A Study on Neonatal Intake of Oleanolic Acid and Metformin in Rats (Rattus norvegicus) with Metabolic Dysfunction: Implications on Lipid Metabolism and Glucose Transport.

Mmahiine Molepo,Emmanuel Mukwevho,Ademola Ayeleso,Kennedy Erlwanger,Trevor Nyakudya

doi:10.3390/molecules23102528

Abstract

Metabolic syndrome, a cluster of different disorders which include diabetes, obesity and cardiovascular diseases, is a global epidemic that is growing at an alarming rate. The origins of disease can be traced back to early developmental stages of life. This has increased mortalities and continues to reduce life expectancies of individuals across the globe. The aim of this study was to investigate the sub-acute and long term effects of neonatal oral administration of oleanolic acid and metformin on lipids (free fatty acids, FFAs) and genes associated with lipid metabolism and glucose transport using a neonatal rat experimental model. In the first study, seven days old pups were randomly grouped into control—distilled water (DW); oleanolic acid (60 mg/kg), metformin (500 mg/kg), high fructose diet (20% w/v, HF), oleanolic acid (OA) + high fructose diet (OA + HF), and Metformin + high fructose diet (MET + HF) groups. The pups were treated for 7 days, and then terminated on postnatal day (PD) 14. In the second study, rat pups were initially treated similarly to study 1 and weaned onto normal rat chow and plain drinking water on PD 21 till they reached adulthood (PD112). Tissue and blood samples were collected for further analyses. Measurement of the levels of free fatty acids (FFAs) was done using gas chromatography-mass spectrometry. Quantitative polymerase chain reaction (qPCR) was used to analyze the gene expression of glut-4, glut-5, fas, acc-1, nrf-1 and cpt-1 in the skeletal muscle. The results showed that HF accelerated accumulation of saturated FFAs within skeletal muscles. The HF fed neonatal rats had increased stearic acid, which was associated with decreased glucose, suppressed expression of glut-4, glut-5, nrf-1 and cpt-1 genes, and increased expression of acc-1 (p < 0.01) and fas. OA + HF and MET + HF treated groups had increased mono- and polyunsaturated FFAs; oleic, and octadecadienoic acids than the HF group. These unsaturated FFAs were associated with increased glut-4, glut-5 and nrf-1 (p < 0.01) and decreased acc-1 and fas (p < 0.05) in both OA + HF and MET + HF treated groups. Conclusions: The present study shows that neonatal oral administration of oleanolic acid and metformin potentially protects against the development of fructose-induced metabolic dysfunction in the rats in both short and long time periods.

Highlights

The World Health Organization (WHO) has indicated that the world’s population living with obesity has doubled to 13% since the 1980s, affecting more than 600 million adults and 42 million children under the age of 5 years in 2014 [1]
Our findings expression more than oleanolic acid (OA) and OA + HF did (Figure 9B) Aldolase-b gene expression was suppressed showed that the rats that were treated with fructose in the neonatal period and later on in adulthood
The present study showed that neonatal intake of oleanolic acid and metformin almost prevented the fructose induced metabolic dysfunction in the rats, sub-acutely and in the long term

Summary

Introduction

The World Health Organization (WHO) has indicated that the world’s population living with obesity has doubled to 13% since the 1980s, affecting more than 600 million adults and 42 million children under the age of 5 years in 2014 [1]. As a risk factor to metabolic syndrome, obesity results in high mortalities both in children and adults, and continues to reduce life expectancies of individuals across the globe [2]. Metabolic syndrome occurs when there is a disruption of metabolic functions in which essential substances such as hormones, enzymes, proteins, or genes are expressed or produced in low or high concentrations in the body causing the metabolic network to fail [3,4] This means that metabolic syndrome occurs when there are abnormalities in the metabolic system. Interventions in lifestyle including adopting a healthy diet, increasing physical activity and weight loss were recommended as the most effective mitigation of obesity and metabolic syndrome [5]

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