Lipidized Prolactin-Releasing Peptide as a New Potential Tool to Treat Obesity and Type 2 Diabetes Mellitus: Preclinical Studies in Rodent Models.

Lucia Mráziková,Lucie Holá,Jaroslav Kuneš,Barbora Neprašová,Blanka Železná,Lenka Maletínská,Anna Mengr,Veronika Strnadová,Andrea Popelová

doi:10.3389/fphar.2021.779962

Abstract

Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.

Highlights

Obesity, along with type 2 diabetes mellitus (T2DM), is reaching pandemic levels worldwide, and both are a prerequisite for the development of metabolic syndrome (MetS), which culminates in an increased risk of metabolic and cardiovascular diseases (Said, Mukherjee, and Whayne 2016; Engin 2017; Tune et al, 2017)
In our studies summarized in this review, various mouse and rat models with different features of MetS were used to investigate the effects of palmitoylated prolactin-releasing peptide (PrRP) analogs as potential anti-obesity and antidiabetic compounds and to explore their mechanism of action
This review summarizes our results with a novel potential anorexigenic drug, palmitoylated PrRP, showing its effects on several parameters characterizing obesity or T2DM in different rodent models

Summary

Introduction

Along with type 2 diabetes mellitus (T2DM), is reaching pandemic levels worldwide, and both are a prerequisite for the development of metabolic syndrome (MetS), which culminates in an increased risk of metabolic and cardiovascular diseases (Said, Mukherjee, and Whayne 2016; Engin 2017; Tune et al, 2017). As demonstrated in experimental models, these peptides have minimal side effects during long-term anti-obesity treatment (Arch 2015; Patel 2015; Bray et al, 2016). In their natural form, anorexigenic peptides have several disadvantages for direct use in pharmacotherapy for obesity, mainly due to their chemical instability, short half-life and low brain penetrance through the blood–brain barrier (BBB) after peripheral application. A peptidomimetic approach to modify natural peptides is currently being used for the development of promising drugs (Kumar 2019). The problem of penetration through the BBB can be solved, for example, by coupling of peptides to fatty acids, e.g., palmitic acid, resulting in increased stability and half-life in organisms (Malavolta and Cabral 2011; Salameh and Banks 2014)

Objectives

Conclusion