Obesity is a major health problem in many countries, leading to serious comorbidities. The gut is the first point in the body at which the quantity and quality of ingested nutrients is monitored. Therefore, it is important to understand the mechanisms by which nutrients are sensed in the gut, the neural pathways activated, and how these may be altered by long term changes in diet leading to increased food intake and obesity. Ingestion of high fat diets and increased adiposity is associated with an inflammatory state and diet-induced obesity is associated with low chronic plasma level of lipopolysaccharide (LPS), a breakdown product of the cell wall of Gram-negative bacteria. This observation, together with recent evidence showing a change in the gut microbiota in obesity and following ingestion of high fat diets, suggests a role for LPS in the development or maintenance of obesity. Vagal afferents express TLR4 (15), but how LPS influences CCK-dependent activation of the vagal afferent pathway or expression of orexigenic and anorexigenic receptors has not been explored. The goal of the proposal is to determine the mechanism by which activation of the vagal afferent pathway by CCK and lipid is attenuated by long term ingestion of a high fat diet, leading to a reduction in short term satiety, hyperphagia and altered body weight regulation. The hypothesis to be tested is that long term ingestion of a high fat diet inhibits the CCK-induced changes in receptor and peptide expression in vagal afferent neurons, resulting in the persistence of an orexigenic phenotype and reduced satiety. The first specific aim will address the role of LPS and TLR4 in the reduced sensitivity of the vagal afferent pathway to CCK in high fat diet-induced obesity. Experiments will determine the effect of chronic ingestion of a high fat diet on intestinal function that lead to an increase in plasma levels of LPS and on change in the phenotype of vagal afferent neurons and whether chronic administration of LPS recapitulates the diet-induced obese phenotype and attenuates CCK-induced changes in vagal afferent function. The role of TLR4 in reduced sensitivity of the vagal afferent pathway to CCK to HF diets will be determined using TLR4 null mice. The second specific aim will address changes at the level of the vagal afferent neurons to determine the mechanism by which a high fat diet inhibits the CCK- or feeding-induced change switch from an orexigenic to an anorexigenic phenotype in vagal afferent neurons. Experiments will determine that the switch from orexigenic to anorexigenic phenotype induced by CCK or feeding in vagal afferent neurons is abolished or attenuated in HF diet-induced obesity and that this occurs either leptin resistance or an upregulation of the ghrelin receptor in vagal afferent neurons, or a decrease production of intestinal apolipoprotein A-IV. The significance of this proposal is that a greater understanding of the plasticity of the vagal afferent pathway, together with the possibility of targeting a luminal site of action of an obesity treatment, will provide better targets for the treatment of obesity and other disorders that involve the sensory innervation of the gut, such as functional bowel disease.

Public Health Relevance

Obesity is a major health concern in many countries and associated with serious comorbidities. This proposal will address the role of inflammatory processes in alteration of the gut-brain pathway that under normal conditions mounts appropriate changes in GI function and food intake but is dysregulated by ingestion of high fat Western diets. A greater understanding of the plasticity of the vagal afferent pathway, together with the possibility of targeting a luminal site of action of an obesity treatment, will provide better targets for the treatment of obesity and other disorders that involve the sensory innervation of the gut, such as functional bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041004-24
Application #
8537408
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Carrington, Jill L
Project Start
1989-08-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
24
Fiscal Year
2013
Total Cost
$304,291
Indirect Cost
$106,056
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
de Lartigue, Guillaume; Ronveaux, Charlotte C; Raybould, Helen E (2014) Deletion of leptin signaling in vagal afferent neurons results in hyperphagia and obesity. Mol Metab 3:595-607
de Lartigue, Guillaume; Barbier de la Serre, Claire; Espero, Elvis et al. (2011) Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol Endocrinol Metab 301:E187-95
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Liou, Alice P; Chavez, Diana I; Espero, Elvis et al. (2011) Protein hydrolysate-induced cholecystokinin secretion from enteroendocrine cells is indirectly mediated by the intestinal oligopeptide transporter PepT1. Am J Physiol Gastrointest Liver Physiol 300:G895-902
Lee, Jennifer; Martin, Elizabeth; Paulino, Gabriel et al. (2011) Effect of ghrelin receptor antagonist on meal patterns in cholecystokinin type 1 receptor null mice. Physiol Behav 103:181-7
de Lartigue, Guillaume; de La Serre, Claire Barbier; Raybould, Helen E (2011) Vagal afferent neurons in high fat diet-induced obesity; intestinal microflora, gut inflammation and cholecystokinin. Physiol Behav 105:100-5
Paulino, G; Darcel, N; Tome, D et al. (2008) Adaptation of lipid-induced satiation is not dependent on caloric density in rats. Physiol Behav 93:930-6
Burdyga, Galina; de Lartigue, Guillaume; Raybould, Helen E et al. (2008) Cholecystokinin regulates expression of Y2 receptors in vagal afferent neurons serving the stomach. J Neurosci 28:11583-92
Donovan, Michael J; Paulino, Gabriel; Raybould, Helen E (2007) CCK(1) receptor is essential for normal meal patterning in mice fed high fat diet. Physiol Behav 92:969-74
Raybould, Helen E (2007) Mechanisms of CCK signaling from gut to brain. Curr Opin Pharmacol 7:570-4

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