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

Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide-1 receptor 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 (TZD) rosiglitazone in obese insulin-resistant (IR) mice. Genetic and pharmacological approaches were used 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 had equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this TZD. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue, 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 improving its insulin-sensitizing efficacy at the same time.

Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.

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 functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. 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.

GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice.

Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r-null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual-receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.

Immunomodulatory effects of whole yeast cells and capsicum in weanling pigs challenged with pathogenic Escherichia coli1.

An experiment was conducted to evaluate growth performance, fecal bacterial counts, frequency of diarrhea, and clinical blood parameters in weanling pigs inoculated with enterotoxigenic Escherichia coli (ETEC) who were fed a whole yeast cell (WYC) product and capsicum, a plant essential oil. Weanling pigs (34 barrows and 30 gilts, 21 d of age, 5.90 ± 1.03 kg BW) were allotted to experimental treatments in a randomized complete block design based on litter, sex, and initial BW. Four pigs were individually housed within each containment chamber and assigned to 1 of 4 dietary treatments, which included a control diet without or with 0.2% WYC (CitriStim; ADM, Decatur, IL) or 10 ppm of capsicum (XTract 6933; Pancosma, Geneva, Switzerland), provided either alone or in combination. After receiving diets for 13 d, pigs were orally inoculated with F18+ ETEC and maintained on their assigned diets for an additional 10 d; a separate cohort of 12 pigs receiving the control diet was sham-inoculated using PBS. Body and feeder weights were recorded, and fecal swabs collected, on 0, 5, and 10 d postinoculation (DPI), with blood sampled at 0, 2, 7, and 10 DPI for isolation of peripheral blood mononuclear cells. Pigs challenged with ETEC and fed diets containing WYC or capsicum alone had a higher frequency of diarrhea when compared with pigs receiving diets without those compounds (P < 0.05). Total fecal bacterial counts in pigs fed the combination of additives were highest when compared with either additive alone (interaction, P = 0.03) at 10 DPI. Blood leukocyte counts were increased in challenged pigs receiving the combination of additives compared with all other challenged treatment groups (interaction, P = 0.04). The addition of WYC increased (main effect, P = 0.01) lymphocyte counts at 7 DPI. Proportions of CD8+ and CD4+CD8+ cells were lower in pigs fed the combination of additives compared with pigs fed either additive alone at 0 and 7 DPI. In conclusion, these data indicate that the combination of the 2 additives elicited higher ETEC shedding and circulating leukocyte counts, and reduced the proportions of cytotoxic and memory T-cells than either additive alone.