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Nutritional Strategy to Prevent Fatty Liver and Insulin Resistance Independent of Obesity by Reducing GIP Responses

ABSTRACT: High intakes of carbohydrates, particularly sucrose, in Western societies are associated with the development of non-alcoholic fatty liver (NAFL) and diabetes mellitus. It is unclear whether this is related to the carbohydrate quantity or the hormonal responses, particularly Glucose-dependent Insulinotropic Polypeptide (GIP) which is released in the proximal intestine. We, therefore, used the glucose-fructose dimer as proximally resorbed, 1,4-linked sucrose or distally resorbed 1,6-linked palatinose. Palatinose compared to sucrose, indeed, resulted in slower glucose absorption and reduced postprandial insulin and GIP levels. After 22 weeks of isocaloric diets, palatinose feeding prevented hepatic steatosis (48.5%) compared to sucrose and improved glucose tolerance, without differences in body composition and food intake. Ablation of GIP receptor (GIPR) signaling in Gipr-/- mice completely prevented the deleterious metabolic effects of sucrose feeding. Furthermore, our microarray analysis indicated that sucrose increased the hepatic expression of Suppressor of Cytokine Signaling 2 (SOCS2), which is involved in the growth hormone signaling pathway and participates in the development of NAFL. Our results suggest that the site of glucose absorption and the GIP response determine liver fat accumulation and insulin resistance. GIP may play a role in sucrose induced fatty liver by regulating the expression of SOCS2.

ORGANISM(S): Mus musculus

PROVIDER: GSE54723 | GEO | 2014/12/05

SECONDARY ACCESSION(S): PRJNA237500

REPOSITORIES: GEO

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Nutritional Strategy to Prevent Fatty Liver and Insulin Resistance Independent of Obesity by Reducing GIP Responses

Project description:High intakes of carbohydrates, particularly sucrose, in Western societies are associated with the development of non-alcoholic fatty liver (NAFL) and diabetes mellitus. It is unclear whether this is related to the carbohydrate quantity or the hormonal responses, particularly Glucose-dependent Insulinotropic Polypeptide (GIP) which is released in the proximal intestine. We, therefore, used the glucose-fructose dimer as proximally resorbed, 1,4-linked sucrose or distally resorbed 1,6-linked palatinose. Palatinose compared to sucrose, indeed, resulted in slower glucose absorption and reduced postprandial insulin and GIP levels. After 22 weeks of isocaloric diets, palatinose feeding prevented hepatic steatosis (48.5%) compared to sucrose and improved glucose tolerance, without differences in body composition and food intake. Ablation of GIP receptor (GIPR) signaling in Gipr-/- mice completely prevented the deleterious metabolic effects of sucrose feeding. Furthermore, our microarray analysis indicated that sucrose increased the hepatic expression of Suppressor of Cytokine Signaling 2 (SOCS2), which is involved in the growth hormone signaling pathway and participates in the development of NAFL. Our results suggest that the site of glucose absorption and the GIP response determine liver fat accumulation and insulin resistance. GIP may play a role in sucrose induced fatty liver by regulating the expression of SOCS2. Expression data from liver tissue of mice fed with isocaloric diets containing either sucrose or palatinose

2014-12-05 | E-GEOD-54723 | biostudies-arrayexpress

Hypothalamic and dorsal vagal glucose-dependent insulinotropic polypeptide receptor (GIPR) neurons employ distinct mechanisms to affect feeding

Project description:Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signalling is critical for GIP-based therapeutics to lower body weight, but pathways leveraged by GIPR agonism pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC)—brain regions critical to the control of energy balance. Hypothalamic expression of Gipr expression was not necessary for the synergistic effect of GIPR/ agonism combined with GLP-1R co-agonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (SAGIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to the parabrachial nucleus and paraventricular hypothalamic nucleusdistal brain regions. ScRNAseq and FISH analysis showed that Gipr neurons in the NTS and AP Gipr neurons were transcriptomically distinct. Peripherally-dosed fluorescent GIPR agonists (GIPRAs) revealed that GIPRA access was restricted to circumventricular organs in the CNS. Together tThese data demonstrate that while the hypothalamus, AP and NTS are key sites for Gipr expression, these subpopulations of Gipr neurons in the hypothalamus, AP and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility to peripherally administered GIPRAs, and the appetite controlling pathways they employ. These results highlight the heterogeneity of the central GIPR signalling axis, and suggest that studies aimed at understandinginto the effects of GIP pharmacology on feeding behaviour should consider the interplay of multiple regulatory pathways.

