title: Identification and saturable nature of signaling pathways induced by metreleptin in humans: comparative evaluation of in vivo, ex vivo, and in vitro administration.
abstract: Signaling pathways activated by leptin in metabolically important organs have largely been studied only in animal and/or cell culture studies. In this study, we examined whether leptin has similar effects in human peripheral tissues in vivo, ex vivo, and in vitro and whether the response would be different in lean and obese humans. For in vivo leptin signaling, metreleptin was administered and muscle, adipose tissue, and peripheral blood mononuclear cells were taken for analysis of signal activation. Experiments were also done ex vivo and with primary cultured cells in vitro. The signal activation was compared between male versus female and obese versus lean humans. Acute in vivo, ex vivo, and/or in vitro metreleptin administration similarly activated STAT3, AMPK, ERK1/2, Akt, mTOR, NF-κB, and/or IKKα/β without any differences between male versus female and obese versus lean subjects. All signaling pathways were saturable at ∼30-50 ng/mL, consistent with the clinical evidence showing no additional effect(s) in obese subjects who already have high levels of leptin. Our data provide novel information on downstream effectors of metreleptin action in humans that may have therapeutic implications.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Hyun-Seuk
authors.initials: HS
authors.lastname: Moon
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Huh
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Fadime
authors.initials: F
authors.lastname: Dincer
authors.affiliation: Division of Minimally Invasive Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Schneider
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Hasselgren
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA cmantzor@bidmc.harvard.edu.
authors.forename: Christos S
authors.initials: CS
authors.lastname: Mantzoros
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020738:Leptin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D020738:Leptin; C415771:metreleptin