Long-term intake of 9-PAHPA or 9-OAHPA modulates favorably the basal metabolism and exerts an insulin sensitizing effect in obesogenic diet-fed mice.

Claire Vigor,Ondrej Kuda,Laurence Balas,Thierry Durand,Christine Feillet-Coudray,Florence Bernex,Béatrice Bonafos,Sylvie Gaillet,Jacques Grober,François Casas,Gilles Fouret,Jean-François Landrier,Laurence Pessemesse,Melha Benlebna,Charles Coudray

doi:10.1007/s00394-020-02391-1

Abstract

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a large family of endogenous bioactive lipids. To date, most of the studied FAHFAs are branched regioisomers of Palmitic Acid Hydroxyl Stearic Acid (PAHSA) that were reported to possess anti-diabetic and anti-inflammatory activity in humans and rodents. Recently, we have demonstrated that 9-PAHPA or 9-OAHPA intake increased basal metabolism and enhanced insulin sensitivity in healthy control diet-fed mice but induced liver damage in some mice. The present work aims to explore whether a long-term intake of 9-PAHPA or 9-OAHPA may have similar effects in obesogenic diet-fed mice. C57Bl6 mice were fed with a control or high fat-high sugar (HFHS) diets for 12 weeks. The HFHS diet was supplemented or not with 9-PAHPA or 9-OAHPA. Whole-body metabolism was explored. Glucose and lipid metabolism as well as mitochondrial activity and oxidative stress status were analyzed. As expected, the intake of HFHS diet led to obesity and lower insulin sensitivity with minor effects on liver parameters. The long-term intake of 9-PAHPA or 9-OAHPA modulated favorably the basal metabolism and improved insulin sensitivity as measured by insulin tolerance test. On the contrary to what we have reported previously in healthy mice, no markedeffect for these FAHFAs was observed on liver metabolism of obese diabetic mice. This study indicates that both 9-PAHPA and 9-OAHPA may have interesting insulin-sensitizing effects in obese mice with lower insulin sensitivity.

Highlights

The burden of nutrition-related chronic diseases is rapidly increasing worldwide [1]
The lipid fraction of the control diet was composed of 12.2% saturated fatty acids (SFA), 60.6% monounsaturated fatty acids (MUFA) and 27.3% polyunsaturated fatty acids (PUFA) and that of the high fat-high sugar (HFHS) diet was composed of 30.4% SFA, 53.4% MUFA and 16.3% PUFA
The possible explanation for this difference if that in the present study the HFHS mice may have received a lower dose of 9-PAHPA or 9-OAHPA compared to the healthy mice fed the control diet in our previous study [11]. This may be due to a lower food intake from the HFHS diet and a lower distribution of Fatty acid esters of hydroxy fatty acids (FAHFAs) in these obese mice because of their higher body weight compared to the control mice. All these results indicate that 9-PAHPA or 9-OAHPA intake may have no major effects on liver when given with a HFHS diet, in the contrary to what we previously observed with the healthy mice fed the control diet [11]

Summary

Introduction

The burden of nutrition-related chronic diseases is rapidly increasing worldwide [1]. INSERM, U1194, Network of Experimental Histology, BioCampus, CNRS, UMS3426, Montpellier, France. Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France. Overweight and obesity are the main causes of the development of metabolic disorders such as type 2 diabetes, hepatic steatosis and cardiovascular diseases, which can lead to significant morbidity and mortality [2]. The International Diabetes Federation estimated that 463 million people in 2019 were affected diabetes worldwide, representing approximately 4.2 million deaths and an estimated $760 billion in health care costs [3, 4]. Non-alcoholic fatty liver disease (NAFLD) is an other emerging global health issue which represents a potential risk factor for insulin resistance and type 2 diabetes [5]. Over 75% of patients with type 2 diabetes are afflicted of NAFLD [6]

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