Obesity is a multivariate disease which has reached epidemic proportions. The neurochemical basis of excessive body weight (BW) gain due to a positive imbalance in energy intake over expenditure, is virtually unknown.. Excessive BW gain may result either from hyperphagia due to impaired signaling in the interconnected appetite regulating network (ARN) in the hypothalamus or it may be of dietary origin, with our without hyperphagia. The objectives of this proposal are to identify the neurochemical disruptions and rearrangements (plasticity) at various loci in the ARN and leptin feedback that underlie excessive BW gain.
In Aim 1, to test the hypothesis that up-regulation of the daily pattern of orexigenic signaling in the ARN is responsible for hyperphagia, we will assess (a) synthesis (gene expression and levels of NPY, GAL, and AGRP) in well characterized and novel hypothalamic sites; (b) activity (food-intake in response to administration of these peptides and antagonists); and (c) receptor gene expression in novel hypothalamic sites.
Aim 2 will test the hypothesis that alteration of the tonic restraint exercised by central anorexigenic signals (CART and the melanocortin, alphaMSH) contributes to hyperphagia.
Aim 3 will test the hypothesis that leptin signaling is altered during hyperphagia by analyzing changes in the daily pattern of leptin gene expression in adipocytes, plasma leptin levels and leptin receptor mRNA in discrete hypothalamic sites and the response to leptin administration. To test these three interrelated hypotheses, we propose to employ a rat model of hyperphagia produced by destruction of the paraventricular nucleus, the target site of action of orexigenic and anorexigenic peptides originating in the arcuate nucleus of the hypothalamus. Finally, in Aim 4, we propose to determine whether similar mechanisms operate in diet-induced obesity. Since the development of effective therapeutic strategies for humans requires a complete understanding of the impairment in neurochemical loci, this proposal to elucidate the neurochemical etiology of hyperphagia and excessive BW gain in rodents models is designed to meet this goal.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Nutrition Study Section (NTN)
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Kitt, Cheryl A
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University of Florida
Schools of Medicine
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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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