2023-04-07 | GSE228192 | GEO

Glucose-dependent Insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake

Project description:Ambiguity regarding the role of glucose-dependent insulinotropic polypeptide (GIP) in obesity arises from conflicting reports asserting that both GIP receptor (GIPR) agonism and antagonism are effective strategies for inhibiting weight gain. To enable identification and manipulation of Gipr-expressing (Gipr) cells we created GIPR-Cre knock-in mice. As GIPR-agonists have recently been reported to suppress food intake we aimed to identify central mediators of this effect. Gipr cells were identified in the arcuate, dorsomedial, and paraventricular nuclei of the hypothalamus, as confirmed by RNAscope in mouse and human. Single cell RNAseq identified clusters of hypothalamic Gipr cells exhibiting transcriptomic signatures for mural, glial and neuronal cells, the latter expressing somatostatin, but little proopiomelanocortin or agouti-related peptide. Activation of Gq-DREADDs in hypothalamic Gipr cells suppressed food intake in vivo, which was not obviously additive with concomitant GLP1R activation. These data identify hypothalamic GIPR as a target for the regulation of energy balance.

2019-07-24 | GSE134726 | GEO

Transcription profiling of human glucose-dependent insulinotropic peptide (GIP)- and adrenocorticotropin-dependent adrenal hyperplasias reveals novel targets for the study of GIP-dependent Cushings syndrome.

Project description:The mechanisms responsible for the ectopic adrenal expression of glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) in GIP-dependent Cushing's syndrome (CS) are unknown. Chronic adrenal stimulation by ACTH in Cushing's disease or GIP in GIP-dependent ACTH-independent macronodular adrenal hyperplasia both lead to the induction of genes implicated in adrenal proliferation and steroidogenesis. OBJECTIVE: The objective of the study was to identify genes differentially expressed specifically in GIP-dependent CS that could be implicated in the ectopic expression of GIPR. METHODS: We used the Affymetrix U133 plus 2.0 microarray oligochips to compare the whole genome expression profile of adrenal tissues from five cases of GIP-dependent bilateral ACTH-independent macronodular adrenal hyperplasia with CS, one case of GIP-dependent unilateral adenoma with CS, five cases of ACTH-dependent hyperplasias, and a pool of adrenals from 62 normal individuals. RESULTS: After data normalization and statistical filtering, 723 genes with differential expression were identified, including 461 genes or sequences with a known functional implication, classified in eight dominant functional classes. Specific findings include repression of perilipin, the overexpression of 13 G protein-coupled receptors, and the potential involvement of Rho-GTPases. We also isolated 94 probe sets potentially linked to the formation of GIP-dependent nodules adjacent to the diffuse hyperplasia. These included probe sets related to the linker histone H1 and repression of RXRa and CCND2. The expression profiles for eight genes were confirmed by real-time RT-PCR. CONCLUSION: This study identified an extensive series of potentially novel target candidate genes that could be implicated in the molecular mechanisms of ectopic expression of the GIPR as well as in the multistep progression of GIP-dependent CS.

2007-10-02 | E-GEOD-4060 | biostudies-arrayexpress

GIP acts on multiple signaling pathways to uncouple bone resorption and formation

Project description:Clinical investigations show that short-term treatment with gastric inhibitory polypeptide (GIP) acutely decreases serum markers of bone resorption and may increase bone formation. We report that the GIP receptor (GIPR) is expressed in human osteoclasts. Furthermore, GIP inhibits osteoclastogenesis, delays and inhibits bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways to impair nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) and nuclear factor-κB (NFκB). Human osteoblasts also express GIPR. Although GIP improves osteoblast survival via cAMP and Akt-mediated pathways, expression of osteoblast-specific genes including RUNX2 and BGLAP and bone formation is not changed by GIP. Treatment of co-cultures of osteoclasts and osteoblasts with GIP decreased bone resorption but did not change formation. Antagonizing the GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoblasts and osteoclasts. Clinical studies are needed to determine if longer-term GIPR activation uncouples bone resorption and formation and improves bone mass

2022-10-01 | GSE201100 | GEO

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

Project description:Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, has been shown to deliver enhanced glycemic control and superior weight loss compared to a selective GLP-1 receptor (GLP-1R) agonist in patients with type 2 diabetes mellitus. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes to the therapy is not fully understood. Here, hyperinsulinemic-euglycemic clamp studies were used to show that tirzepatide is a highly effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes to the insulin sensitization, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice. In the absence of GLP-1R induced weight loss, tirzepatide improved systemic insulin sensitivity by enhancing glucose disposal in WAT. To corroborate these results, chronic treatment with a long-acting GIPR agonist (LAGIPRA) was also found to enhance insulin sensitivity by increasing insulin stimulated glucose uptake in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched chain amino and keto acids in the circulation. Whole-body insulin sensitization was associated with pronounced 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 GIP and GLP-1 receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.

