PPAR agonist 8

KKAy mice (male, 6-week-old, high fat and high glucose diet-induced T2DM model)^[1]

50 mg/kg

p.o.; daily; 24 days

Restored body weight to near-normal control levels, avoiding weight gain associated with RGZ treatment.
Markedly decreased plasma total cholesterol (TC) and triglyceride (TG) levels.
Surpassed RGZ in reducing fasting blood glucose and homeostatic model assessment of insulin resistance (HOMA-IR) levels.
Significantly improved oral glucose tolerance tests (OGTT) and insulin tolerance tests (ITT) area under the curve (AUC) values.
Reduced liver weight, liver weight-to-body weight ratio, hepatic TC and TG accumulation, and cholesterol deposition in liver tissue; promoted fecal cholesterol excretion; decreased plasma alanine transaminase (ALT) levels.
Ameliorated hepatic steatosis and lipid accumulation as shown by H&E and Oil Red O staining.
Upregulated hepatic mRNA expression of glucose metabolism-related genes (glucokinase (Gck), glucose transporter 2 (Glut2), insulin receptor substrate 1 (Irs1)) and cholesterol efflux genes (ATP binding cassette subfamily A member 1 (Abca1), ATP binding cassette subfamily G member 5 (Abcg5), ATP binding cassette subfamily G member 8 (Abcg8)); downregulated hepatic mRNA expression of gluconeogenic genes (glucose-6-phosphatase (G6pc), fructose-Bisphosphatase 2 (Fbp2)), cholesterol synthesis gene (3-hydroxy-3-methylglutaryl-CoA synthase 1 (Hmgcs1)), adipogenesis-related factors (cluster of differentiation 36 (Cd36), stearoyl-CoA desaturase (Scd1), ELOVL fatty acid elongase 6 (Elovl6), Pparγ1), and inflammatory cytokines (Il1α, Il1β); increased hepatic mRNA expression of Pparα and Pparδ.
Ameliorated islet hypertrophy, disorganized islet cell arrangement, and islet cholesterol accumulation; increased islet ABCA1 expression and insulin secretion.
Reduced epididymal and subcutaneous white adipose tissue (eWAT, sWAT) mass, avoided adipogenic side effects of RGZ, and ameliorated adipocyte hypertrophy and adipose tissue macrophage infiltration.