title: Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21.
abstract: The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co-administration of leptin with other weight loss-inducing hormones equally restores leptin responsiveness in diet-induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site-specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin-4 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin-4 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter-regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin-4. We conclude that leptin re-sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long-acting leptin analogs are additively efficacious when used in combination with other weight-lowering agents.
authors.affiliation: Metabolic Disease Institute, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45230, USA.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Sullivan
authors.forename: Kirk
authors.initials: K
authors.lastname: Habegger
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Kabra
authors.forename: Erin
authors.initials: E
authors.lastname: Grant
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.forename: Radha
authors.initials: R
authors.lastname: Krishna
authors.forename: Jenna
authors.initials: J
authors.lastname: Holland
authors.forename: Jazzminn
authors.initials: J
authors.lastname: Hembree
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Michael J
authors.initials: MJ
authors.lastname: DeGuzman
authors.forename: Marc E
authors.initials: ME
authors.lastname: Siladi
authors.forename: Vadim S
authors.initials: VS
authors.lastname: Kraynov
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Axelrod
authors.forename: Richard
authors.initials: R
authors.lastname: DiMarchi
authors.forename: Jason K
authors.initials: JK
authors.lastname: Pinkstaff
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D000818:Animals; D001835:Body Weight; D004032:Diet / Q000009:adverse effects*; D004338:Drug Combinations; D000077270:Exenatide; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000494:pharmacology*; D020738:Leptin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008958:Models, Molecular; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D004338:Drug Combinations; D020738:Leptin; D010455:Peptides; D014688:Venoms; C414620:fibroblast growth factor 21; D011092:Polyethylene Glycols; D005346:Fibroblast Growth Factors; D000077270:Exenatide