Dataset Information

Proteomic changes in the hypothalamus after treatment with GLP-1RA, Tesaglitazar, or GLP-1RA/Tesaglitazar (GLP-1RA mediated Tesaglitazar delivery)

ABSTRACT: The peroxisome proliferator-activated receptors alpha and gamma (PPAR?/?) play important roles in the regulation of energy, lipid and glucose metabolism. Drugs targeting these proteins such as Fibrates and TZDs have both shown beneficial cardiovascular effects in clinical trials, which together with their complementary action on glucose and lipid metabolism spurred the development of PPAR?/? dual-agonists (Glitazars) for the treatment of type-2 diabetes (T2D) and dyslipidemia. While effectively improving glucose and lipid metabolism in clinical trials, the development of many Glitazars was terminated due to unfavorable effects on the cardiovascular and/or renal system. Here we evaluate a single molecule conjugate of the PPAR?/? dual-agonist Tesaglitazar covalently attached to the incretin hormone glucagon-like peptide-1 receptor agonist (GLP-1RA). We hypothesized that GLP-1-mediated delivery of Tesaglitazar as well as synergism between the two agents would lead to overal beneficial effects and decrease the TZD risk profile.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Natalie Krahmer

LAB HEAD: Natalie Krahmer

PROVIDER: PXD033653 | Pride | 2022-10-07

REPOSITORIES: Pride

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			Action	DRS
	20200918_FK_DIA-60min_Kerstin-HT_wt1-1.raw	Raw
	20200918_FK_DIA-60min_Kerstin-HT_wt1-2.raw	Raw
	20200918_FK_DIA-60min_Kerstin-HT_wt1-3.raw	Raw
	20200918_FK_DIA-60min_Kerstin-HT_wt1-4.raw	Raw
	20200918_FK_DIA-60min_Kerstin-HT_wt1-5.raw	Raw

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Publications

GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice.

Quarta Carmelo C Stemmer Kerstin K Novikoff Aaron A Yang Bin B Klingelhuber Felix F Harger Alex A Bakhti Mostafa M Bastidas-Ponce Aimee A Baugé Eric E Campbell Jonathan E JE Capozzi Megan M Clemmensen Christoffer C Collden Gustav G Cota Perla P Douros Jon J Drucker Daniel J DJ DuBois Barent B Feuchtinger Annette A Garcia-Caceres Cristina C Grandl Gerald G Hennuyer Nathalie N Herzig Stephan S Hofmann Susanna M SM Knerr Patrick J PJ Kulaj Konxhe K Lalloyer Fanny F Lickert Heiko H Liskiewicz Arek A Liskiewicz Daniela D Maity Gandhari G Perez-Tilve Diego D Prakash Sneha S Sanchez-Garrido Miguel A MA Zhang Qian Q Staels Bart B Krahmer Natalie N DiMarchi Richard D RD Tschöp Matthias H MH Finan Brian B Müller Timo D TD

Nature metabolism 20220822 8

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/ ...[more]

PMID: 35995995

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Project description:Pancreatic β-cells have the key homeostatic function of releasing insulin to keep blood glucose in the normal range. It is not fully understood how β-cell mass is determined. Ablation of a nuclear receptor, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), in mouse pancreatic β-cells results in glucose intolerance and 50% fewer β-cells during the postnatal period. By testing islets isolated from these mice and cultured β-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces β-catenin thus upregulating target genes like cyclin D1. Beta-cell expansion triggered by glucagon-like peptide 1 (GLP-1) is known to be mediated by β-catenin controlling cyclin D1. We show that in the absence of COUP-TFII, exendin-4, an agonist of the GLP-1 receptor, does not fully induce cyclin D1 expression, while overexpression of β-catenin induces cyclin D1. A marked decrease in cyclin D1 expression is detected in islets isolated from transgenic mice lacking both GLP-1 receptor and gastric inhibitory peptide receptor. COUP-TFII is therefore required for GLP-1 activation of the β-catenin-dependent pathway in pancreatic β-cells to increase β-cell number. To understand the molecular mechanisms by which COUP-TFII controls β-cell mass, we determined the RNA profile of COUP-TFII knockdown β-cells using Affymetrix oligonucleotide microarrays. Computational analysis identified clusters of genes shared by different gene regulatory Networks that are up or down regulated namely genes involved in Wnt/β-catenin signaling, insulin signaling and lipid/carbohydrate metabolism. We determined the RNA profile of COUP-TFII knockdown β-cells (832/13 INS-1 cells transfected with COUP-TFII specific siRNA) with respect to control cells (832/13 INS-1 cells transfected with scrambled siRNA) using Affymetrix expression analysis technical manual 701025Rev.5 (Affymetrix, Santa Clara, California, USA). Briefly, 1 mg of total cellular mRNA was reverse transcribed into cDNA (SuperScript Choice System Invitrogen, Carlsbad, CA) using oligo-dT primers and a T7 RNA polymerase promoter site. The cDNA was in vitro transcribed and biotin-labeled for microarray analysis using the Affymetrix IVT labeling kit. The concentration of labelled cRNA was measured using a NanoDrop ND-1000 spectrophotometer. Labeled cRNA was fragmented in a fragmentation buffer for 35 min at 94°C. The quality of labeled and fragmented cRNA was analyzed using the Agilent bioanalyzer 2100 (Van Lommel et al, 2006). Fragmented cRNA was hybridized to the rat 230 2.0 array (Affymetrix) during 16h at 45°C. Arrays were washed and stained in a fluidics station (Affymetrix) and scanned using the Affymetrix 3000 GeneScanner.