MiR-100 overexpression attenuates high fat diet induced weight gain, liver steatosis, hypertriglyceridemia and development of metabolic syndrome in mice

Abstract

Background Diet-induced obesity can result in the development of a diverse spectrum of cardiovascular and metabolic diseases, including type 2 diabetes, dyslipidemia, non-alcoholic liver steatosis and atherosclerotic disease. MicroRNAs have been described to be important regulators of metabolism and disease development. Methods In the current study, we investigated the effects of ubiquitous miR-100 overexpression on weight gain and the metabolic phenotype in a newly generated transgenic mouse strain under normal chow and high fat diet and used microarray expression analysis to identify new potential target genes of miR-100. Results While transgenic overexpression of miR-100 did not significantly affect weight and metabolism under a normal diet, miR-100 overexpressing mice showed a reduced weight gain under a high fat diet compared to wildtype mice, despite an equal calorie intake. This was accompanied by less visceral and subcutaneous fat development and lover serum LDL cholesterol. In addition, transgenic miR-100 mice were more glucose tolerant and insulin sensitive and demonstrated increased energy expenditure under high fat diet feeding. A comprehensive gene expression profiling revealed the differential expression of several genes involved in lipid storage- and metabolism, among them CD36 and Cyp4A14. Our data showed a direct regulation of CD36 by miR-100, leading to a reduced fatty acid uptake in primary hepatocytes overexpressing miR-100 and the downregulation of several downstream mediators of lipid metabolism such as ACC1, FABP4, FAS and PPARγ in the liver. Conclusions Our findings demonstrate a protective role of miR-100 in high fat diet induced metabolic syndrome and liver steatosis, partially mediated by the direct repression of CD36 and attenuation of hepatic lipid storage, implicating miR-100 as a possible therapeutic target in liver steatosis.

Unveiling the Role of the Fatty Acid Binding Protein 4 in the Metabolic-Associated Fatty Liver Disease

“…The combination of n-3 long chain polyunsaturated fatty acids and flavan-3-ols prevented the high-fat high-fructose diet-induced MAFLD and liver FABP4 expression [ 131 ], suggesting an impact of FABP4 in the disease. Moreover, the reduction in the liver expression of FABP4 by the ubiquitous miR-100 overexpression was in line with the effect of this molecule protecting from high fat diet-induced liver steatosis [ 132 ]. The Huang-Qi San, a combination of three traditional Chinese medicines used for the treatment of several diseases, given its anti-oxidant, anti-diabetic, hepatoprotective, immunological and anti-inflammatory properties, reduced both plasma FABP4 levels and liver lipid accumulation in high fat diet-fed rats [ 133 ].…”

MicroRNA-100 Reduced Fetal Bovine Muscle Satellite Cell Myogenesis and Augmented Intramuscular Lipid Deposition by Modulating IGF1R

“…Transgenic mice with miR-100 overexpression demonstrated reduced weight gain and increased glucose tolerance, insulin sensitivity, and energy expenditure compared to wild-type controls on a high-fat diet, despite similar calorie intake [81]. Moreover, serum and visceral adipose miR-100 levels were lower in obese normoglycemic and type 2 diabetic human individuals compared to lean and non-diabetics [40].…”

Epigenetic Regulation of Estrogen Receptor Genes’ Expressions in Adipose Tissue in the Course of Obesity

“…The overexpression of these two miRNAs was reported in the adipose tissue of obese individuals [ 26 , 54 , 55 ]. However, preclinical studies suggested their different roles in the development of obesity-associated complications: while the overexpression of miR-100 protects against liver steatosis, hypertriglyceridemia, and the development of metabolic syndrome in mice, the obesity-related increase in miR-143 levels predisposes them to insulin resistance [ 56 , 57 ]. In our study, we found negative correlations between the expressions of these two miRNAs and ESR1 mRNA levels in the SAT of the obese study participants.…”