title: Co-agonist of glucagon and GLP-1 reduces cholesterol and improves insulin sensitivity independent of its effect on appetite and body weight in diet-induced obese C57 mice.
abstract: Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduce body weight without inducing hyperglycemia in rodents. However, the effect of a co-agonist on insulin sensitivity and lipid metabolism has not been thoroughly assessed. Diet-induced obese (DIO) mice received 0.5 mg·kg(-1) of co-agonist or 2.5 mg·kg(-1) of glucagon or 8 μg·kg(-1) of exendin-4 by subcutaneous route, twice daily, for 28 days. A separate group of mice was pair-fed to the co-agonist-treated group for 28 days. Co-agonist treatment reduced food intake and reduced body weight up to 28 days. In addition, it reduced leptin levels and increased fibroblast growth factor 21 (FGF21) levels in plasma, when compared with control and pair-fed groups. Co-agonist treatment decreased triglyceride levels in serum and liver and reduced serum cholesterol, mainly due to reduction in low-density lipoprotein (LDL) cholesterol. These changes were not seen with pair-fed controls. Co-agonist treatment improved glucose tolerance and increased insulin sensitivity, as observed during glucose and insulin-tolerance test, hyperinsulinemic clamp, and reduced gluconeogenesis, as observed in pyruvate-tolerance test. The effects on insulin sensitivity and lipid levels are mostly independent of the food intake or body weight lowering effect of the co-agonist.
authors.affiliation: a Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.forename: Amit
authors.initials: A
authors.lastname: Joharapurkar
authors.forename: Nirav
authors.initials: N
authors.lastname: Dhanesha
authors.forename: Samadhan
authors.initials: S
authors.lastname: Kshirsagar
authors.forename: Kartik
authors.initials: K
authors.lastname: Patel
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bahekar
authors.forename: Gaurang
authors.initials: G
authors.lastname: Shah
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain
mesh_terms: D000818:Animals; D001066:Appetite / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects*; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism; D004032:Diet; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005934:Glucagon / Q000819:agonists* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D005943:Gluconeogenesis / Q000187:drug effects; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D020738:Leptin; D018027:Receptors, Glucagon; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D002784:Cholesterol