Pancreatic β-cells are critical regulators of glucose homeostasis, and they vary dramatically in their glucose stimulated metabolic response and levels of insulin secretion. It is unclear whether these parameters are influenced by the developmental origin of individual β-cells. Using HOTcre, a Cre-based genetic switch that uses heat-induction to precisely control the temporal expression of transgenes, we labeled two populations of β-cells within the developing zebrafish pancreas. These populations originate in distinct pancreatic buds and exhibit gene expression profiles suggesting distinct functions during development. We find that the dorsal bud derived β-cells are quiescent and exhibit a marked decrease in insulin expression postembryonically. In contrast, ventral bud derived β-cells proliferate actively, and maintain high levels of insulin expression compared with dorsal bud derived β-cells. Therapeutic strategies to regulate β-cell proliferation and function are required to cure pathological states that result from excessive β-cell proliferation (e.g., insulinoma) or insufficient β-cell mass (e.g., diabetes mellitus). Our data reveal the existence of distinct populations of β-cells in vivo and should help develop better strategies to regulate β-cell differentiation and proliferation.

Improving the control of energy homeostasis can lower cardiovascular risk in metabolically compromised individuals. To identify new regulators of whole-body energy control, we conducted a high-throughput screen in transgenic reporter zebrafish for small molecules that modulate the expression of the fasting-inducible gluconeogenic gene pck1. We show that this in vivo strategy identified several drugs that affect gluconeogenesis in humans as well as metabolically uncharacterized compounds. Most notably, we find that the translocator protein ligands PK 11195 and Ro5-4864 are glucose-lowering agents despite a strong inductive effect on pck1 expression. We show that these drugs are activators of a fasting-like energy state and, notably, that they protect high-fat diet–induced obese mice from hepatosteatosis and glucose intolerance, two pathological manifestations of metabolic dysregulation. Thus, using a whole-organism screening strategy, this study has identified new small-molecule activators of fasting metabolism.

Rapid environmental change is predicted to compromise population survival, and the resulting strong selective pressure can erode genetic variation, making evolutionary rescue unlikely. Non-genetic inheritance may provide a solution to this problem and help explain the current lack of fit between purely genetic evolutionary models and empirical data. We hypothesize that epigenetic modifications can facilitate evolutionary rescue through ‘epigenetic buffering’. By facilitating the inheritance of novel phenotypic variants that are generated by environmental change—a strategy we call ‘heritable bet hedging’—epigenetic modifications could maintain and increase the evolutionary potential of a population. This process may facilitate genetic adaptation by preserving existing genetic variation, releasing cryptic genetic variation and/or facilitating mutations in functional loci. Although we show that examples of non-genetic inheritance are often maladaptive in the short term, accounting for phenotypic variance and non-adaptive plasticity may reveal important evolutionary implications over longer time scales. We also discuss the possibility that maladaptive epigenetic responses may be due to ‘epigenetic traps’, whereby evolutionarily novel factors (e.g. endocrine disruptors) hack into the existing epigenetic machinery. We stress that more ecologically relevant work on transgenerational epigenetic inheritance is required. Researchers conducting studies on transgenerational environmental effects should report measures of phenotypic variance, so that the possibility of both bet hedging and heritable bet hedging can be assessed. Future empirical and theoretical work is required to assess the relative importance of genetic and epigenetic variation, and their interaction, for evolutionary rescue.