GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice

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posted on 2023-11-07, 20:40 authored by Ellen C Furber, Karissa Hyatt, Kyla Collins, Xinxin Yu, Brian A Droz, Adrienne Holland, Jessica L. Friedrich, Samantha Wojnicki, Debra L Konkol, Libbey S O'Farrell, Hana E Baker, Tamer Coskun, Philipp E Scherer, Christine M Kusminski, Michael E Christe, Kyle W Sloop, Ricardo J Samms

Recent studies have found that GIPR agonism can enhance the metabolic efficacy of GLP-1R agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin sensitizing thiazolidinedione, rosiglitazone in obese insulin resistant (IR) mice. Genetic and pharmacological approaches were employed to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA-sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR null mice dosed with rosiglitazone displayed equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist (LAGIPRA) prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this thiazolidinedione. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue (BAT), which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while at the same time improving its insulin sensitizing efficacy.

Highlights

· Body weight gain resulting from treatment with the insulin sensitizing thiazolidinedione rosiglitazone does not require the GIPR.

· Treatment with a GIPR agonist prevents the hyperphagic and obesogenic activity of rosiglitazone.

· Activation of the GIPR improves the insulin sensitizing actions of rosiglitazone.