Leptin is an adipose-derived hormone that is now well-known for its ability to reduce food intake and body weight. However, during chronic leptin treatment, food intake is initially suppressed, but then returns to normal or near normal levels despite leptin s continued suppression of body weight gain. This proposal explores mechanisms that potentially underlie this recovery of feeing. The overarching hypothesis is that food intake returns to normal during chronic leptin treatment due to the action of metabolically-driven ingestive controls that are not subject to leptin-induced inhibition. We specifically test the hypothesis that hindbrain catecholamine neurons are important contributors to the recovery of food intake during chronic leptin treatment. Subsets of these neurons have potent stimulatory effects on feeding and widespread actions on fat, glucose and protein mobilization that are essential for effective defense against glucoprivation. Although their essential role in glucorestoration during acute glucoprivic emergency is now unequivocal, the contribution of hindbrain catecholamine neurons to appetite and energy homeostasis during chronically altered metabolic states has not been studied. We know that the stimulation of feeding by these catecholamine neurons is not suppressed by leptin and that they possess neural connections that potentially allow them to override leptin s inhibitory effect on feeding. To test our hypotheses, we have developed a model of chronic central leptin treatment in which we have carefully defined the changes in food intake with respect to the status of body fat stores. This model allows us to define 4 metabolically distinct metabolic states. Besides providing a consistent reference for changes in behavior and neuronal activity during leptin treatment, this model provides a healthy, normophagic but """"""""fatless"""""""" rat which provides a new viewpoint for understanding the interaction of multiple metabolic controls of feeding and energy homeostasis. Experiments in Specific Aim 1 will determine the contribution of hindbrain catecholamine neurons to the behavioral, metabolic and endocrine responses during chronic central leptin treatment. We examine the possibility that the recovery of feeding during chronic leptin treatment may be related to the response of hindbrain catecholamine neurons to the fatless state.
Specific Aim 2 will examine the contribution of hindbrain catecholamine neurons to central patterns of neuronal activation during different phases of chronic central leptin treatment.
Specific Aim 3 will attempt to block the recovery of feeding during chronic leptin treatment by intravenous macronutrient infusions, similar to those shown in previous work to be effective in blocking feeding in response to acute pharmacologically-induced deficits in metabolic fuels. The possibility that the status of body fat stores may alter the glucoregulatory function of hindbrain catecholamine neurons has direct importance for the management of diabetes and its complications, since these neurons control key glucoregulatory responses and are central to survival of inadvertent hypoglycemic bouts.

Public Health Relevance

Hindbrain catecholamine neurons have been demonstrated to be essential for glucose homeostasis and for elicitation of a variety of responses that protect the brain against glucose deficit. In this proposal, we will determine how the activity of these neurons is altered by body fat depletion induced by chronic leptin treatment. Understanding how the status of body fat stores influences the function of glucoregulatory catecholamine neurons has importance for management of diabetes and its complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081546-03
Application #
7858026
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Hyde, James F
Project Start
2008-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$305,789
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Li, Ai-Jun; Wang, Qing; Dinh, Thu T et al. (2016) Mercaptoacetate blocks fatty acid-induced GLP-1 secretion in male rats by directly antagonizing GPR40 fatty acid receptors. Am J Physiol Regul Integr Comp Physiol 310:R724-32
Li, Ai-Jun; Wang, Qing; Davis, Hana et al. (2015) Orexin-A enhances feeding in male rats by activating hindbrain catecholamine neurons. Am J Physiol Regul Integr Comp Physiol 309:R358-67
Li, Ai-Jun; Wang, Qing; Elsarelli, Megan M et al. (2015) Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats. Endocrinology 156:2807-20
Li, Ai-Jun; Wang, Qing; Dinh, Thu T et al. (2014) Stimulation of feeding by three different glucose-sensing mechanisms requires hindbrain catecholamine neurons. Am J Physiol Regul Integr Comp Physiol 306:R257-64
Darling, Rebecca A; Zhao, Huan; Kinch, Dallas et al. (2014) Mercaptoacetate and fatty acids exert direct and antagonistic effects on nodose neurons via GPR40 fatty acid receptors. Am J Physiol Regul Integr Comp Physiol 307:R35-43
Wiater, Michael F; Li, Ai-Jun; Dinh, Thu T et al. (2013) Leptin-sensitive neurons in the arcuate nucleus integrate activity and temperature circadian rhythms and anticipatory responses to food restriction. Am J Physiol Regul Integr Comp Physiol 305:R949-60
Li, Ai-Jun; Wang, Qing; Dinh, Thu T et al. (2013) Hindbrain catecholamine neurons control rapid switching of metabolic substrate use during glucoprivation in male rats. Endocrinology 154:4570-9
Routh, Vanessa H; Donovan, Casey M; Ritter, Sue (2012) 2. Hypoglycemia Detection. Transl Endocrinol Metab 3:47-87
Li, Ai-Jun; Wiater, Michael F; Oostrom, Marjolein T et al. (2012) Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms. Am J Physiol Regul Integr Comp Physiol 302:R1313-26
Ritter, Sue; Li, Ai-Jun; Wang, Qing et al. (2011) Minireview: The value of looking backward: the essential role of the hindbrain in counterregulatory responses to glucose deficit. Endocrinology 152:4019-32

Showing the most recent 10 out of 14 publications