Slowing of intestinal transit by fat depends on an ondansetron - sensitive, efferent serotonergic pathway. Neurogastroenterol Motil 15:317-22
Lin, Henry C; Neevel, Corynn; Chen, Peng-Sheng et al. (2003) Slowing of intestinal transit by fat or peptide YY depends on beta-adrenergic pathway. Am J Physiol Gastrointest Liver Physiol 285:G1310-6
Lin, Henry C; Chey, William Y (2003) Cholecystokinin and peptide YY are released by fat in either proximal or distal small intestine in dogs. Regul Pept 114:131-5
Lin, H C; Perdomo, O L; Zhao, X T (2001) Intestinal transit in dogs is accelerated by volume distension during fat-induced jejunal brake. Dig Dis Sci 46:19-23
Furness, J B; Koopmans, H S; Robbins, H L et al. (2000) Identification of intestinofugal neurons projecting to the coeliac and superior mesenteric ganglia in the rat. Auton Neurosci 83:81-5
Zhao, X T; Wang, L; Lin, H C (2000) Slowing of intestinal transit by fat depends on naloxone-blockable efferent, opioid pathway. Am J Physiol Gastrointest Liver Physiol 278:G866-70
Zhao, X T; Walsh, J H; Wong, H et al. (1999) Intestinal fat-induced inhibition of meal-stimulated gastric acid secretion depends on CCK but not peptide YY. Am J Physiol 276:G550-5
Lin, H C; Zhao, X T; Chu, A W et al. (1997) Fiber-supplemented enteral formula slows intestinal transit by intensifying inhibitory feedback from the distal gut. Am J Clin Nutr 65:1840-4
Lin, H C; Zhao, X T; Wang, L (1997) Intestinal transit is more potently inhibited by fat in the distal (ileal brake) than in the proximal (jejunal brake) gut. Dig Dis Sci 42:19-25