2021-04-29 | GSE173522 | GEO

Glucose-dependent insulinotropic polypeptide ameliorates obesity and insulin resistance by attenuating S100A8/9 in myeloid cells

Project description:Our data mark GIP as a beneficial immunoregulator during obesity and suggest a novel untapped therapeutic potential for specific targeted GIP analogs. Emerging studies suggest that glucose-dependent insulin tropic polypeptide (GIP) affect obesity-associated inflammation. Yet, whether GIP can directly regulate immune cell activity and the respective metabolic consequences remained unknown. Here, we targeted GIP-receptor-deficiency to immune cells using bone marrow (BM) chimerism approach and the reconstituted chimeric mice were subjected to a high fat diet (HFD) regimen. Mice reconstituted with Gipr-/- BM gained significantly more weight, despite similar food consumption. This was accompanied by increased epididymal adipose tissue (epiWAT) mass, adipocyte hypertrophy, enhanced hepatic steatosis, insulin resistance and significant myelopoiesis in the circulation, epiWAT and inguinal adipose tissue (ingWAT). In accordance these mice also exhibited reduced energy expenditure and ingWAT beiging. Mechanistically, impaired GIP-governed regulation of S100A8/9 in myeloid cells was responsible for the perturbed energy homeostasis, increased insulin resistance and intensified inflammatory response under nutrient overload. Collectively, our results outline a beneficial immunoregulatory role for GIP in immune cells during obesity.

2019-01-02 | GSE109371 | GEO

RNA-seq Analysis of intestinal tubes from the Unfed and Fed Xenopus laevis tadpoles

Project description:In this study, we assessed nutrient-dependent organ morphogenesis in Xenopus laevis. We performed the RNA-seq analysis of the gastrointestinal (GI) tract for both fed and unfed tadpoles to identify feeding-dependent inter-organ transmitters secreted from GI tract post-prandially during development. We found that one of the GI hormones, glucose-dependent insulinotropic polypeptide (GIP), is required for thyroid morphogenesis.

2022-01-24 | GSE194146 | GEO

Microarray analysis among non-alcoholic fatty liver, non-alcoholic steatohepatitis, and type 2 diabetes mellitus rats

Project description:Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with NAFLD and its progression. Microarrays were used to identify hepatic gene expression changes in each of these models. The goal is to identify a predictor of different NAFLD progressions. Non-alcoholic fatty liver disease (NAFLD) is recognized as a low-grade systemic inflammatory state with both hepatic and extra-hepatic manifestations. We aimed to identify common key regulators and adaptive pathways in different NAFLD phenotypes. NAFL, NASH and NAFL+T2DM rat models were used to represent simple fatty liver, fatty liver with severe hepatic manifestations, and fatty liver with severe metabolic manifestations, respectively. We applied microarray analysis to characterize the key regulators and adaptive pathways in different NAFLD phenotypes. There are 12 samples in our study which belonged to 4 groups, and each group contains 3 different samples.

2015-01-23 | E-GEOD-65220 | biostudies-arrayexpress

Gene expression in human subcutaneous adipose tissue after administration of Gastric Insulinotropic Peptide (GIP)

Project description:The intention of this clinical study was to investigate the effect of GIP administration for 240 min on gene expression in human subcutaneous adipose tissue. Three conditions have been tersted: 1. Sole infusion of GIP or NaCl as control; 2. GIP or NaCl administration under euglycemic-hyperinsulinemic clamp conditions; 3. GIP or NaCl administration under hyperglycemic-hyperinsulinemic clamp conditions to mimic the postprandial state. In each participant a complete physical examination and evaluation of medical history was performed, including an oral glucose tolerance test (oGTT) with 75 g glucose after overnight fast to ensure the metabolic state. Standard fasting laboratory and clinical chemistry evaluations were done. Synthetic human GIP (1-42) was dissolved in saline (0.9% NaCl-solution) under sterile conditions. All studies were done in the morning in the overnight fasted state (>10h since last meal). The effect of GIP administration on gene expression in subcutaneous adipose tissue was studied under 3 different conditions in a single blind design. Either the participants received only a GIP- or a saline- infusion (0.9% NaCl-isotonic solution, Fresenius, Germany) for 240 min. At different investigation days participants underwent euglycemic (EU)- and hyperglycemic (HC), hyperinsulinemic clamps combined with GIP- or placebo-infusions for 240 min at different examination days in a randomized, single-blind, crossover design. The capillary glucose concentration was 80mg/dl during EU-clamp and 140mg/dl during HC-clamp. The following numbers of treatments were performed: EU with GIP-infusion (N=9); EU with NaCl-infusion (N=9); HC with GIP-infusion (N=8), HC with NaCl-infusion (N=8); sole GIP-infusion (N=11) and sole placebo-infusion (N=11). Between examination days an intermission time of at least 7 days was maintained.

2012-09-05 | E-GEOD-40589 | biostudies-arrayexpress

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