Obesity is a major public health concern: the prevalence of obesity in the US has increased dramatically, reaching rates greater than 30%. Although lifestyle and pharmacological therapies are successful in the short term, subsequent regain of lost weight is common. Surgical approaches such as gastric banding and Roux-en-Y gastric bypass (RYGB) achieve weight losses of greater than 20% or 25% of body weight maintained for up to 15 years. RYGB results in rapid restoration of insulin sensitivity prior to appreciable weight loss. The mechanisms underlying the success of RYGB are poorly understood. RYGB is a dual procedure involving creation of a small gastric pouch and bypass of the remaining stomach and upper intestines such that ingested calories are rapidly delivered to more distal intestinal sites. How each separately contributes to the beneficial effects of the surgery has not been experimentally assessed. The present proposal directly assesses the consequences of nutrient delivery to the small intestine and will identify the underlying mechanisms using rat and nonhuman primate experiments. The experiments under the first specific aim expand our current rat model of intestinal nutrient delivery in lean rats to a diet-induced obesity model focusing on the elucidation of central and peripheral mechanisms. Our preliminary data in lean rats demonstrate that small volumes of jejunal nutrient infusions produce persistent reductions in food intake well beyond their caloric content and support a role for gut peptides in mediating these changes. The proposed experiments will further characterize such feeding inhibition in obese rats and will directly assess the roles of specific gut peptides, alterations in taste preferences and neural homeostatic signaling systems in the suppressions of food intake. Additional experiments will compare the hormonal profiles produced by intestinal nutrient infusion to that following sleeve gastrectomy, another bariatric procedure with significant efficacy. Finally, we will assess the potential role of vagal afferent signaling in mediating the effects of intestinal infusions. The experiments under the second specific aim translate these findings to nonhuman primates using our established nonhuman primate model that has been successful in elucidating feedback controls on food intake and gastric emptying that have direct relevance to man. Here we propose to characterize the feeding inhibitory effects of small intestinal nutrient delivery in rhesus monkeys as well as in our unique obese Bonnet macaques to assess potential mechanisms of action and determine the efficacy of such nutrient delivery for producing long term changes in food intake and body weight. .

Public Health Relevance

of the proposed work is to provide an understanding of the mechanisms underlying the reductions in eating and body weight following gastric bypass surgery. This understanding could lead to less invasive but effective obesity therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK019302-38
Application #
8729475
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Yanovski, Susan Z
Project Start
1977-05-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
38
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Moran, Timothy H; Ladenheim, Ellen E (2016) Physiologic and Neural Controls of Eating. Gastroenterol Clin North Am 45:581-599
Dailey, Megan J; Moran, Timothy H; Holland, Peter C et al. (2016) The antagonism of ghrelin alters the appetitive response to learned cues associated with food. Behav Brain Res 303:191-200
Boersma, Gretha J; Tamashiro, Kellie L; Moran, Timothy H et al. (2016) Corticosterone administration in drinking water decreases high-fat diet intake but not preference in male rats. Am J Physiol Regul Integr Comp Physiol 310:R733-43
Moody, Laura; Liang, Joy; Choi, Pique P et al. (2015) Wheel running decreases palatable diet preference in Sprague-Dawley rats. Physiol Behav 150:53-63
Liang, Nu-Chu; Bello, Nicholas T; Moran, Timothy H (2015) Wheel running reduces high-fat diet intake, preference and mu-opioid agonist stimulated intake. Behav Brain Res 284:1-10
Treesukosol, Yada; Liang, Nu-Chu; Moran, Timothy H (2015) Alterations in sucrose sham-feeding intake as a function of diet-exposure in rats maintained on calorically dense diets. Appetite 92:278-86
Dailey, Megan J (2014) Nutrient-induced intestinal adaption and its effect in obesity. Physiol Behav 136:74-8
Treesukosol, Yada; Sun, Bo; Moghadam, Alexander A et al. (2014) Maternal high-fat diet during pregnancy and lactation reduces the appetitive behavioral component in female offspring tested in a brief-access taste procedure. Am J Physiol Regul Integr Comp Physiol 306:R499-509
Yang, Yan; Moghadam, Alexander A; Cordner, Zachary A et al. (2014) Long term exendin-4 treatment reduces food intake and body weight and alters expression of brain homeostatic and reward markers. Endocrinology 155:3473-83
Dailey, Megan J; Moghadam, Alexander A; Moran, Timothy H (2014) Nutrient-specific feeding and endocrine effects of jejunal infusions in obese animals. Am J Physiol Regul Integr Comp Physiol 306:R420-8

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