This K23 proposal on the role of leptin in neuroendocrine function and the treatment of HA combines a rigorous research agenda, close personal mentoring, and coursework tailored to train Dr. Jean L. Chan as an independent clinical investigator. Dr. Chan is currently a third-year fellow in Endocrinology and Metabolism who has an interest in human leptin physiology and treatment studies and has recently completed the first interventional study to evaluate the role of leptin in the neuroendocrine and immune response to fasting in healthy lean men - a subject of profound physiologic interest with substantial clinical relevance and significance for both high-leptin and low-leptin states. She is also currently enrolled at Harvard Medical School in the Clinical Scholar's program designed to train postdoctoral fellows in clinical investigation. For the K23 proposal, she intends to evaluate whether a threshold level of leptin is of importance in the neuroendocrine response to fasting by studying obese leptin-resistant men and whether gender has an effect on this response by studying women, who have different leptin physiology from men. The study design will involve double-blind, randomized, placebo-controlled fasting studies with leptin administration. This research may elucidate the compensatory neuroendocrine mechanisms responsible for the plateauing effect of caloric restriction in the treatment of obesity and contribute to our understanding of the neuroendocrine abnormalities associated with eating disorders. This proposal will also evaluate leptin as a potential treatment to restore menstrual cycles in women with HA, a low-leptin state associated with abnormalities in GnRH pulsatility as well as other neuroendocrine axes and bone metabolism. Dr. Chan is currently conducting a pilot study to evaluate the feasibility of this hypothesis and will use a larger, placebo-controlled study design with leptin administration for the K23 proposal. Dr. Christos Mantzoros, an established expert and leader in the leptin field, will be Dr. Chan's mentor. The Clinical Scholars program will encompass a thesis-level research effort, and Dr. Chan has assembled a thesis committee who is monitoring and guiding her progress. She will also have the opportunity to take advanced biostatistics classes at Harvard Public Health School. The proposed research will not only provide critically important and novel scientific information in the area of leptin physiology in humans but it will serve as the foundation for developing new avenues of future research.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23RR018860-03
Application #
7024982
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Wilde, David B
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$130,269
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Brennan, Aoife M; Lee, Jennifer H; Tsiodras, Sotirios et al. (2009) r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans. Eur J Endocrinol 160:173-6
Hwang, Janice J; Chan, Jean L; Ntali, Georgia et al. (2008) Leptin does not directly regulate the pancreatic hormones amylin and pancreatic polypeptide: interventional studies in humans. Diabetes Care 31:945-51
Chan, Jean L; Wong, Shekman L; Mantzoros, Christos S (2008) Pharmacokinetics of subcutaneous recombinant methionyl human leptin administration in healthy subjects in the fed and fasting states: regulation by gender and adiposity. Clin Pharmacokinet 47:753-64
Chan, Jean L; Williams, Catherine J; Raciti, Patricia et al. (2008) Leptin does not mediate short-term fasting-induced changes in growth hormone pulsatility but increases IGF-I in leptin deficiency states. J Clin Endocrinol Metab 93:2819-27
Chan, Jean L; Mietus, Joseph E; Raciti, Patricia M et al. (2007) Short-term fasting-induced autonomic activation and changes in catecholamine levels are not mediated by changes in leptin levels in healthy humans. Clin Endocrinol (Oxf) 66:49-57
Chan, Jean L; Wong, Shekman L; Orlova, Christine et al. (2007) Pharmacokinetics of recombinant methionyl human leptin after subcutaneous administration: variation of concentration-dependent parameters according to assay. J Clin Endocrinol Metab 92:2307-11
Chan, Jean L; Mun, Edward C; Stoyneva, Violeta et al. (2006) Peptide YY levels are elevated after gastric bypass surgery. Obesity (Silver Spring) 14:194-8
Chan, J L; Stoyneva, V; Kelesidis, T et al. (2006) Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin. Diabetologia 49:169-73
Lee, Jennifer H; Chan, Jean L; Sourlas, Epaminondas et al. (2006) Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. J Clin Endocrinol Metab 91:2605-11
Chan, Jean L; Matarese, Giuseppe; Shetty, Greeshma K et al. (2006) Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proc Natl Acad Sci U S A 103:8481-6

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