|
Research Summary
Neuroendocrine control of pituitary function. Hypothalamic regulation of energy homeostasis. Neuroendocrine-immune interactions.
Research Activities
Hypothalamic regulation of energy homeostasis: This project focuses on the melanocortin neuropeptide system which plays a key role in regulating appetite and body weight and is an important target for leptin in the hypothalamus. Studies center on the regulation of proopiomelanocortin (POMC) and the POMC-derived peptides, a-MSH, g-MSH and ß-EP, together with the newly discovered agouti related protein (AGRP) which is synthesized in the hypothalamus and is a potent antagonist of the MSH peptides. a-MSH inhibits feeding and AGRP is an orexigenic peptide which antagonizes the actions of a-MSH at specific melanocortin receptors. Ongoing studies are examining the regulation of POMC and AGRP gene expression, peptide processing and peptide release in the rat hypothalamus by both leptin and insulin as well as interactions between the POMC and AGRP neurons themselves which both express melanocortin receptors. The role of leptin in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis is also being studied. The HPA axis plays a key role in energy homeostasis and is intricately related to the obesity syndromes in leptin deficient animals. Transgenic mice which overexpress a-MSH and g-MSH have also been developed to further understand the role that these neuropeptides play in modulating feeding behavior, metabolic and endocrine responses. Current studies are focusing on the modulation of peripheral insulin sensitivity by the hypothalamic melanocortin system.
Cytokines and Hypothalamic-Pituitary-Immune Interactions: This project focuses on inflammatory cytokines and mechanisms of HPA activation and on the modulation of cytokine and HPA responses to inflammation by leptin and the melanocortin system. There is evidence that leptin, which plays a key role in regulating energy homeostasis, can also modulate the inflammatory response. a-MSH is synthesized in the hypothalamus and in the periphery and can be regulated by leptin. a-MSH has potent anti-inflammatory properties and can antagonize many of the actions of the inflammatory cytokines. Little is known, however, about the role of the endogenous melanocortin system, consisting of a-MSH, the melanocortin receptors, and the MSH antagonist, AGRP, in modulating cytokine and neuroendocrine responses. This project will examine the role of leptin, a-MSH and AGRP in modulating pro-inflammatory (IL-1ß, IL-6, TNF-a) and anti-inflammatory cytokine (IL-1ra and IL-10) responses to endotoxin and IL-1ß in the rhesus monkey. Major goals are to determine the physiological roles that a-MSH and AGRP play both centrally and peripherally in modulating the HPA response to an inflammatory challenge and to determine if the effects of leptin on the HPA axis are mediated in part by a-MSH. A rodent model will be used to examine the effects of endotoxin on POMC and AGRP gene expression in the hypothalamus and the effects of leptin on IL-1ß-stimulated CRH release from the hypothalamus in vitro. Mice which overexpress a-MSH and agouti protein will also be utilized to study the role of the melanocortin system and of leptin in modulating cytokine and neuroendocrine responses to endotoxin.
Positions & Appointments
| 1999-present |
Professor, Department of Medicine |
Columbia University, College of Physicians & Surgeons |
New York, NY |
| 1999-present |
Director, Neuroendocrine Unit |
Columbia University Medical Center |
New York, NY |
| 1989-1998 |
Associate Professor, Department of Medicine |
Columbia University, College of Physicians & Surgeons |
New York, NY |
| 1998-present |
Attending Physician |
Presbyterian Hospital |
New York, NY |
| 1989-1998 |
Associate Attending Physician |
Presbyterian Hospital |
New York, NY |
Education and Training
| 1966-1970 |
B.S., Biochemistry |
Cornell University, Ithaca, NY |
| 1971-1975 |
M.D. |
Cornell University Medical College, Ithaca, NY |
Honors and Awards
1983 Harold and Golden Lamport Research Award
Committees and Society Memberships
Diplomate, American Board of Internal Medicine
Diplomate, Subspecialty Board of Endocrinology and Metabolism
The Endocrine Society
Society for Neuroscience
International Society of Neuroendocrinology
Pituitary Society
American Neuroendocrine Society
American Association for the Advancement of Science
Selected Publications:
1. Xiao E, Xia-Zhang L, Vulliemoz N, Ferin M, Wardlaw SL. (2003) Leptin modulates inflammatory cytokine and neuroendocrine responses to endotoxin in the primate. Endocrinology
144:
2. Xiao E, Xia-Zhang L, Vulliemoz N, Ferin M, Wardlaw SL. (2003) Agouti-related protein stimulates the hypothalamic-pituitary-adrenal axis and enhances the HPA response to interleukin-1 in the primate. Endocrinology
144:1736-41
3. Savontaus E, Conwell IM, Wardlaw SL. (2002) Effects of adrenalectomy on AGRP, POMC, NPY and CART gene expression in the hypothalamus of fed and fasted rats. Brain Research : .
958:130-8
4. Wardlaw, SL. (2001) Obesity as a neuroendocrine disease: Lessons to be learned from POMC and melanocortin receptor mutations in mice and men. J Clin Endocrinol Metab
86:1442-6
5. Korner J, Savontaus E, Chua SC, Leibel RL, Wardlaw SL. (2001) Leptin regulation of AGRP and NPY mRNA in the rat hypothalamus. J Neuroendocrinology : ,
13:959-66
6. Korner J, Chua SC, Williams JA, Leibel RL, Wardlaw SL. (1999) Regulation of hypothalamic proopiomelanocortin by leptin in lean and obese rats. Neuroendocrinology
70:377-83
| |
