Abstract
BackgroundDiet-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.MethodsIn 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.ResultsWhile 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.ConclusionsOur 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.
Highlights
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
Starting with a comprehensive gene expression profile in liver tissue we identified two genes downregulated by miR-100 namely Cytochrome P450 omega-hydroxylase 4A14 (Cyp4A14) and cluster of differentiation 36 (CD36), which are known to be involved in lipid metabolism and storage
Generation of a conditional miR‐100 overexpressing transgenic mouse line To investigate the function of miR-100 in liver metabolism, we developed a conditional miR-100 transgenic mouse line for a gain-of function approach together with a specialized service provider (Genoway, Lyon, France)
Summary
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. Metabolism defines the entirety of finely regulated biochemical processes which convert fuel from food into energy to facilitate the organism’s growth, survival and development. To maintain this energetic balance, cells have to be constantly provided with energy and substrates. Smolka et al Mol Med (2021) 27:101 necessary to synthesize nucleic acids, carbohydrates, proteins and lipids This is enabled by a complex orchestra of metabolic pathways as well as nutrient sensors in tissues and organs. MiRNAs play a pivotal role as fine tuners of metabolic processes in mammals (Rottiers and Naar 2012) and several “metabomiRs” have been shown to regulate cholesterol and fatty acid metabolism as well as to influence non-alcoholic liver steatosis and insulin resistance (Gerin et al 2010; Horie et al 2010; Li et al 2020; Marquart et al 2010; NajafiShoushtari et al 2010), thereby adding a new complexity to the metabolic network
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