Ghrelin is a gut-derived acylated peptide hormone that stimulates secretion of growth hormone and ACTH, as well as orexigenesis. Our central thesis is that ghrelin protects mammals against starvation by: increasing appetite and food intake;increasing secretion of GH to protect lean body mass;decreasing locomotor activity to preserve calories;and regulating partitioning, including glucose homeostasis. The overall hypothesis of this application is that (1) cortisol and insulin are the dominant negative regulators of ghrelin release during normal daily patterns of feeding and fasting, and (2) this specific control mechanism is altered by obesity, such that the lack of adequate ghrelin suppression contributes to overeating. Our laboratory has developed sensitive and specific sandwich assays for intact active acyl-ghrelin and des-acyl ghrelin. Using these assays, we will address the following specific aims: 1: Determine the temporal relationships between pulsatile acyl- and des-acyl ghrelin secretion and plasma concentrations of insulin, cortisol and growth hormone in healthy lean and obese adults. This will provide the preliminary data for predicting the outcomes of the direct interventions in Specific Aims 2 and 3. In addition, the data will allow for the direct comparison of the same relationships in lean versus obese. The hypotheses will be tested using a minimal mathematical model of ghrelin release (Specific Aim 4). 2: Determine the effect of cortisol on ghrelin secretion to determine its role in diurnal variation in ghrelin secretion. The results of these experiments will translate the hypothesis of ghrelin regulation by cortisol into a minimal mathematical model. 3: Determine whether insulin inhibits ghrelin secretion and whether glucose-related ghrelin suppression is mediated by insulin. It is proposed that suppression of ghrelin by insulin will depend on insulin sensitivity/resistance in a similar fashion to glucose disposal as measured using a euglycemic insulin clamp. The results of these experiments will assist the translation of the hypothesis of ghrelin regulation by insulin into a minimal mathematical model. 4: Identify differences in ghrelin regulation between lean and obese subjects and determine the mechanism(s) for dysregulation of ghrelin in obesity using a minimal model of ghrelin regulation (MMGR). To unify the relationships between ghrelin, insulin and cortisol from Specific Aims 2 and 3, we will reconstruct the system interactions and verify the consistency of the physiological hypotheses that cortisol and insulin comprise the dominant controls of the secretion of ghrelin and determine the manner in which the ensemble that regulates the secretion of ghrelin is altered in obesity. Our studies are expected to illuminate underlying mechanisms involving ghrelin in the development of obesity;this may lead to new approaches to the treatment for obesity and related conditions, such as diabetes mellitus and Metabolic Syndrome.PROJECT NARRATIVE: Our studies are expected to illuminate underlying mechanisms involving ghrelin in the development of obesity;this may lead to new approaches to the treatment for obesity and related conditions, such as diabetes mellitus and Metabolic Syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076037-04
Application #
8001981
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Maruvada, Padma
Project Start
2008-02-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
4
Fiscal Year
2011
Total Cost
$540,558
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Rogers, Nicole H; Walsh, Heidi; Alvarez-Garcia, Oscar et al. (2016) Metabolic Benefit of Chronic Caloric Restriction and Activation of Hypothalamic AGRP/NPY Neurons in Male Mice Is Independent of Ghrelin. Endocrinology 157:1430-42
Nass, Ralf; Nikolayev, Alexander; Liu, Jianhua et al. (2015) The level of circulating octanoate does not predict ghrelin O-acyl transferase (GOAT)-mediated acylation of ghrelin during fasting. J Clin Endocrinol Metab 100:E110-3
Conroy, Rushika; Febres, Gerardo; McMahon, Donald J et al. (2014) Recombinant human leptin does not alter gut hormone levels after gastric bypass but may attenuate sweet cravings. Int J Endocrinol 2014:120286
Nass, Ralf; Liu, Jianhua; Patrie, James et al. (2014) Four-hour infusion of hydrocortisone does not suppress the nocturnal increase of circulating acyl- or desacyl-ghrelin concentrations in healthy young adults. J Clin Endocrinol Metab 99:E1696-700
Nass, Ralf; Farhy, Leon S; Liu, Jianhua et al. (2014) Age-dependent decline in acyl-ghrelin concentrations and reduced association of acyl-ghrelin and growth hormone in healthy older adults. J Clin Endocrinol Metab 99:602-8
Goldstone, Anthony P; Prechtl, Christina G; Scholtz, Samantha et al. (2014) Ghrelin mimics fasting to enhance human hedonic, orbitofrontal cortex, and hippocampal responses to food. Am J Clin Nutr 99:1319-30
Nass, Ralf (2013) Growth hormone axis and aging. Endocrinol Metab Clin North Am 42:187-99
Tong, Jenny; Dave, Nimita; Mugundu, Ganesh M et al. (2013) The pharmacokinetics of acyl, des-acyl, and total ghrelin in healthy human subjects. Eur J Endocrinol 168:821-8
Gupta, Rohit K; Kuppusamy, Tamil; Patrie, James T et al. (2013) Association of plasma des-acyl ghrelin levels with CKD. Clin J Am Soc Nephrol 8:1098-105
Müller, Timo D; Müller, Anne; Yi, Chun-Xia et al. (2013) The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms. Nat Commun 4:1968

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