This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bagnasco, M. Articles by Kalra, S. P. Search for Related Content PubMed PubMed Citation Articles by Bagnasco, M. Articles by Kalra, S. P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

Evidence for the Existence of Distinct Central Appetite, Energy Expenditure, and Ghrelin Stimulation Pathways as Revealed by Hypothalamic Site-Specific Leptin Gene Therapy

Departments of Neuroscience (M.B., S.P.K.) and Physiology and Functional Genomics (M.G.D., P.S.K.), McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-0244

Address all correspondence and requests for reprints to: Satya P. Kalra, Ph.D., Department of Neuroscience, College of Medicine, University of Florida McKnight Brain Institute, P.O. Box 100244, Gainesville, Florida 32610. E-mail: skalra{at}ufbi.ufl.edu.

To identify the specific hypothalamic sites in which leptin acts to decrease energy intake and/or increase energy expenditure, recombinant adeno-associated virus vector-encoding leptin was microinjected bilaterally into one of four hypothalamic sites in female rats. Leptin transgene expression in the ventromedial nucleus and paraventricular nucleus induced comparable decreases in daily food intake (FI; 18–20%) and body weight (BW; 26–29%), accompanied by drastic reductions in serum leptin (81–97%), insulin (92–93%), free fatty acids (35–36%), and normoglycemia. Leptin transgene expression in the arcuate nucleus (ARC) decreased BW gain (21%) and FI (11%) to a lesser range, but the metabolic hormones were suppressed to the same extent. Leptin transgene expression in the medial preoptic area (MPOA) decreased BW and metabolic hormones without decreasing FI. Finally, leptin transgene expression in all four sites augmented serum ghrelin and thermogenic energy expenditure, as shown by uncoupling protein-1 mRNA expression in brown adipose tissue. Proopiomelanocortin gene expression in the ARC was up-regulated by leptin expression in all four sites, but neuropeptide Y gene expression in the ARC was suppressed by leptin transgene expression in the ARC but not in the MPOA. Thus, whereas leptin expression in the paraventricular nucleus, ventromedial nucleus, or ARC suppresses adiposity and insulin by decreasing energy intake and increasing energy expenditure, in the MPOA it suppresses these variables by increasing energy expenditure alone.

This article has been cited by other articles:

				M. K. Singh, F. Elefteriou, and G. Karsenty Cocaine and Amphetamine-Regulated Transcript May Regulate Bone Remodeling as a Circulating Molecule Endocrinology, August 1, 2008; 149(8): 3933 - 3941. [Abstract] [Full Text] [PDF]

				Q. Gao and T. L. Horvath Cross-talk between estrogen and leptin signaling in the hypothalamus Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E817 - E826. [Abstract] [Full Text] [PDF]

				R. B. S. Harris, T. J. Bartness, and H. J. Grill Leptin Responsiveness in Chronically Decerebrate Rats Endocrinology, October 1, 2007; 148(10): 4623 - 4633. [Abstract] [Full Text] [PDF]

				M. F. Wiater, B. D. Hudson, Y. Virgin, and S. Ritter Protein appetite is increased after central leptin-induced fat depletion Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1468 - R1473. [Abstract] [Full Text] [PDF]

				B. M. McGowan, S. A. Stanley, N. E. White, A. Spangeus, M. Patterson, E. L. Thompson, K. L. Smith, J. Donovan, J. V. Gardiner, M. A. Ghatei, et al. Hypothalamic mapping of orexigenic action and Fos-like immunoreactivity following relaxin-3 administration in male Wistar rats Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E913 - E919. [Abstract] [Full Text] [PDF]

				S. Stanley, K. Wynne, B. McGowan, and S. Bloom Hormonal Regulation of Food Intake Physiol Rev, October 1, 2005; 85(4): 1131 - 1158. [Abstract] [Full Text] [PDF]

				S. P. Kalra, N. Ueno, and P. S. Kalra Stimulation of Appetite by Ghrelin Is Regulated by Leptin Restraint: Peripheral and Central Sites of Action J. Nutr., May 1, 2005; 135(5): 1331 - 1335. [Abstract] [Full Text] [PDF]

				K. Wynne, S. Stanley, B. McGowan, and S. Bloom Appetite control J. Endocrinol., February 1, 2005; 184(2): 291 - 318. [Abstract] [Full Text] [PDF]

				N. Ueno, M. G. Dube, A. Inui, P. S. Kalra, and S. P. Kalra Leptin Modulates Orexigenic Effects of Ghrelin and Attenuates Adiponectin and Insulin Levels and Selectively the Dark-Phase Feeding as Revealed by Central Leptin Gene Therapy Endocrinology, September 1, 2004; 145(9): 4176 - 4184. [Abstract] [Full Text] [PDF]

				C. Schulz, K. Paulus, and H. Lehnert Central Nervous and Metabolic Effects of Intranasally Applied Leptin Endocrinology, June 1, 2004; 145(6): 2696 - 2701. [Abstract] [Full Text] [PDF]

				P. Marzullo, B. Verti, G. Savia, G. E. Walker, G. Guzzaloni, M. Tagliaferri, A. Di Blasio, and A. Liuzzi The Relationship between Active Ghrelin Levels and Human Obesity Involves Alterations in Resting Energy Expenditure J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 936 - 939. [Abstract] [Full Text] [PDF]

				J. L. Chan, J. Bullen, J. H. Lee, N. Yiannakouris, and C. S. Mantzoros Ghrelin Levels Are Not Regulated by Recombinant Leptin Administration and/or Three Days of Fasting in Healthy Subjects J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 335 - 343. [Abstract] [Full Text] [PDF]