Chronic metabolic effects of novel gut-oriented small-molecule GPR119 agonists in diet-induced obese mice

The pharmacological activation of G-protein coupled receptor-119 (GPR119) modulates glucose, energy, and hepatic lipid homeostasis in type-2 diabetes (T2D). We developed synthetic small-molecule GPR119 agonists targeting gastrointestinal receptors. This study investigates the chronic metabolic effec...

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Published in:	Biomedicine & pharmacotherapy Vol. 181; p. 117675
Main Authors:	Patil, Mohan, Thapa, Dinesh, Warne, Leon N., Lareu, Ricky R., Dallerba, Elena, Lian, Jerome, Massi, Massimiliano, Carlessi, Rodrigo, Falasca, Marco
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 01.12.2024
Subjects:	Animals Blood Glucose - drug effects Blood Glucose - metabolism Body Weight - drug effects Diet, High-Fat - adverse effects Dipeptidyl-Peptidase IV Inhibitors - pharmacology DPP-IV inhibitor Glucose Tolerance Test Hepatic steatosis Hypoglycemic Agents - pharmacology Liver - drug effects Liver - metabolism Liver - pathology Male Mice Mice, Inbred C57BL Mice, Obese Obesity Obesity - drug therapy Obesity - metabolism Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - metabolism Sitagliptin Phosphate - pharmacology Synthetic GPR119 agonists Type-2 diabetes PP MCP-1 NAFLD CDC DPP-IV DMSO GPR119 HFD ALT hr MASH CHO WAT Synthetic GPR119 agonists RIPA AUC EECs SC Type-2 diabetes NF-κB ANOVA GPCRs CMC SREBP1 BMI Obesity AST GLP-1 g T2D O-LPI DIO Hepatic steatosis IL-6 GIP DPP-IV inhibitor HCL PYY TG TNF-α H & E AMPK SEM ipGTT TP ELISA
ISSN:	0753-3322, 1950-6007, 1950-6007
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Summary:	The pharmacological activation of G-protein coupled receptor-119 (GPR119) modulates glucose, energy, and hepatic lipid homeostasis in type-2 diabetes (T2D). We developed synthetic small-molecule GPR119 agonists targeting gastrointestinal receptors. This study investigates the chronic metabolic effects of lead candidates, ps297 and ps318, individually and in combination with sitagliptin, a dipeptidyl peptidase-IV (DPP-IV) inhibitor, in high-fat diet (HFD)-induced obese (DIO) mice. In a 10-week dose-escalation protocol, DIO mice were orally treated with the investigational agents alone (10–90 mg/kg/day) and in combination with sitagliptin (20 mg/kg/day). Weekly body weight, food intake, and random blood glucose levels were monitored during the treatment phase. Post-treatment, an intraperitoneal glucose tolerance test (ipGTT), estimation of plasma biomarkers and haematological assessment were conducted. The treatment’s effect on hepatic steatosis was studied by estimating liver biomarkers and histological examinations. Ten-week sitagliptin combination therapy with the investigational entities restored incretins, insulin, and other metabolic hormonal secretions, accompanied by improved glucose homeostasis and retarded weight gain. Interestingly, monotherapy with investigational agents improved liver health by reducing liver weight, liver enzymes, and inflammation. Hepatic effects were further enhanced by co-administration of sitagliptin, evident by amelioration in hepatic steatosis endpoints such as liver weight, plasma liver enzyme concentrations, hepatic triglycerides (TG), total cholesterol (CHO), hydroxyproline content, and cytokine levels. Histopathological investigations confirmed regression in hepatic steatosis in the combination groups. These findings demonstrate the therapeutic potential of novel gut-oriented GPR119 agonists in combination with a DPP-IV inhibitor to ameliorate metabolic dysfunction-associated steatohepatitis (MASH), warranting further mechanistic investigations. [Display omitted] •Compounds ps297 and ps318 are gut-oriented GPR119 agonists.•Therapy in obese mice improved hepatic health despite minimal glycaemic impact.•Co-administration with sitagliptin enhanced GLP-1 levels, aiding glycaemic control.•Combination therapy further enhanced hepatic health by improving steatosis markers.•Histology confirmed reduced hepatic steatosis progression in combination therapy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0753-3322 1950-6007 1950-6007
DOI:	10.1016/j.biopha.2024.117675