Developmental insults contribute to increases in non-communicable diseases, including cardiovascular diseases (CVD), diabetes mellitus (DM) and several cancers (Barouki et al., 2012; Zarean and Poursafa, 2019; Kumar et al., 2020). Inappropriate exposure to endogenous steroids or environmental steroid mimics serves as one such insult (Abruzzese et al., 2018; Puttabyatappa et al., 2017), that is known to program the metabolic axis (Cardoso and Padmanabhan, 2019).

Our studies with sheep demonstrated prenatal exposure to testosterone (T), an endogenous steroid or bisphenol A (BPA), the environmental steroid-mimic produces reproductive and metabolic perturbations that are characteristic of polycystic ovary syndrome-like phenotype in the female offspring (T (Padmanabhan and Veiga-Lopez, 2013); BPA (Veiga-Lopez et al., 2016; Padmanabhan et al., 2010)), albeit the phenotype is less severe in the BPA model. At the metabolic level, both prenatal T (Ferreira et al., 2021; Puttabyatappa and Padmanabhan, 2017) and BPA (Veiga-Lopez et al., 2016; Puttabyatappa et al., 2019)) models manifested insulin resistance and adipocyte dysfunctions (T (Cardoso et al., 2016); BPA (Veiga-Lopez et al., 2016)). Specifically, prenatal exposure to excess T, an estrogen precursor, induced dyslipidemia, peripheral insulin resistance, ectopic lipid accumulation, and an increase in the distribution of small adipocytes in female offspring (Veiga-Lopez et al., 2013a). Prenatal exposure to BPA, a xenoestrogen with estrogenic action, induced insulin resistance, adipocyte hypertrophy and adipose depot-specific disruptions in markers of adipose differentiation in female offspring.

Adipose tissue, composed of adipocytes, is primarily a fuel reservoir that also serves as an endocrine organ, secreting several adipokines that regulate other metabolic tissues like muscle, liver and pancreas. Recent research has established the role of adipose tissue as a dominant regulator of glucose homeostasis and whole-body metabolism (Luo and Liu, 2016; Maliszewska and Kretowski, 2021). The role of adipose depot as a major contributor to insulin resistance (Kim et al., 2015) is underlined by the observation that both excess of adipose, as seen in obesity (Koenen et al., 2021) and deficiency of adipose, as seen in lipodystrophy (Patni and Garg, 2022) can lead to development of insulin resistance. Similarly, aberrant changes in adipocyte differentiation such as increased adipocyte size is also associated with the development of insulin resistance (Stenkula and Erlanson-Albertsson, 2018). Because adipose tissues are compartmentalized into discrete depots and distributed throughout the body, there are functional depot-specific differences in their influence of tissue-specific insulin resistance (Luong et al., 2019). Subcutaneous adipose tissue (SAT), the fat beneath the skin and visceral adipose tissue (VAT), the intra-abdominal fat, form the major adipose depots of the body. While SAT favors uptake and storage of lipids and is associated with a metabolically healthy phenotype, VAT promotes lipid turnover and is associated with cardiometabolic disorders (Arner and Ryden, 2022). The smaller depots that are associated with specific organ systems such as the epicardiac adipose tissue (ECAT) and perirenal adipose tissue (PRAT) can influence the organs in their proximity (Lee et al., 2013). Perturbations in ECAT are associated with obesity-related insulin resistance (Iacobellis and Leonetti, 2005), a risk factor for cardiovascular diseases (Russo et al., 2018) while disruption in PRAT is associated with cardiovascular diseases and chronic kidney disease risk (Huang et al., 2020; Liu et al., 2019).

Knowledge of adipose depot-specific changes in gene transcription and their regulation are therefore much needed to delineate the roles they play in eliciting organ-specific changes in insulin sensitivity. Our recent studies with prenatal T-treated animals demonstrated adipose depot-specific transcriptional changes manifested as increased proinflammatory genes in VAT, reduced adipocyte differentiation genes in VAT and SAT, increased cardiomyocyte function gene expression in ECAT, and increased vascular related gene expression in PRAT (Dou et al., 2021a). Our studies with prenatal BPA-treated sheep, which focused only on VAT and SAT, found increased expression of genes involved in adipocyte development and differentiation and thermogenic brown/beige adipocyte development in the SAT, while in VAT proinflammatory genes and genes involved in adipogenesis and maintenance of insulin sensitivity were upregulated (Dou et al., 2020). While these results from prenatal steroid (endogenous or environmental)-treated models demonstrate depot-specific regulation, the mechanisms by which these changes are facilitated is unknown.

Non-coding RNAs (ncRNA) like long non-coding RNA (lncRNA) and microRNA (miRNA) exert epigenetic control by regulating gene expression at the transcriptional and post-translational levels and serve as sensors of environmental insults (Wei et al., 2017). Dysregulation of lncRNA (Wang et al., 2021; Luo et al., 2016; Huang et al., 2018) and miRNA (Li et al., 2019) are important regulators of the pathological response to environmental exposures. Some lncRNAs are important regulators in adipogenesis and adipocyte metabolism and several miRNAs have been implicated in metabolic diseases (Agbu and Carthew, 2021). Small nuclear RNA (snRNA) are involved in regulating gene expression by splicing (Li et al., 2021) while small nucleolar RNA (snoRNA) guide posttranscriptional modifications on ribosomal RNA and snRNA (Bratkovič et al., 2020). snRNA and snoRNA are largely unexplored but are gaining importance for their potential role in adipogenesis and metabolic health (Chao et al., 2021, 2022). Given the emerging role of ncRNA in metabolic homeostasis, we hypothesized that prenatal exposure to excess T (an endogenous androgen) or BPA (an environmental estrogen-mimic) will induce steroid and adipose depot-specific disruptions in the ncRNA landscape that are consistent with the reported transcriptomic and phenotypic outcomes.