title: PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure.
abstract: Insulin and leptin intracellular signaling pathways converge and act synergistically on the hypothalamic phosphatidylinositol-3-OH kinase/3-phosphoinositide-dependent protein kinase 1 (PDK1). However, little is known about whether PDK1 in agouti-related peptide (AGRP) neurons contributes to energy homeostasis. We generated AGRP neuron-specific PDK1 knockout (AGRPPdk1(-/-)) mice and mice with selective expression of transactivation-defective Foxo1 (Δ256Foxo1(AGRP)Pdk1(-/-)). The AGRPPdk1(-/-) mice showed reductions in food intake, body length, and body weight. The Δ256Foxo1(AGRP)Pdk1(-/-) mice showed increased body weight, food intake, and reduced locomotor activity. After four weeks of calorie-restricted feeding, oxygen consumption and locomotor activity were elevated in AGRPPdk1(-/-) mice and reduced in Δ256Foxo1(AGRP)Pdk1(-/-) mice. In vitro, ghrelin-induced changes in [Ca(2+)](i) and inhibition of ghrelin by leptin were significantly attenuated in AGRPPdk1(-/-) neurons compared to control neurons. However, ghrelin-induced [Ca(2+)](i) changes and leptin inhibition were restored in Δ256Foxo1(AGRP)Pdk1(-/-) mice. These results suggested that PDK1 and Foxo1 signaling pathways play important roles in the control of energy homeostasis through AGRP-independent mechanisms.
authors.affiliation: Division of Molecular Medicine and Medical Genetics, International Center for Medical Research and Treatment, Kobe University Graduate School of Medicine, Japan.
authors.forename: Yongheng
authors.initials: Y
authors.lastname: Cao
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakata
authors.forename: Shiki
authors.initials: S
authors.lastname: Okamoto
authors.forename: Eisuke
authors.initials: E
authors.lastname: Takano
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hirata
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nakajima
authors.forename: Kristy
authors.initials: K
authors.lastname: Iskandar
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hosoda
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.forename: Jun
authors.initials: J
authors.lastname: Nakae
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D031204:Caloric Restriction; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D055786:Gene Knockout Techniques; D054439:Ghrelin / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008297:Male; D053486:Melanocortins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D054369:Agouti-Related Protein; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D054439:Ghrelin; D020738:Leptin; D053486:Melanocortins; D009479:Neuropeptides; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; C578579:Pdpk1 protein, rat; D017346:Protein Serine-Threonine Kinases; D002118:Calcium