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Hypothalamic NPY and Agouti-Related Protein Are Increased in Human Illness But Not in Prader-Willi Syndrome and Other Obese Subjects

Graduate School Neurosciences Amsterdam (A.P.G., U.A.U., D.F.S.), Netherlands Institute for Brain Research, 1105 AZ Amsterdam ZO, The Netherlands; Endocrine Unit (A.P.G., S.R.B.), Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom

Address all correspondence and requests for reprints to: D. F. Swaab, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam ZO, The Netherlands. E-mail: tgoldstone{at}yahoo.com

Abstract

Animal studies have demonstrated the importance of orexigenic NPY and agouti-related protein (AGRP) hypothalamic neurons, which are inhibited by the adipocyte hormone leptin, in the regulation of body weight and neuroendocrine secretion. We have examined NPY and AGRP neurons in postmortem human hypothalami from controls, Prader-Willi syndrome and other obese subjects, using quantitative immunocytochemistry (ICC) and in situ hybridization, to identify causes of leptin resistance in human obesity. Using combined ICC and in situ hybridization, AGRP, but not POMC, was colocalized with NPY in infundibular nucleus neurons. Infundibular nucleus (including median eminence) NPY ICC staining or mRNA expression, and AGRP ICC staining, increased with premorbid illness duration. NPY ICC staining and mRNA expression were reduced in obese subjects, but AGRP ICC staining was unchanged, correcting for illness duration. This suggests normal responses of NPY and AGRP neurons to peripheral signals, such as leptin and insulin, in human illness and obesity. The pathophysiology of obesity and illness-associated anorexia appear to lie in downstream or separate neuronal circuits, but the infundibular neurons may mediate neuroendocrine responses to illness. The implications for pharmacological treatment of human obesity are discussed.

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