Biomaterial Database

Glucagon like receptor 1/ glucagon dual agonist acutely enhanced hepatic lipid clearance and suppressed de novo lipogenesis in mice. 2017

Vijay R More, and Julie Lao, and David G McLaren, and Anne-Marie Cumiskey, and Beth Ann Murphy, and Ying Chen, and Stephen Previs, and Steven Stout, and Rajesh Patel, and Santhosh Satapati, and Wenyu Li, and Edward Kowalik, and Daphne Szeto, and Andrea Nawrocki, and Alessandro Pocai, and Liangsu Wang, and Paul Carrington

Cardiometabolic Diseases Biology- Discovery, Merck & Co., Inc., Kenilworth, NJ, United States of America.

Lipid lowering properties of glucagon have been reported. Blocking glucagon signaling leads to rise in plasma LDL levels. Here, we demonstrate the lipid lowering effects of acute dosing with Glp1r/Gcgr dual agonist (DualAG). All the experiments were performed in 25 week-old male diet-induced (60% kCal fat) obese mice. After 2 hrs of fasting, mice were injected subcutaneously with vehicle, liraglutide (25nmol/kg) and DualAG (25nmol/kg). De novo cholesterol and palmitate synthesis was measured by deuterium incorporation method using D2O. 13C18-oleate infusion was used for measuring fatty acid esterification. Simultaneous activation of Glp1r and Gcgr resulted in decrease in plasma triglyceride and cholesterol levels. DualAG enhanced hepatic LDLr protein levels, along with causing decrease in content of plasma ApoB48 and ApoB100. VLDL secretion, de novo palmitate synthesis and fatty acid esterification decreased with acute DualAG treatment. On the other hand, ketone levels were elevated with DualAG treatment, indicating increased fatty acid oxidation. Lipid relevant changes were absent in liraglutide treated group. In an acute treatment, DualAG demonstrated significant impact on lipid homeostasis, specifically on hepatic uptake, VLDL secretion and de novo synthesis. These effects collectively reveal that lipid lowering abilities of DualAG are primarily through glucagon signaling and are liver centric.

UI	MeSH Term	Description	Entries
D008099	Liver	A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.	Livers
D008297	Male		Males
D008810	Mice, Inbred C57BL	One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases.	Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D002784	Cholesterol	The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.	Epicholesterol
D005934	Glucagon	A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal GLUCAGON-LIKE PEPTIDES. Glucagon is secreted by PANCREATIC ALPHA CELLS and plays an important role in regulation of BLOOD GLUCOSE concentration, ketone metabolism, and several other biochemical and physiological processes. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1511)	Glucagon (1-29),Glukagon,HG-Factor,Hyperglycemic-Glycogenolytic Factor,Proglucagon (33-61),HG Factor,Hyperglycemic Glycogenolytic Factor
D000067756	Glucagon-Like Peptide Receptors	G-PROTEIN COUPLED CELL SURFACE RECEPTORS that bind GLUCAGON-LIKE PEPTIDES and are expressed by cells in pancreatic, intestinal, and neural tissues. These receptors regulate cellular responses to BLOOD GLUCOSE, INSULIN, and INFLAMMATION signals.	GLPR Protein,Glucagon-Like Peptide Receptor,Glucagon-Like Receptor,GLPR Proteins,Glucagon-Like Receptors,Glucagon Like Peptide Receptor,Glucagon Like Peptide Receptors,Glucagon Like Receptor,Glucagon Like Receptors,Peptide Receptor, Glucagon-Like,Peptide Receptors, Glucagon-Like,Protein, GLPR,Proteins, GLPR,Receptor, Glucagon-Like,Receptor, Glucagon-Like Peptide,Receptors, Glucagon-Like,Receptors, Glucagon-Like Peptide
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D014280	Triglycerides	An ester formed from GLYCEROL and three fatty acid groups.	Triacylglycerol,Triacylglycerols,Triglyceride
D050155	Lipogenesis	De novo fat synthesis in the body. This includes the synthetic processes of FATTY ACIDS and subsequent TRIGLYCERIDES in the LIVER and the ADIPOSE TISSUE. Lipogenesis is regulated by numerous factors, including nutritional, hormonal, and genetic elements.	Lipogeneses
D050356	Lipid Metabolism	Physiological processes in biosynthesis (anabolism) and degradation (catabolism) of LIPIDS.	Metabolism, Lipid