Both behavioral and metabolic consequences of uncontrolled, insulin-deficient diabetes mellitus (uDM) arise in part from the response of key brain areas such as the hypothalamic arcuate nucleus (ARC) and ventromedial hypothalamic nucleus (VMN) to changes in the humoral milieu, including marked decreases in the circulating levels of both insulin and leptin, and elevated levels of ghrelin. Rodent models of uDM therefore constitute a unique and valuable tool with which to study these neuroendocrine control systems. Among ARC neuronal subsets activated in uDM are those that express orexigenic (or 'food intake-stimulatory') peptides such as neuropeptide Y (NPY) and agouti-related peptide (AgRP), whereas adjacent anorexigenic, melanocortin-producing (or 'POMC') neurons are inhibited, a combination of responses implicated in the pronounced increase of food intake characteristic of uDM (termed "diabetic hyperphagia"). At the cellular level, signaling via the insulin receptor substrate-phosphotidylinositol-3 kinase (IRS-PI3K) pathway plays a critical role in insulin action in peripheral tissues and while this pathway is also critical for both leptin and insulin action in the CNS, the specific neuronal subsets involved remain to be determined. Signaling molecules downstream of PI3K include protein kinase B (PKB) and mammalian target of rapamycin (mTOR), both of which are also implicated in hypothalamic control of food intake. Growing evidence also suggests that hypothalamic neurocircuits that sense input from insulin, leptin and ghrelin participate in the control of insulin sensitivity in peripheral tissues, and our recent work implicates dysfunction of these neurocircuits, triggered by reduced PI3K signaling, in the progressive insulin resistance seen in rats with uDM induced by the b-cell toxin, streptozotocin (STZ). Based on these observations, we propose in Specific Aim 1 to employ mouse models of STZ-induced uDM that enable us to identify the specific brain areas and neuronal subsets in which signal transduction via the IRS-PI3K-PKB pathway regulates food intake and glucose metabolism. Specifically, we will use a combination of Cre-loxP genetic and adenoviral gene therapy techniques to increase PKB specifically in NPY/Agrp neurons, POMC neurons, neurons that express leptin receptors, or VMN neurons (that express the transcription factor SF- 1) in mice with STZ-induced uDM. In this way, we will identify neuronal subsets in the ARC and VMN in which reduced PKB signaling contributes to feeding and metabolic consequences of uDM. Similarly, Aim 2 seeks to delineate the role of reduced hypothalamic mTOR signaling in behavioral and metabolic responses to uDM in rats.
In Aim 3, we investigate mechanisms underlying increased plasma ghrelin levels in uDM and determine the contribution made by this increase to hyperphagia and insulin resistance in this setting. Together, this information will shed new light on neuroendocrine mechanisms controlling food intake and insulin sensitivity and help to clarify how dysfunction within these systems contributes to the pathogenesis of disordered feeding behavior and glucose metabolism in obesity and diabetes.

Public Health Relevance

Obesity and diabetes mellitus are closely related metabolic disorders that take an increasing toll on human health. Recent findings suggest that dysfunction of key hypothalamic neurons that regulate food intake, autonomic function and glucose metabolism contributes to the link between these metabolic disorders. The identification of neuronal circuits upon which hormones such as insulin, leptin and ghrelin act to control both food intake and glucose metabolism is therefore an important scientific priority. Towards this end, this proposal employs rat and mouse models of uncontrolled diabetes mellitus to further define neuroendocrine mechanisms controlling food intake, body fat storage and insulin sensitivity in peripheral tissues. By improving our understanding of how mechanisms driving obesity and diabetes are linked to one another within the brain, our ultimate goal is to find new strategies for their prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083042-18
Application #
8310112
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Hyde, James F
Project Start
1994-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
18
Fiscal Year
2012
Total Cost
$377,325
Indirect Cost
$150,021
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
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
Gao, Yuanqing; Ottaway, Nickki; Schriever, Sonja C et al. (2014) Hormones and diet, but not body weight, control hypothalamic microglial activity. Glia 62:17-25
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
Cheng, Andrew M; Rizzo-DeLeon, Norma; Wilson, Carole L et al. (2014) Vasodilator-stimulated phosphoprotein protects against vascular inflammation and insulin resistance. Am J Physiol Endocrinol Metab 307:E571-9
Rojas, J M; Schwartz, M W (2014) Control of hepatic glucose metabolism by islet and brain. Diabetes Obes Metab 16 Suppl 1:33-40
Meek, Thomas H; Wisse, Brent E; Thaler, Joshua P et al. (2013) BDNF action in the brain attenuates diabetic hyperglycemia via insulin-independent inhibition of hepatic glucose production. Diabetes 62:1512-8
Berkseth, Kathryn E; Schur, Ellen; Schwartz, Michael W (2013) A role for natriuretic peptides in the central control of energy balance? Diabetes 62:1379-81
Thaler, Joshua P; Guyenet, Stephan J; Dorfman, Mauricio D et al. (2013) Hypothalamic inflammation: marker or mechanism of obesity pathogenesis? Diabetes 62:2629-34

Showing the most recent 10 out of 40 publications