Obesity, a multivariate disease, can occur with or without accompanying hyperphagia. There is a growing sense of alarm that a large percentage of eating disorders and obesity may be environmental in origin. Among the environmental factors, neurotoxins and certain neural injury producing infections have drawn considerable attention and concern in recent years. This proposal focuses on the neurochemical basis of obesity produced experimentally by neurotoxins. Our long-term objectives are to understand the operative function of the brain circuitry involved in the development of obesity caused by neurotoxin-induced neural injury. Within the hypothalamus an interconnected network of neuropeptides including Neuropeptide Y, galanin and opioids, evokes normal feeding in the rat. We propose to test the hypothesis that obesity produced by three specific neurotoxins known to inflict varied cellular damage is either due to the increased secretion of one or more of these excitatory neuropeptides or due to an increase in receptor sensitivity in the hypothalamic paraventricular nucleus - perifornical (PVN-PF) area. The following neurotoxins will be employed: Ibotenic acid to selectively destroy cell bodies in the ventromedial hypothalamus; colchicine to block axonal transport in the ventromedial nucleus; 6-hydroxydopamine to damage the ascending ventral catecholaminergic bundle in the mid-brain. Secretion of neuropeptide Y, galanin and opioids will be measured in vivo by the push- pull cannula technique and in vitro in short-term cultures of the PVN-PF, and synthesis will be assessed by quantitation of mRNA and peptide contents will be measured in various hypothalamic sites. The second possibility of increase in receptor sensitivity will be assessed by quantitation of food intake after the intracerebroventricular injection of agonists and antagonists or immunoneutralization of neuropeptides. Neuropeptide receptor affinity and number in membranes from microdissected hypothalamic sites will be measured. It is anticipated that elucidating the patterns of neuropeptidergic signalling associated with neurotoxin- induced obesity will shed light on the etiology of idiopathic obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032727-03
Application #
2431228
Study Section
Psychobiology, Behavior, and Neuroscience Review Committee (PBN)
Program Officer
Kitt, Cheryl A
Project Start
1995-08-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1999-05-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Kalra, S P (2011) Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention? Gene Ther 18:319-25
Kalra, Satya P (2008) Disruption in the leptin-NPY link underlies the pandemic of diabetes and metabolic syndrome: new therapeutic approaches. Nutrition 24:820-6
Kalra, Satya P (2008) Central leptin insufficiency syndrome: an interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions. Peptides 29:127-38
Kalra, Satya P (2007) Global life-long health benefits of repression of hypothalamic NPY system by central leptin gene therapy. Curr Top Med Chem 7:1675-81
Kalra, Satya P; Kalra, Pushpa S (2007) To subjugate NPY is to improve the quality of life and live longer. Peptides 28:413-8
Dube, Michael G; Kalra, Satya P; Kalra, Pushpa S (2007) Low abundance of NPY in the hypothalamus can produce hyperphagia and obesity. Peptides 28:475-9
Boghossian, Stephane; Ueno, Naohiko; Dube, Michael G et al. (2007) Leptin gene transfer in the hypothalamus enhances longevity in adult monogenic mutant mice in the absence of circulating leptin. Neurobiol Aging 28:1594-604
Ueno, Naohiko; Inui, Akio; Kalra, Pushpa S et al. (2006) Leptin transgene expression in the hypothalamus enforces euglycemia in diabetic, insulin-deficient nonobese Akita mice and leptin-deficient obese ob/ob mice. Peptides 27:2332-42
Boghossian, Stephane; Dube, Michael G; Torto, Rita et al. (2006) Hypothalamic clamp on insulin release by leptin-transgene expression. Peptides 27:3245-54
Boghossian, Stephane; Lecklin, Anne; Dube, Michael G et al. (2006) Increased leptin expression in the dorsal vagal complex suppresses adiposity without affecting energy intake and metabolic hormones. Obesity (Silver Spring) 14:1003-9

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