title: The DPP-IV inhibitor linagliptin and GLP-1 induce synergistic effects on body weight loss and appetite suppression in the diet-induced obese rat.
abstract: Linagliptin is a dipeptidyl peptidase (DPP)-IV inhibitor approved for the treatment of type 2 diabetes. DPP-IV inhibitors are considered weight neutral, suggesting that elevation of endogenous incretin levels is not sufficient to promote weight loss per se. Here we evaluated the effect of linagliptin in combination with subcutaneous treatment of GLP-1(7-36) on body weight regulation in diet-induced obese (DIO) rats. Linagliptin administered perorally (1.5mg/kg, b.i.d.), but not subcutaneously (0.5mg/kg, b.i.d.), evoked a very modest body weight loss (2.2%) after 28 days of treatment. GLP-1 (0.5mg/kg, s.c.) treatment alone induced a body weight loss of 4.1%. In contrast, combined linagliptin (1.5mg/kg, p.o., or 0.5mg/kg, s.c.) and GLP-1 (0.5mg/kg) treatment evoked a marked anorectic response with both routes of linagliptin administration being equally effective on final body weight loss (7.5-8.0%). In comparison, liraglutide monotherapy (0.2mg/kg, s.c., b.i.d.) reduced body weight by 10.1%. Interestingly, the weight lowering effect of combined linagliptin and GLP-1 treatment was associated with a marked increase in chow preference, being more pronounced as compared to liraglutide treatment. In addition, linagliptin and GLP-1 co-treatment, but not liraglutide, specifically increased prepro-dynorphin mRNA levels in the caudate-putamen, an effect not obtained with administration of the compounds individually. In conclusion, co-treatment with linagliptin and GLP-1 synergistically reduces body weight in obese rats. The anti-obesity effect was caused by appetite suppression with a concomitant change in diet preference, which may potentially be associated with increased dynorphin activity in forebrain regions involved in reward anticipation and habit learning.
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark. Electronic address: hbh@gubra.dk.
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Gitte
authors.initials: G
authors.lastname: Hansen
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Sarah
authors.initials: S
authors.lastname: Paulsen
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Vrang
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Jelsing
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects; D019422:Dietary Sucrose / Q000008:administration & dosage / Q000009:adverse effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage*; D000069476:Linagliptin; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015431:Weight Loss / Q000187:drug effects* / Q000502:physiology
chemical_list: D001067:Appetite Depressants; D019422:Dietary Sucrose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D052216:Glucagon-Like Peptide 1
keywords: DPP-IV inhibitor; Dynorphin; GLP-1; Linagliptin; Obesity; Weight loss