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.
Highlights
Obesity is a global epidemic that continues to rise and results in the increased occurrence of associated metabolic disorders such as type 2 diabetes (T2D) and cardiovascular diseases [1e3]
In vitro studies revealed that the tesaglitazar-[F7, P34]-NPY1R agonist (NPY) conjugate selectively activates Peroxisome proliferator-activated receptor gamma (PPARg) in neuropeptide Y1 receptor (NPY1R)-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells
The amount of adipocytes is mainly determined during childhood and adolescence, and as a result, hypertrophy is the preferred mechanism for the extension of adipose tissue as the ability of de novo adipogenesis is often exceeded in obese patients [4,7]
Summary
Obesity is a global epidemic that continues to rise and results in the increased occurrence of associated metabolic disorders such as type 2 diabetes (T2D) and cardiovascular diseases [1e3]. An imbalance between energy expenditure and energy intake leads to an increased storage of lipids in adipose tissue This excess fat can either be stored in newly differentiated adipocytes, resulting in an increased cell number (hyperplasia), or in already existing adipocytes, causing enlarged cells (hypertrophy) [4]. Peroxisome proliferator-activated receptor gamma (PPARg) agonists are known for their outstanding anti-diabetic potential as they promote adipogenesis and lead to the development of small, metabolically healthy adipocytes [8e12]. These molecules further regulate a variety of processes in other cell types [13,14]. The clinical application of some PPARg agonists is accompanied by side effects including congestive heart failure, Abbreviations: T2D, type 2 diabetes; PPARa/g, peroxisome proliferator-activated receptor alpha/gamma; GPCR, G protein-coupled receptor; NPY1R, neuropeptide Y1 receptor; NPY, neuropeptide Y; tesa, tesaglitazar; tesa-NPY, [K4(GFLG-tesa), F7, P34]-NPY; Fabp, fatty acid binding protein 4; FFA, free fatty acids; Cidec, cell death-inducing DEFA-like effector c; Mcp-1, monocyte chemotactic protein
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