MicroRNAs Induced During Adipogenesis that Accelerate Fat Cell Development Are Downregulated in Obesity

Abstract

OBJECTIVE-We investigated the regulation and involvement of microRNAs (miRNAs) in fat cell development and obesity.RESEARCH DESIGN AND METHODS-Using miRNA microarrays, we profiled the expression of Ͼ370 miRNAs during adipogenesis of preadipocyte 3T3-L1 cells and adipocytes from leptin deficient ob/ob and diet-induced obese mice. Changes in key miRNAs were validated by RT-PCR. We further assessed the contribution of the chronic inflammatory environment in obese adipose tissue to the dysregulated miRNA expression by tumor necrosis factor (TNF)-␣ treatment of adipocytes. We functionally characterized two adipocyte-enriched miRNAs, miR-103 and miR-143, by a gain-of-function approach.RESULTS-Similar miRNAs were differentially regulated during in vitro and in vivo adipogenesis. Importantly, miRNAs that were induced during adipogenesis were downregulated in adipocytes from both types of obese mice and vice versa. These changes are likely associated with the chronic inflammatory environment, since they were mimicked by TNF-␣ treatment of differentiated adipocytes. Ectopic expression of miR-103 or miR-143 in preadipocytes accelerated adipogenesis, as measured both by the upregulation of many adipogenesis markers and by an increase in triglyceride accumulation at an early stage of adipogenesis.CONCLUSIONS-Our results provide the first experimental evidence for miR-103 function in adipose biology. The remarkable inverse regulatory pattern for many miRNAs during adipogenesis and obesity has important implications for understanding adipose tissue dysfunction in obese mice and humans and the link between chronic inflammation and obesity with insulin resistance. Diabetes 58

A chromatin perspective of adipogenesis

“…A wide number of miRNAs, such as miR-103 and miR-143 increase during in vivo and in vitro adipocyte differentiation and their ectopic expression increases adipogenesis. 109 Interestingly, these miRNAs were found to be downregulated in mouse models of obesity, thus suggesting that they play a role in phenotypic maintenance and function of mature adipose cells. Another report showed downregulation of miR-31, miR-125b-5p and miR-326 during adipocyte differentiation from adipose-derived stem cells, suggesting a role for these miRNAs in this process.…”

Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective

“…Because microRNAs (miRNAs) have been shown to be important in gene regulation, it is not surprising that they have been implicated in the development of obesity (Williams and Mitchell 2012). Therefore, the understanding of the regulatory Several miRNAs expression patterns have been profiled during adipocyte differentiation (Kajimoto et al 2006;Xie et al 2009;Ortega et al 2010), others have been linked to adipocyte phenotype, and other obesity parameters (Kajimoto et al 2006;Takanabe et al 2008;Klöting et al 2009;Xie et al 2009;Ortega et al 2010;Heneghan et al 2011;Keller et al 2011;Ortega et al 2013) (Figure 2). For example, miR-21 was strongly expressed in human adipose tissue and positively correlated with BMI (Keller et al 2011).…”

Elevated circulating microRNA-122 is associated with obesity and insulin resistance in young adults

“…Although basic studies have highlighted the significance of miRNAs in the regulation of obesity and insulin resistance (13,14,15,16), few studies have investigated circulating miRNAs levels as potential biomarkers for obesity in humans. Recently, Ortega et al (17) have revealed that plasma miR-142-3p, miR-140-5p, miR-15a, miR-520c-3p, and miR-423-5p may constitute novel biomarkers for risk estimation and classification of morbidly obese patients.…”