title: The adipokine leptin mediates muscle- and liver-derived IGF-1 in aged mice.
abstract: Muscle- and liver-derived IGF-1 play important roles in muscle anabolism throughout growth and aging. Yet, prolonged food restriction is thought to increase longevity in part by lowering levels of IGF-1, which in turn reduces the risk for developing various cancers. The dietary factors that modulate IGF-1 levels are, however, poorly understood. We tested the hypothesis that the adipokine leptin, which is elevated with food intake and suppressed during fasting, is a key mediator of IGF-1 levels with aging and food restriction. First, leptin levels in peripheral tissues were measured in young mice fed ad libitum, aged mice fed ad libitum, and aged calorie-restricted (CR) mice. A group of aged CR mice were also treated with recombinant leptin for 10 days. Later, aged mice fed ad libitum were treated with saline (VEH) or with a novel leptin receptor antagonist peptide (Allo-aca) and tissue-specific levels of IGF-1 were determined. On one hand, recombinant leptin induced a three-fold increase in liver-derived IGF-1 and a two-fold increase in muscle-derived IGF-1 in aged, CR mice. Leptin also significantly increased serum growth hormone levels in the aged, CR mice. On the other, the leptin receptor antagonist Allo-aca did not alter body weight or muscle mass in treated mice compared to VEH mice. Allo-aca did, however, produce a significant (20%) decline in liver-derived IGF-1 as well as an even more pronounced (>50%) decrease in muscle-derived IGF-1 compared to VEH-treated mice. The reduced IGF-1 levels in Allo-aca treated mice were not accompanied by any significant change in growth hormone levels compared to VEH mice. These findings suggest that leptin receptor antagonists may represent novel therapeutic agents for attenuating IGF-1 signaling associated with aging, and could potentially mimic some of the positive effects of calorie restriction on longevity.
authors.affiliation: Georgia Regents University, Medical College of Georgia, Augusta, GA, USA. Electronic address: mhamrick@gru.edu.
authors.forename: M W
authors.initials: MW
authors.lastname: Hamrick
authors.affiliation: Georgia Regents University, Medical College of Georgia, Augusta, GA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dukes
authors.affiliation: Wake Forest School of Medicine, Winston Salem, NC, USA.
authors.forename: P
authors.initials: P
authors.lastname: Arounleut
authors.affiliation: Georgia Regents University, Medical College of Georgia, Augusta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Davis
authors.affiliation: Georgia Regents University, Medical College of Georgia, Augusta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Periyasamy-Thandavan
authors.affiliation: Georgia Regents University, Medical College of Georgia, Augusta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mork
authors.affiliation: Case Western Reserve University, Cleveland, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Herberg
authors.affiliation: Georgia Regents University, Medical College of Georgia, Augusta, GA, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Johnson
authors.affiliation: Georgia Regents University, Medical College of Georgia, Augusta, GA, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Isales
authors.affiliation: Georgia Regents University, Medical College of Georgia, Augusta, GA, USA.
authors.forename: W D
authors.initials: WD
authors.lastname: Hill
authors.affiliation: Temple University, Philadelphia, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Otvos
authors.affiliation: Georgia Regents University, Medical College of Georgia, Augusta, GA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Belin de Chantemèle
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D031204:Caloric Restriction; D004435:Eating; D013006:Growth Hormone / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008136:Longevity / Q000502:physiology; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: C585337:D-Ser Allo-aca peptide; D020738:Leptin; D010455:Peptides; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
keywords: Aging; Calorie restriction; Food intake; Longevity