Delivery of miRNAs to the adipose organ for metabolic health

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Abstract

Despite the increasing prevalence of obesity and diabetes, there is no efficient treatment to combat these epidemics. The adipose organ is the main site for energy storage and plays a pivotal role in whole body lipid metabolism and energy homeostasis, including remodeling and dysfunction of adipocytes and adipose tissues in obesity and diabetes.

Thus, restoring and balancing metabolic functions in the adipose organ is in demand. MiRNAs represent a novel class of drugs and drug targets, as they are heavily involved in the regulation of many cellular and metabolic processes and diseases, likewise in adipocytes.

In this review, we summarize key regulatory activities of miRNAs in the adipose organ, discuss various miRNA replacement and inhibition strategies, promising delivery systems for miRNAs and reflect the future of novel miRNA-based therapeutics to target adipose tissues with the ultimate goal to combat metabolic disorders.

Introduction

The prevalence of obesity is one of the major health burdens approaching pandemic proportions worldwide [1], [2]. In 2016, the World Health Organization (WHO) has estimated that around 2 billion adults are overweight, 650 million of which are affected by obesity with a body mass index (BMI) ≥ 30 kg/m2. If the current trend continues, it is suggested that by 2025, 33 out of 53 European countries will have a prevalence of obesity over 20% of the population [3].

Obesity is a highly complex and heterogeneous disorder that is associated with an increased risk for the pathogenesis of type 2 diabetes, and the premature development of related metabolic, cardiovascular or chronic inflammatory diseases, as well as certain cancers. Among others, these diseases include dyslipidaemia, non-alcoholic fatty liver disease, chronic kidney disease, hypertension, coronary heart disease or stroke [4]. Type 2 diabetes (T2DM) is a progressive chronic metabolic disease characterized by hyperglycemia, often caused by insulin resistance in liver, adipose tissues and skeletal muscle, combined with an insufficient secretion of insulin by pancreatic β cells to compensate this resistance [4]. Currently, about 422 million people worldwide suffer from diabetes and 1.6 million deaths can be directly attributed to diabetes each year. Both the number of cases and the prevalence of diabetes have been steadily increasing over the past few decades as recently outlined by the WHO (https://www.who.int/news-room/fact-sheets/detail/diabetes; April 2021). Furthermore, patients with normal BMI and having high body fat mass belong to the normal weight obesity (NWO) category and appear to represent a new class of patients developing an enhanced risk for cardio-metabolic morbidity and mortality [4]. Indeed, the concept of NWO has its importance, since the exclusive measurement of the BMI is not sufficient to detect obesity. Waist circumference, lipid profiles and fat measures are additional needs to sensibilize patients with normal BMI and central obesity for their higher mortality risk [5], [6].

Today, lifestyle changes, diet, physical activity and multiple combination therapies are the most common interventions available to address obesity related diseases [7]. Regarding pharmacological treatment of obesity/diabetes only a few U.S. Food and Drug Administration (FDA) approved drugs are currently available, showing only limited success [8], [9].

In T2DM therapy, most of them are glucose lowering medications with metformin as initial therapy, often administered in combination with basal insulin, sulfonylurea, thiazolidinedione, dipeptidyl peptidase 4 (DPP-4) inhibitor, sodium glucose co-transporter (SGLT2) inhibitor or glucagon-like peptide-1 receptor (GLP-1 R) agonists [10]. Although highly effective, long term safety aspects and the frequent occurrence of multiple comorbidities limit the enthusiasm for available drugs and underline the need for new therapeutic options. Regarding anti-obesity therapy, four drugs are currently approved by the FDA, and all of them are to promote body weight loss in obese patients [11]. Among them are controlled-release phentermine/topiramate (sympathomimetic amine/anticonvulsant) or naltrexone/bupropion (antagonist of opioid receptors/inhibitor of noradrenaline and dopamine transporters) combination therapeutics, orlistat (inhibitor of gastric, pancreatic and diacylglycerol lipases and αβ-hydrolase 12), and liraglutide (GLP-1 receptor agonist). These drugs differ in their molecular mechanisms, efficacy and safety profiles and according to their administration guidelines a reduction of body weight of at least 5% from the baseline level is aimed at [12]. Although the medications are carefully tailored to the needs of the individual subjects, the drugs are known to exert severe adverse side effects and are insufficient in a long-term clinical perspective. In this context, it is fair to say that obesity treatment is not satisfactory so far, even if bariatric surgery is proven to be effective for patients with morbid obesity. To overcome these limitations new strategies and innovative approaches are needed to combat obesity/diabetes more efficiently. One ongoing approach in research is the discovery of novel drugs, in particular biomolecule-based agents, where protein-, lipid- or RNA-related drugs turned out to be highly promising. An equally important point concerns the exploration of new therapeutic targets. One of those targets is the adipose organ that is becoming increasingly interesting for pharmaceutical research.

