Evidence for the existence of distinct central appetite, energy expenditure, and ghrelin stimulation pathways as revealed by hypothalamic site-specific leptin gene therapy.

Abstract	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.
Authors	M Bagnasco, M G Dube, P S Kalra, S P Kalra
Journal	Endocrinology (Endocrinology) Vol. 143 Issue 11 Pg. 4409-21 (Nov 2002) ISSN: 0013-7227 [Print] United States
PMID	12399438 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Blood Glucose Carrier Proteins Fatty Acids, Nonesterified Ghrelin Insulin Ion Channels Leptin Luminescent Proteins Membrane Proteins Mitochondrial Proteins Neuropeptide Y Peptide Hormones RNA, Messenger Ucp1 protein, rat Uncoupling Protein 1 Green Fluorescent Proteins Pro-Opiomelanocortin
Topics	Adipose Tissue, Brown (chemistry) Animals Appetite (physiology) Arcuate Nucleus of Hypothalamus (metabolism) Blood Glucose (metabolism) Carrier Proteins (genetics) Energy Intake Energy Metabolism Fatty Acids, Nonesterified (blood) Female Gene Expression Ghrelin Green Fluorescent Proteins Hypothalamus (drug effects, metabolism) In Situ Hybridization Insulin (blood) Ion Channels Leptin (blood, genetics) Luminescent Proteins (genetics) Membrane Proteins (genetics) Microinjections Mitochondrial Proteins Neuropeptide Y (genetics) Paraventricular Hypothalamic Nucleus (metabolism) Peptide Hormones (blood) Preoptic Area (metabolism) Pro-Opiomelanocortin (genetics) RNA, Messenger (analysis) Rats Rats, Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction Transfection Uncoupling Protein 1 Ventromedial Hypothalamic Nucleus (metabolism) Weight Gain

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