Transcriptomics may bridge the gap between GWAS and physiological studies by deciphering information residing in genes [
44]. Transcriptomic biomarkers include protein-coding RNAs (mRNAs) and non-coding RNAs (ncRNAs) that can be measured using RNA sequencing and array-based gene expression methods [
45]. Tissue-specific analyses of the mRNA transcriptome of adipocytes from visceral and subcutaneous fat cells revealed more than a thousand genes whose expression was altered in obese as compared to lean individuals [
46,
47]. Due to the rare availability of tissue samples in large epidemiological studies, alteration in the peripheral blood transcriptome was used as a valid alternative in the identification of transcriptomic biomarkers in obesity [
47]. Whole-blood mRNA levels determined by array-based transcriptional profiling were correlated with BMI in two large independent population-based cohort studies (KORA F4 and SHIP-TREND) comprising a total of 1977 individuals [
46]. The obesity-associated gene expression signatures pointed to key metabolic pathways involved in protein synthesis, enhanced cell death from proinflammatory or lipotoxic stimuli, enhanced insulin signaling, and reduced defense control against reactive oxygen species [
46]. Protein-coding genes represent less than 2% of the total genomic sequence, whereas about 98% of the DNAs are transcribed as ncRNAs [
48]. The development of high-throughput sequencing technologies allowed the identification of ncRNAs, such as miRNAs and long ncRNAs (lncRNAs) [
48]. miRNAs elicit post-transcriptional repression of gene expression and several studies suggested that specific miRNAs were differentially expressed in adipose tissue of obese individuals as compared to those with normal weight [
49]. miRNAs have shown to exert important regulatory roles in adipogenesis, adipocyte differentiation, and insulin signaling [
50,
51]. Although these findings require invasive methods for sample collection (biopsies of adipose tissue) and consequently are based on an only a limited number of participants—often from clinical studies—they provide valuable insights into the mechanistic understanding of the ongoing progressive disbalances observed during obesity progression [
52,
53]. On the other hand, circulating miRNAs (cmiRNAs) are released by tissues into the bloodstream and, therefore, are regarded as promising candidate biomarkers for further clinical application since samples can be collected by minimally invasive methods [
44]. As cmiRNAs are released into the bloodstream, they serve as key messengers between cells and tissues, participating in the metabolic organ crosstalk [
54]. A recent systematic review identified 33 cmiRNAs with dysregulated expression in serum or plasma in people with obesity compared to lean controls that have been replicated by two or more independent research groups [
55]. A majority of the genes identified via obesity-related cmiRNAs is involved in fatty acid metabolism and phosphoinositide 3-kinase (PI3K-Akt) pathways [
55]. In addition to the miRNAs, recently, lncRNAs also gained importance in obesity research as key regulators of adipogenesis, inflammation, and insulin sensitivity [
56‐
60]. For example, a functional lncRNA arising from the CEBPα locus involved in adipogenesis was shown to prevent CEBPα gene methylation, resulting in elevated expression of the CEBPα mRNA [
61]. Overall, transcriptomic studies face innumerous challenges, including the fact that the transcriptome varies by tissues and cell types as well as within these tissues and over time. Although an exciting prospect, the isolation and profiling of cmiRNAs from human samples remains challenging, mostly due to their extremely low concentrations. Differences in sample extraction, cmiRNA isolation, quantification, or profiling methods may yield inaccurate and/or non-reproducible results [
62]. More research on ncRNAs that integrates experimental and bioinformatic tools is needed to gain a better knowledge of whether they could be successfully applied in preventive and clinical care.