Therefore, the overall aim of this review is to outline the metabolic role of adipose tissues with special emphasis on key regulatory activities of miRNAs. A brief summary of promising delivery platforms for miRNA therapeutics is presented to provide an overview of different nanoparticle classes. Finally, we discuss recent progress in the development of miRNA therapeutics and critically reflect the future of novel miRNA based therapies to address adipose tissue dysfunction.

Section snippets

Adipose organ

The adipose organ comprises about 15–20% in males and about 20–30% in females of total body weight in healthy individuals [13], [14], and based on its location fat tissues can be divided into subcutaneous (SAT) and visceral (VAT) adipose depots. Lipids are stored within two different types of adipocytes classified as white and brown adipocytes. Interestingly, metabolically active brown adipose tissue (BAT) was only recognized more than one decade ago in healthy adult humans, but has gained

miRNAs and their role in adipose tissue

MiRNAs play important regulatory roles in many biological processes associated with obesity and T2DM, including adipocyte formation, differentiation, insulin regulation as well as carbohydrate and fat metabolism [53]. During adipogenesis miRNAs can accelerate or inhibit adipocyte differentiation and hence regulate fat cell development. In obese adipose tissue a dysregulation of miRNAs was identified by several reports [54]. Therefore, normalizing miRNA insufficiencies by either inhibiting or

miRNA based therapeutic strategies

For the purpose of miRNA-based therapy two different pharmaceutical approaches prevail. The first one is to use miRNA inhibitors, which are single-stranded antisense miRNA oligonucleotides (AMOs) that have a complementary sequence to the targeted miRNA thereby preventing miRNA binding to its endogenous mRNA targets. This approach is typically referred to as antagonist therapy. The second one concerns the use of miRNA mimics which are double-stranded oligonucleotides that have the function to

Delivery routes, targeting strategies and clinical translation

One of the greatest challenges in drug delivery is to reach the specific target tissue. After systemic administration the drug carriers should remain in the circulation till they reach their desired target. On site, the delivery system has to cross physical and biological barriers depending on the target tissue. In case of miRNAs, the delivery vehicle has to protect its cargo from rapid degradation by nucleases that are abundantly present in the blood stream. Once in contact with biological

Discussion

MiRNAs are deeply involved in many cellular processes, and their dysregulation actively causes various pathological diseases. Therefore, they are highly interesting candidates as therapeutics or as therapeutic targets.

However, miRNA mimics and inhibitors in therapeutic applications typically require a delivery system to improve their stability and efficiency in vivo and to enhance their therapeutic index. This additional necessity of a delivery system was supposed to be a disadvantage in the

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

This work was supported by Gottfried Schatz Research Center, Medical University of Graz, Austria; CNRS, France; Institute for Diabetes and Cancer (IDC) at the Helmholtz Zentrum München, Germany; German Center for Diabetes Research (DZD), Germany; FP7-HEALTH DIABAT (HEALTH-F2-2011-278373); French Agence Nationale de la Recherche (ANR-10-BLAN-1105 miRBAT).

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