Expression data from from human differentiated primary adipocytes treated with GIP alone and in combination with Insulin

Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions in the presence and absence of insulin to model post-prandial and post-absorptive states. Transcriptional profiling of human adipocytes demonstrated differential gene, pathway, and upstream regulation by GIP indicative of modulation of both carbohydrate and lipid metabolism. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin. GIPR agonists increased lipolysis in the absence of insulin, an effect that was fully suppressed when co-administered with insulin. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially, by cooperating with insulin to augment glucose and lipid clearance in the fed state, while enhancing lipid release when insulin levels are reduced in the fasted state. This novel paradigm illustrates key mechanisms by which GIPR/GLP-1R agonists such as tirzepatide likely regulate adipocyte function to enhance weight loss as well as improve glucose and lipid metabolism in T2D. Expression data from from human differentiated primary adipocytes treated with GIP alone and in combination with Insulin 36 Total samples were analyzed utilizing the quantile normalization method, followed by principal component analysis (PCA) and outlier analysis to check any potential pattern or outliers among the samples. One-way ANOVA using R software was applied to the normalized mRNA expression to test the comparisons between each treatment and vehicle. For each comparison, both the p values and the fold changes were reported, and the mRNAs with p value less than 0.05 and fold change no less than 1.5 were selected for further analysis.