Figure 5.

piRNA dysregulation in the context of metabolic disorders. (A) RNA-sequencing of sperm from progenitor males fed for 12 weeks on a high-fat diet (HFD) revealed alterations in the expression of many small non-coding RNAs, including piRNAs. F1 animals have reduced birth weight and decreased β-cell mass. Glucose intolerance is observed exclusively in F1 females. (B) In a piwi-mutant Drosophila model, depletion of piRNAs in the fat body, which has functions equivalent to mammalian liver, results in defects in glucose and lipid metabolism as observed in metabolic disorders such as diabetes. The link between the decline in piRNA expression and the observed metabolic phenotype remains however to be established. (C) The expression profile of piRNAs in rat islet cells changes during postnatal development and β-cell maturation. Dysregulation of piRNA levels is also observed in the islets of non-obese diabetic Goto-Kakisaki (GK) rats. In vitro experiments mimicking the changes in the level of certain piRNAs observed in GK rats result in defective insulin secretion of healthy rat islets in response to glucose. Depletion of piRNAs secondary to silencing of the PIWI-like genes Piwil2 and Piwil4 in adult islets promotes β-cell proliferation, which is normally very low in adulthood.