In a recent report Yoshihara and

In a recent report, Yoshihara and colleagues (2016) used transcriptomes derived from freshly isolated islets of 2-week-old neonatal, 6-week-old young adult, or 12-week-old adult mice to interrogate how maturation is regulated to acquire glucose responsiveness. The authors observed that estrogen-related receptor gamma (ERRγ), an orphan nuclear receptor, is upregulated during the maturation process in β cells. Three different genetically engineered mouse models, β cell-specific, inducible β cell-specific, and pancreas-specific ERRγ knockout mice, all point to the orphan nuclear receptor being important for maintaining appropriate GSIS function. A link between ERRγ, maturation, and mitochondrial biology was also identified in a previous observation that ERRγ is critical for the transition to oxidative metabolism in the postnatal heart by regulating a set of nuclear-encoded mitochondrial genes (Alaynick et al., 2007). Indeed, ERRγ-deficient β cells exhibited abnormal mitochondrial morphology and a decrease in oxygen consumption rate in response to glucose stimulation. What are the functional roles of ERRγ in β cell maturation? RNA sequencing and microarray analysis using ERRγ deficient islets revealed that the orphan nuclear receptor is involved in regulation of genes related to ATP biosynthesis, cation transport, oxidative phosphorylation, electron transport, and secretion. Interestingly, the genes which are governed by ERRγ in β cells are common among postnatal transcriptional changes that occur during maturation in islet cells. It is generally accepted that the differentiation of human induced pluripotent stem cells (hiPSCs) to functional β cells offers exciting opportunities to treat diabetes. Thus, several groups have now reported protocols for the generation of glucose-responsive functional β cells from hiPSCs (Rezania et al., 2014). Although most protocols agree that the β-like cells attain maturity and respond to glucose when transplanted under the kidney 87 6 into mice in vivo, the insulin-producing cells derived from hiPSCs in vitro manifest different degrees of immaturity and fail to respond to ambient glucose and/or hormones by secreting insulin in a manner that is comparable to native β cells, prompting the continued use of the term “β-like cells.” In previous efforts to identify markers of maturity, urocortin 3 was identified in both murine β cells and hiPSC-derived β-like cells, suggesting they possibly share identical maturation steps. Advancing these efforts further, Yoshihara et al. exploited hiPSCs, derived from the human endothelial cell line (HUVEC), to generate β-like cells and observed that overexpression of ERRγ in these cells led to improved C-peptide secretion in response to glucose stimulation that is comparable to the response in human islets. Transcriptomic analyses of these iPSC-derived β-like cells revealed that ERRγ increases expression of genes involved in the generation of precursor metabolites, oxidation reduction, electron transport complex, oxidative phosphorylation, and mitochondrial organization. Intriguingly, this single gene-induced maturation of iPSC-derived β-like cells enables the amelioration of hyperglycemia in streptozocin-induced diabetic NOD-SCID mice by transplantation of those cells under the kidney capsule in vivo. These observations provide important new clues on β cell maturation and synthesis of functional hPSC-derived β cells for potential clinical use. However, we need to understand how ERRγ is induced in β cells during the physiological maturation step in vivo (Figure 1). Weaning from fat-rich breast milk to carbohydrate-rich normal chow facilitates glucose-stimulated oxidative phosphorylation, insulin secretion, and cell replication (Stolovich-Rain et al., 2015). It has also been reported that weaning triggers islet-specific changes in microRNA expression (Jacovetti et al., 2015). The increase of miR-29b-3p attenuates Mct1, an anaerobic glycolytic enzyme like LDHA, and decrease of miR-17-5p and miR-181b-5p induces phosphofructokinase (Pfkp) and phosphatase and tensin homolog (PTEN) coincide with weaning. These microRNA alterations allow the acquisition of GSIS and also limit β cell proliferation. DNA methylation through de novo DNA methyltransferase DNMT3A is reportedly essential for postnatal functional maturation of β cells (Dhawan et al., 2015). DNMT3A binds to the promoters of hexokinase 1 and lactate dehydrogenase A (LDHA) genes and enhances GSIS. A balance between DNA methylation and demethylation also coordinates alterations in β cell function and proliferation during aging (Avrahami et al., 2015). The potential associations between ERRγ and DNA methylation or microRNA could be investigated in DNMT3A-deficient or microRNA-modified β cells. Thyroid hormone promotes GSIS by enhancing MAFA expression in immature β cells (Aguayo-Mazzucato et al., 2013), and the role of ERRγ, if any, in this process is not known. Furthermore, how neural glucose sensing, which is also required for early postnatal β cell proliferation and GSIS in adulthood (Tarussio et al., 2014), factors into this scenario is unclear. Postnatal maturation of β cells in vivo likely occurs secondary to an interplay among various factors, and it will interesting to investigate whether ERRγ is the player that holds them all together.