Abstract
BackgroundMicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by targeting specific mRNA species for degradation or interfering with translation. Specific miRNAs are key regulators of adipogenesis, and are expressed at different levels in adipose tissue from lean and obese mice. The degree of lipid accumulation and distribution of white adipose tissue differs between males and females, and it is unknown whether sex differences in adipose tissue-specific miRNA expression may contribute to this dimorphism. Typically, sex differences are attributed to hormones secreted from ovaries or testes. However, the sex chromosome complement (XX versus XY) is also a determinant of sex differences and may regulate miRNA expression in adipocytes.ResultsTo identify sex differences in adipose tissue miRNA expression and to understand the underlying mechanisms, we performed high-throughput miRNA sequencing in gonadal fat depots of the Four Core Genotypes mouse model. This model, which consists of XX female, XX male, XY female, and XY male mice, allowed us to assess independent effects of gonadal type (male vs. female) and sex chromosome complement (XX vs. XY) on miRNA expression profiles. We have also assessed the effects of a high fat diet on sex differences in adipose tissue miRNA profiles. We identified a male–female effect on the overall miRNA expression profile in mice fed a chow diet, with a bias toward higher expression in male compared to female gonadal adipose tissue. This sex bias disappeared after gonadectomy, suggesting that circulating levels of gonadal secretions modulate the miRNA expression profile. After 16 weeks of high fat diet, the miRNA expression distribution was shifted toward higher expression in XY vs. XX adipose tissue. Principal component analysis revealed that high fat diet has a substantial effect on miRNA profile variance, while gonadal secretions and sex chromosome complement each have milder effects.ConclusionsOur results demonstrate that the overall miRNA expression profile in adipose tissue is influenced by gonadal hormones and the sex chromosome complement, and that expression profiles change in response to gonadectomy and high fat diet. Differential miRNA expression profiles may contribute to sex differences in adipose tissue gene expression, adipose tissue development, and diet-induced obesity.
Highlights
MicroRNAs are small non-coding RNA molecules that regulate gene expression by targeting specific messenger RNA (mRNA) species for degradation or interfering with translation
Study design to identify sex differences in adipose tissue miRNAs under three physiological conditions To assess the effect of gonadal hormones and sex chromosomes on miRNA levels in adipose tissue, we sequenced miRNAs in the gonadal fat depot of Four Core Genotypes (FCG) mice
We assessed the effect on adipose tissue miRNA profile of high fat diet, and its interaction with sex, by comparing mice on chow and high fat diets (Fig. 1b)
Summary
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by targeting specific mRNA species for degradation or interfering with translation. Specific miRNAs are key regulators of adipogenesis, and are expressed at different levels in adipose tissue from lean and obese mice. MicroRNAs (miRNAs) are small noncoding RNA molecules that modulate gene expression by targeting mRNA transcripts for degradation or interfering with mRNA translation [1, 2]. These 21- to 22-nucleotide molecules are derived from the processing of longer mRNAs transcribed from intergenic regions or introns of proteincoding genes [3, 4]. It is generally thought that miRNAs act to fine-tune mRNA levels, but there is evidence of full repression of specific protein production in some cases [11,12,13]
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