title: Food intake reductions and increases in energetic responses by hindbrain leptin and melanotan II are enhanced in mice with POMC-specific PTP1B deficiency.
abstract: Leptin regulates energy balance through central circuits that control food intake and energy expenditure, including proopiomelanocortin (POMC) neurons. POMC neuron-specific deletion of protein tyrosine phosphatase 1B (PTP1B) (Ptpn1(loxP/loxP) POMC-Cre), a negative regulator of CNS leptin signaling, results in resistance to diet-induced obesity and improved peripheral leptin sensitivity in mice, thus establishing PTP1B as an important component of POMC neuron regulation of energy balance. POMC neurons are expressed in the pituitary, the arcuate nucleus of the hypothalamus (ARH), and the nucleus of the solitary tract (NTS) in the hindbrain, and it is unknown how each population might contribute to the phenotype of POMC-Ptp1b(-/-) mice. It is also unknown whether improved leptin sensitivity in POMC-Ptp1b(-/-) mice involves altered melanocortin receptor signaling. Therefore, we examined the effects of hindbrain administration (4th ventricle) of leptin (1.5, 3, and 6 μg) or the melanocortin 3/4R agonist melanotan II (0.1 and 0.2 nmol) in POMC-Ptp1b(-/-) (KO) and control PTP1B(fl/fl) (WT) mice on food intake, body weight, spontaneous physical activity (SPA), and core temperature (T(C)). The results show that KO mice were hypersensitive to hindbrain leptin- and MTII-induced food intake and body weight suppression and SPA compared with WT mice. Greater increases in leptin- but not MTII-induced T(C) were also observed in KO vs. WT animals. In addition, KO mice displayed elevated hindbrain and hypothalamic MC4R mRNA expression. These studies are the first to show that hindbrain administration of leptin or a melanocortin receptor agonist alters energy balance in mice likely via participation of hindbrain POMC neurons.
authors: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia PA, USA.
authors: Bart C
authors: BC
authors: De Jonghe
authors: Matthew R
authors: MR
authors: Hayes
authors: Derek J
authors: DJ
authors: Zimmer
authors: Scott E
authors: SE
authors: Kanoski
authors: Harvey J
authors: HJ
authors: Grill
authors: Kendra K
authors: KK
authors: Bence
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000494:pharmacology; D001069:Appetite Regulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007276:Injections, Intraventricular; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009928:Organ Specificity; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012249:Rhombencephalon / Q000187:drug effects / Q000378:metabolism*; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001067:Appetite Depressants; D020738:Leptin; C574273:MC4R protein, mouse; D009419:Nerve Tissue Proteins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; C079282:melanotan-II; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1