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  • Several questions remain to be addressed The


    Several questions remain to be addressed. The hormones and metabolites that modulate expression of EERγ in the steps leading to maturation need to be identified to learn more about physiological and pathophysiological regulation of EERγ in β cells. Considering that ERRγ repressed cell cycle genes in β cells, and conversely, that high-fat-diet-fed, β cell-specific ERRγ knockout mice demonstrated increased β cell mass (Yoshihara et al., 2016), it will be useful to understand the dynamics of overexpression of ERRγ without limiting an increase in functional β cell mass. Studies are warranted to explore whether ERRγ-mediated maturation is also essential for generation of mature β cells derived from neogenesis from pancreatic ducts, or by transdifferentiation of α cells, acinar cells, hepatocytes, or intestinal cells. Will ERRγ-regulated genes be able to restore GSIS in β cells that are dedifferentiated or have lost their identity? The findings by Yoshihara et al. indicate that maintenance of oxidative phosphorylation is apparently important not only for maturation but also for endowing proper glucose responsiveness in adult β cells and provides a strong rationale for exploiting ERRγ in the long-term goal of replenishing functional human β cells to treat diabetes.
    Introduction Mature neurons have exceedingly high energy demands, requiring a continuous supply of adenosine triphosphate (ATP) for survival, excitability, as well as for the synaptic signaling and circuitry underlying different behaviors. Neurons utilize aerobic metabolism of glucose, but not fat, to meet their fluctuating needs (Escartin et al., 2006, Magistretti, 2003). Indeed, the predominance of pyruvate as the mitochondrial substrate for ATP generation suggests the possibility of a distinct neuronal mitochondrial phenotype. Defects in neuronal metabolism, especially in mitochondrial OxPhos, are associated with aging and diverse human neurological diseases (Lazarov et al., 2010, Mattson et al., 2008, Schon and Przedborski, 2011, Stoll et al., 2011, Wallace, 2005). In addition, neuronal metabolism (especially glucose uptake) and blood flow are tightly coupled with neuronal activity, an 520 3 receptor to the increased energy demand from complex tasks such as learning and memory (Howarth et al., 2012, Patel et al., 2004, Shulman et al., 2004). This neurometabolic and neurovascular coupling provides the basis for widely used brain imaging techniques including fMRI and positron emission tomography (Fox et al., 1988, Shulman et al., 2004). However, the molecular underpinnings regulating neuronal metabolism and its link to behavior remain poorly understood. Though such metabolic adaptations are at least partially mediated by transcriptional mechanisms that modulate the expression of metabolic genes (Alberini, 2009, Magistretti, 2006), the key transcription factors involved remain to be identified.
    Discussion In addition to ERRγ, closely related proteins ERRα and ERRβ have been shown as important transcriptional regulators of cellular metabolism in peripheral tissues. The three ERR proteins clearly have non-overlapping functions, since the individual ERR KO mouse exhibits different phenotypes (Alaynick et al., 2007, Luo et al., 1997, Luo et al., 2003). On the other hand they bind to overlapping loci in the genome, as illustrated in the mouse heart for ERRα and ERRγ (Dufour et al., 2007). Our current and previous studies as well as data from the Allen Brain Atlas indicate that all three ERR proteins are expressed in the brain, but with distinct time and spatial patterns (Gofflot et al., 2007, Lorke et al., 2000, Real et al., 2008). For example, ERRβ is primarily expressed in the developing brain, and ERRα expression pattern in the adult brain is more ubiquitous compared to ERRβ and ERRγ. This is significant because different brain cell types (neurons, astrocytes, oligodendrocytes, etc.) and same cell types in different brain regions and during different developmental stages exhibit diverse metabolic properties (Fünfschilling et al., 2012, Goyal et al., 2014, Vilchez et al., 2007). The nature and importance of these differences and how such differential metabolic regulation is achieved remain poorly understood. Our current study reveals that ERRγ is essential for metabolism and learning/memory of the mature neurons in the hippocampus. Future studies are needed to determine whether the three ERR proteins regulate distinct cellular metabolism, functions, and related behaviors in different cell types, brain regions, and developmental stages.