Effects of Oleacein on High-Fat Diet-Dependent Steatosis, Weight Gain, and Insulin Resistance in Mice

Many reports indicate that the protective action of nutraceuticals in the Mediterranean diet, against metabolic and cardiovascular diseases, can be attributed to the action of polyphenolic components of extra-virgin olive oil (EVOO). Here, we evaluated the protective effects of oleacein, one of the most abundant secoiridoids in EVOO, on the damages/metabolic alterations caused by high-fat diet (HFD) in male C57BL/6JolaHsd mice. After 5 weeks of treatment with 20 mg/kg of oleacein, body weight, glycemia, insulinemia, serum lipids, and histologic examination of liver tissue indicated a protective action of oleacein against abdominal fat accumulation, weight gain, and liver steatosis, with improvement of insulin-dependent glucose and lipid metabolism. Both serum parameters and hepatic histologic examination were altered in mice fed with HFD. By contrast, in the animals that received oleacein, plasma glucose, cholesterol and triglyceride serum levels, and liver histology were similar to controls fed with normocaloric diet. In addition, protein levels of FAS, SREBP-1, and phospho-ERK in liver were positively modulated by oleacein, indicating an improvement in liver insulin sensitivity. In a group of obese mice, treatment with oleacein determined a light, but still significant reduction of the increase in body weight, mainly due to lesser liver steatosis enlargement, associated with reduced levels of SREBP-1 and phospho-ERK and lower levels of total serum cholesterol; in these animals, altered plasma glucose and triglyceride serum levels were not reverted by oleacein. These results indicate that HFD-related hepatic insulin resistance may be partially prevented by oral administration of oleacein, suggesting a protective role of this nutraceutical against diet-dependent metabolic alterations. Additional studies are necessary to check whether oleacein can be used as an adjuvant to improve insulin sensitivity in humans.

[1]  S. Bonacci,et al.  Simple and efficient sustainable semi-synthesis of oleacein [2-(3,4-hydroxyphenyl) ethyl (3S,4E)-4-formyl-3-(2-oxoethyl)hex-4-enoate] as potential additive for edible oils. , 2018, Food chemistry.

[2]  A. Barros,et al.  Critical Review on the Significance of Olive Phytochemicals in Plant Physiology and Human Health , 2017, Molecules.

[3]  Paul W. Franks,et al.  Lifestyle precision medicine: the next generation in type 2 diabetes prevention? , 2017, BMC Medicine.

[4]  M. Agha,et al.  The rising prevalence of obesity: part A: impact on public health , 2017, International journal of surgery. Oncology.

[5]  M. D. de Angelis,et al.  Metformin causes a futile intestinal–hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state , 2017, Molecular metabolism.

[6]  M. Pozo-Bayón,et al.  Targeted Metabolomic Analysis of Polyphenols with Antioxidant Activity in Sour Guava (Psidium friedrichsthalianum Nied.) Fruit , 2016, Molecules.

[7]  J. Goldstein,et al.  Insulin induction of SREBP-1c in rodent liver requires LXRα-C/EBPβ complex , 2016, Proceedings of the National Academy of Sciences.

[8]  D. Russo,et al.  Normocaloric Diet Restores Weight Gain and Insulin Sensitivity in Obese Mice , 2016, Front. Endocrinol..

[9]  Peng-Fei Jiang,et al.  Electroacupuncture Improves Insulin Resistance by Reducing Neuroprotein Y/Agouti-Related Protein Levels and Inhibiting Expression of Protein Tyrosine Phosphatase 1B in Diet-induced Obese Rats. , 2016, Journal of acupuncture and meridian studies.

[10]  Ching‐Chang Lee,et al.  Abdominal Obesity and Insulin Resistance in People Exposed to Moderate-to-High Levels of Dioxin , 2016, PloS one.

[11]  Yuichiro Yamada,et al.  Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance , 2015, Journal of diabetes research.

[12]  C. di Loreto,et al.  Oral Administration of Oleuropein and Its Semisynthetic Peracetylated Derivative Prevents Hepatic Steatosis, Hyperinsulinemia, and Weight Gain in Mice Fed with High Fat Cafeteria Diet , 2015, International journal of endocrinology.

[13]  S. Filetti,et al.  PDE5 expression in human thyroid tumors and effects of PDE5 inhibitors on growth and migration of cancer cells , 2015, Endocrine.

[14]  I. Andreadou,et al.  Nutraceutical oleuropein supplementation prevents high fat diet-induced adiposity in mice , 2015 .

[15]  A. Brunetti,et al.  Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells , 2014, Front. Endocrinol..

[16]  G. Sindona,et al.  Biomimetic synthesis and antioxidant evaluation of 3,4-DHPEA-EDA [2-(3,4-hydroxyphenyl) ethyl (3S,4E)-4-formyl-3-(2-oxoethyl)hex-4-enoate]. , 2014, Food chemistry.

[17]  R. Maggio,et al.  Effects of the Olive-Derived Polyphenol Oleuropein on Human Health , 2014, International journal of molecular sciences.

