title: Targeted leptin receptor blockade: role of ventral tegmental area and nucleus of the solitary tract leptin receptors in body weight homeostasis.
abstract: The present investigation examined whether leptin stimulation of ventral tegmental area (VTA) or nucleus of the solitary tract (NTS) has a role in body weight homeostasis independent of the medial basal hypothalamus (MBH). To this end, recombinant adeno-associated viral techniques were employed to target leptin overexpression or overexpression of a dominant negative leptin mutant (leptin antagonist). Leptin antagonist overexpression in MBH or VTA increased food intake and body weight to similar extents over 14 days in rats. Simultaneous overexpression of leptin in VTA with antagonist in MBH resulted in food intake and body weight gain that were less than with control treatment but greater than with leptin alone in VTA. Notably, leptin overexpression in VTA increased P-STAT3 in MBH along with VTA, and leptin antagonist overexpression in the VTA partially attenuated P-STAT3 levels in MBH. Interestingly, leptin antagonist overexpression elevated body weight gain, but leptin overexpression in the NTS failed to modulate either food intake or body weight despite increased P-STAT3. These data suggest that leptin function in the VTA participates in the chronic regulation of food consumption and body weight in response to stimulation or blockade of VTA leptin receptors. Moreover, one component of VTA-leptin action appears to be independent of the MBH, and another component appears to be related to leptin receptor-mediated P-STAT3 activation in the MBH. Finally, leptin receptors in the NTS are necessary for normal energy homeostasis, but mostly they appear to have a permissive role. Direct leptin activation of NTS slightly increases UCP1 levels, but has little effect on food consumption or body weight.
authors.affiliation: Department of Pharmacology and TherapeuticsCollege of Medicine, University of Florida, PO Box 100267, Gainesville, Florida 32610, USADepartment of Veterans AffairsMedical Center, Gainesville, Florida 32608-1197, USA.
authors.forename: M
authors.initials: M
authors.lastname: Matheny
authors.affiliation: Department of Pharmacology and TherapeuticsCollege of Medicine, University of Florida, PO Box 100267, Gainesville, Florida 32610, USADepartment of Veterans AffairsMedical Center, Gainesville, Florida 32608-1197, USA.
authors.forename: K Y E
authors.initials: KY
authors.lastname: Strehler
authors.affiliation: Department of Pharmacology and TherapeuticsCollege of Medicine, University of Florida, PO Box 100267, Gainesville, Florida 32610, USADepartment of Veterans AffairsMedical Center, Gainesville, Florida 32608-1197, USADepartment of Pharmacology and TherapeuticsCollege of Medicine, University of Florida, PO Box 100267, Gainesville, Florida 32610, USADepartment of Veterans AffairsMedical Center, Gainesville, Florida 32608-1197, USA.
authors.forename: M
authors.initials: M
authors.lastname: King
authors.affiliation: Department of Pharmacology and TherapeuticsCollege of Medicine, University of Florida, PO Box 100267, Gainesville, Florida 32610, USADepartment of Veterans AffairsMedical Center, Gainesville, Florida 32608-1197, USADepartment of Pharmacology and TherapeuticsCollege of Medicine, University of Florida, PO Box 100267, Gainesville, Florida 32610, USADepartment of Veterans AffairsMedical Center, Gainesville, Florida 32608-1197, USA.
authors.forename: N
authors.initials: N
authors.lastname: Tümer
authors.affiliation: Department of Pharmacology and TherapeuticsCollege of Medicine, University of Florida, PO Box 100267, Gainesville, Florida 32610, USADepartment of Veterans AffairsMedical Center, Gainesville, Florida 32608-1197, USA scarpace@ufl.edu.
authors.forename: P J
authors.initials: PJ
authors.lastname: Scarpace
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D050154:Adiposity / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000502:physiology*; D004435:Eating / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology; D008297:Male; D024101:Mitochondrial Proteins / Q000502:physiology; D023421:Models, Animal; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D017552:Solitary Nucleus / Q000502:physiology*; D000071256:Uncoupling Protein 1; D017557:Ventral Tegmental Area / Q000502:physiology*
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1
keywords: gene therapy; leptin; neuroendocrinology; signal transduction