NPY1R-targeted peptide-mediated delivery of a dual PPARα/γ agonist to adipocytes enhances adipogenesis and prevents diabetes progression

Abstract

ObjectivePPARα/γ dual agonists have been in clinical development for the treatment of metabolic diseases including type 2 diabetes and dyslipidemia. However, severe adverse side effects led to complications in clinical trials. As most of the beneficial effects rely on the compound activity in adipocytes, the selective targeting of this cell type is a cutting-edge strategy to develop safe anti-diabetic drugs. The goal of this study was to strengthen the adipocyte-specific uptake of the PPARα/γ agonist tesaglitazar via NPY1R-mediated internalization.MethodsNPY1R-preferring peptide tesaglitazar-[F7, P34]-NPY (tesa-NPY) was synthesized by a combination of automated SPPS and manual couplings. Following molecular and functional analyses for proof of concept, cell culture experiments were conducted to monitor the effects on adipogenesis. Mice treated with peptide drug conjugates or vehicle either by gavage or intraperitoneal injection were characterized phenotypically and metabolically. Histological analysis and transcriptional profiling of the adipose tissue were performed.ResultsIn vitro studies revealed that the tesaglitazar-[F7, P34]-NPY conjugate selectively activates PPARγ in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells. In vivo studies using db/db mice demonstrated that the anti-diabetic activity of the peptide conjugate is as efficient as that of systemically administered tesaglitazar. Additionally, tesa-NPY induces adipocyte differentiation in vivo.ConclusionsThe use of the tesaglitazar-[F7, P34]-NPY conjugate is a promising strategy to apply the beneficial PPARα/γ effects in adipocytes while potentially omitting adverse effects in other tissues.

The role of peroxisome proliferator-activated receptors (PPAR) in immune responses

“…These dual agonists improve lipid parameters and reduce cardiovascular complications through PPARα in addition to the insulin-sensitizing effects mediated via PPARγ [156]. Combined with a cutting-edge approach for cell-type specific uptake of PPARα/γ dual agonists by peptide-mediated internalization and controlled release into adipocytes, these compounds could potentially reduce the intolerable side effects of PPARγ agonists and provide major benefit for the treatment of DM2 [157].…”

Shuttling of Peptide‐Drug Conjugates by G Protein‐Coupled Receptors Is Significantly Improved by Pulsed Application

“…It has received great pharmaceutical potential when the group of Reubi reported specific overexpression of the Y 1 R in breast cancer and derived metastases [27] . Moreover, the receptor has been targeted with toxophore‐loaded peptides [18] or boron‐containing peptides for boron‐neutron‐capture therapy, [17] which requires high amounts of boron delivered. Previous investigations have already characterized that the Y 1 R internalizes after ligand stimulation in an arrestin‐dependent mechanism and specific binding motifs for arrestin have been identified [21,28,29] .…”

“…Furthermore, Wittrisch et al. reported high levels of hY 1 R in human adipose tissue, 3T3‐L1 preadipocytes as well as adipocytes [18] . Hence, the Y 1 R is of great pharmaceutical interest and displays an attractive and promising drug shuttle target for both, cancer and obesity [15] …”

Bioinformatics Analysis of Key Genes and Pathways for Obesity Associated Type 2 Diabetes Mellitus as a Therapeutic Target

“…Previous studies indicated that ITGB4 [143], SEMA3D [144], FCAR (Fc fragment of IgA receptor) [145], KIT (KIT proto-oncogene, receptor tyrosine kinase) [146], PGLYRP1 [147], IL17RB [148], BIRC5 [149] and PTGS1 [150] plays an important role in asthma, but these genes might be linked with progression of obesity associated type 2 diabetes mellitus. GRK2 [151], ADCY3 [152], FASN (fatty acid synthase) [153], DGKD (diacylglycerol kinase delta) [154], DGKQ (diacylglycerol kinase theta) [154], IP6K1 [155], ANXA1 [156], SUCNR1 [157], PRNP (prion protein) [158], CXCR4 [159], CAV1 [160], LCN2 [161], AQP9 [162], NMU (neuromedin U) [163], NPY1R [164], FFAR2 [165], OSM (oncostatin M) [166] and TREM1 [167] were reported in obesity associated type 2 diabetes mellitus. UNC13B [168], PFKFB3 [169], FCN1 [170] and SLC11A1 [171] were involved in progression of type 1 diabetes, but these genes might be liable for progression of obesity associated type 2 diabetes mellitus.…”