[18]  D. Russo,et al.  Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: focus on protection against cardiovascular and metabolic diseases , 2014, Journal of Translational Medicine.

[19]  J. Flemmig,et al.  Components of a standardised olive leaf dry extract (Ph. Eur.) promote hypothiocyanite production by lactoperoxidase. , 2014, Archives of biochemistry and biophysics.

[20]  F. Costanzo,et al.  Early Effects of a Hypocaloric, Mediterranean Diet on Laboratory Parameters in Obese Individuals , 2014, Mediators of inflammation.

[21]  I. Szeto,et al.  Hydroxytyrosol prevents diet-induced metabolic syndrome and attenuates mitochondrial abnormalities in obese mice. , 2014, Free radical biology & medicine.

[22]  Shaodong Guo.  Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. , 2014, The Journal of endocrinology.

[23]  Shaodong Guo.  Decoding insulin resistance and metabolic syndrome for promising therapeutic intervention. , 2014, The Journal of endocrinology.

[24]  ChiefariEusebio,et al.  Evidence That an HMGA1 Gene Variant Associates with Type 2 Diabetes, Body Mass Index, and High-Density Lipoprotein Cholesterol in a Hispanic-American Population , 2014 .

[25]  M. Cooper,et al.  Glucose homeostasis can be differentially modulated by varying individual components of a western diet. , 2013, The Journal of nutritional biochemistry.

[26]  C. Homko,et al.  Comparison of In Vivo Effects of Insulin on SREBP-1c Activation and INSIG-1/2 in Rat Liver and Human and Rat Adipose Tissue , 2012, Obesity.

[27]  A. Fusco,et al.  The HMGA1-IGF-I/IGFBP system: a novel pathway for modulating glucose uptake. , 2012, Molecular endocrinology.

[28]  V. Koteliansky,et al.  The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals. , 2012, Cell metabolism.

[29]  S. Yoon,et al.  Oleuropein attenuates hepatic steatosis induced by high-fat diet in mice. , 2011, Journal of hepatology.

[30]  Mengwei Zang,et al.  AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. , 2011, Cell metabolism.

[31]  T. Park,et al.  Hepatoprotective effect of oleuropein in mice: mechanisms uncovered by gene expression profiling. , 2010, Biotechnology journal.

[32]  Y. Heo,et al.  Sasa borealis leaves extract improves insulin resistance by modulating inflammatory cytokine secretion in high fat diet-induced obese C57/BL6J mice , 2010, Nutrition research and practice.

[33]  Russell Keast,et al.  Biological Activities of Phenolic Compounds Present in Virgin Olive Oil , 2010, International journal of molecular sciences.

[34]  P. Sacchetta,et al.  Synthesis, biological evaluation, and molecular modeling of oleuropein and its semisynthetic derivatives as cyclooxygenase inhibitors. , 2009, Journal of agricultural and food chemistry.

[35]  W. Blaner,et al.  Transcriptional activity of the murine retinol-binding protein gene is regulated by a multiprotein complex containing HMGA1, p54 nrb/NonO, protein-associated splicing factor (PSF) and steroidogenic factor 1 (SF1)/liver receptor homologue 1 (LRH-1). , 2009, The international journal of biochemistry & cell biology.

[36]  A. Fusco,et al.  The insulin receptor: a new anticancer target for peroxisome proliferator-activated receptor-gamma (PPARgamma) and thiazolidinedione-PPARgamma agonists. , 2008, Endocrine-related cancer.

[37]  Richard N Redinger,et al.  The pathophysiology of obesity and its clinical manifestations. , 2007, Gastroenterology & hepatology.

[38]  C. Byrne,et al.  Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease (NAFLD). , 2007, Drug discovery today.

[39]  S. Kahn,et al.  Mechanisms linking obesity to insulin resistance and type 2 diabetes , 2006, Nature.

[40]  N. Kaplowitz,et al.  Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model. , 2006, Journal of hepatology.

[41]  R. Keast,et al.  Phytochemistry: Ibuprofen-like activity in extra-virgin olive oil , 2005, Nature.

[42]  R. Nucci,et al.  Olea europaea L. leaf extract and derivatives: antioxidant properties. , 2002, Journal of agricultural and food chemistry.

[43]  J. Goldstein,et al.  The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor , 1997, Cell.

[44]  M. Servili,et al.  Simple and hydrolyzable compounds in virgin olive oil. 3. Spectroscopic characterizations of the secoiridoid derivatives. , 1993 .

[45]  R. Kushner,et al.  Introduction: The State of Obesity in 2017. , 2018, The Medical clinics of North America.

[46]  M. Malloy,et al.  Evidence that an HMGA1 gene variant associates with type 2 diabetes, body mass index, and high-density lipoprotein cholesterol in a Hispanic-American population. , 2014, Metabolic syndrome and related disorders.

[47]  D. Foti,et al.  The insulin receptor: a new anticancer target for peroxisome proliferator-activated receptor-g (PPARg) and thiazolidinedione- PPARg agonists , 2008 .