This application investigates the hypothesis that energy balance and body fuel stores in the form of adipose tissue are subject to homeostatic regulation. The key elements of this regulatory system include hormonal signals such as leptid (the adipocyte hormone encoded by the ob gene) and adrenal glucocorticoids, and hypothalamic peptides such as neuropeptide Y (NPY, a peptide that stimulates food intake and promote weight gain), and corticotrophin releasing hormone (CFH, which promotes weight loss by reducing caloric intake and increasing expenditure). Leptin is proposed to be a negative feedback signal secreted in proportion to the level of adipose sores that acts in the brain to promote weight loss by the combined effect of inhibiting NPY and stimulating CRH signaling pathways in the hypothalamus. Glucocorticoids are proposed to modify this leptin effect by opposing its hypothalmic actions.
The Specific Aims of this proposal seek to test this model of neuroendocrine control of energy homeostasis by determining 1) the compensatory mechanisms(s) by which mice with genetic NPY deficiency maintain normal energy balance, 2) whether the relative contributions of NYP and CRH as mediators of leptin action can change as a result of weight loss or genetic obesity, 3) if NPY acts directly in the brain to inhibit CRH biosynthesis, and 4) whether CRH signaling can influence food intake and energy balance independently of its effects on the hypothalamic- pituitary-adrenal axis. To accomplish these objectives, studies are proposed using methods established in the applicants' laboratory, including cannulation of the rodent cerebroventricular system for delivery of neuropharaceuticals, detailed measurements of food intake and body composition, determination of plasma hormone levels by radioimmunoassay, and quantitation of neuropeptide mRNA levels by in situ hybridization. Fulfilling the objectives of t his application will make an important contribution to our understanding of the fundamental processes that underlie the regulation of body adiposity. Substantial progression the development of effective therapeutic strategies for disorders of body weight across the spectrum ranging from obesity to wasting illness can be anticipated from this new knowledge.
| Dorfman, Mauricio D; Krull, Jordan E; Scarlett, Jarrad M et al. (2017) Deletion of Protein Kinase C ? in POMC Neurons Predisposes to Diet-Induced Obesity. Diabetes 66:920-934 |
| Scarlett, Jarrad M; Schwartz, Michael W (2015) Gut-brain mechanisms controlling glucose homeostasis. F1000Prime Rep 7:12 |
| Schur, Ellen A; Melhorn, Susan J; Oh, Seok-Kyun et al. (2015) Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans. Obesity (Silver Spring) 23:2142-8 |
| Berkseth, Kathryn E; Guyenet, Stephan J; Melhorn, Susan J et al. (2014) Hypothalamic gliosis associated with high-fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study. Endocrinology 155:2858-67 |
| Morton, Gregory J; Kaiyala, Karl J; Foster-Schubert, Karen E et al. (2014) Carbohydrate feeding dissociates the postprandial FGF19 response from circulating bile acid levels in humans. J Clin Endocrinol Metab 99:E241-5 |
| Morton, Gregory J; Meek, Thomas H; Schwartz, Michael W (2014) Neurobiology of food intake in health and disease. Nat Rev Neurosci 15:367-78 |
| van Praag, Henriette; Fleshner, Monika; Schwartz, Michael W et al. (2014) Exercise, energy intake, glucose homeostasis, and the brain. J Neurosci 34:15139-49 |
| Guyenet, Stephan J; Nguyen, Hong T; Hwang, Bang H et al. (2013) High-fat diet feeding causes rapid, non-apoptotic cleavage of caspase-3 in astrocytes. Brain Res 1512:97-105 |
| Lu, Min; Sarruf, David A; Li, Pingping et al. (2013) Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues. J Biol Chem 288:10722-35 |
| Lee, Donghoon; Thaler, Joshua P; Berkseth, Kathryn E et al. (2013) Longer T(2) relaxation time is a marker of hypothalamic gliosis in mice with diet-induced obesity. Am J Physiol Endocrinol Metab 304:E1245-50 |
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