Alcohol is likely to affect neurons nonselectively, and the understanding of its action in the CNS requires elucidation of underlying neuronal circuits and associated cellular processes. We have identified a Drosophila signaling system, comprising neurons expressing neuropeptide F (NPF, a homolog of mammalian neuropeptide Y) and its receptor, NPFR1, that acutely mediates sensitivity to ethanol sedation. Flies deficient in NPF͞NPFR1 signaling showed decreased alcohol sensitivity, whereas those overexpressing NPF exhibited the opposite phenotype. Furthermore, controlled functional disruption of NPF or NPFR1 neurons in adults rapidly confers resistance to ethanol sedation. Finally, the NPF͞NPFR1 system selectively mediates sedation by ethanol vapor but not diethyl ether, indicating that the observed NPF͞NPFR1 activity reflects a specialized response to alcohol sedation rather than a general response to intoxication by sedative agents. Together, our results provide the molecular and neural basis for the strikingly similar alcohol-responsive behaviors between flies and mammals.acute ethanol response ͉ neuropeptide Y ͉ neuropeptide F receptor A lcohol, a widely abused drug, impacts the functioning of the CNS in diverse animals. The behavioral responses to acute alcohol exposure are remarkably similar among humans, rodents, and even fruit flies. Alcohol induces an excitatory state at lower concentrations but exerts a sedative effect at higher doses (1, 2). The current knowledge about how this drug impacts the functioning of the CNS is rather limited. Ethanol is highly soluble in both water and lipids, and is likely to act on neurons in a nonselective manner. However, the sensitivity of neurons in different neural circuits to this drug may vary greatly (3). Thus, elucidation of neuronal circuits and underlying molecular mechanisms essential for alcohol sensitivity is a prerequisite for understanding how alcohol interferes with the functioning of the CNS.Neuropeptides are a group of chemically diverse signal molecules implicated in modulating a broad spectrum of physiological processes and behaviors (4). Mammalian neuropeptide Y (NPY) is a 36 aa neuromodulator present abundantly in many regions of the CNS, and acts thorough a number of Y receptor subtypes (5). Mice lacking NPY or Y1 displayed increased ethanol consumption and resistance to alcohol sedation, whereas animals overexpressing NPY showed opposite behavioral phenotypes (6, 7). These results provide genetic evidence of a critical role of the NPY signaling system in acute ethanol response. However, the elucidation of the physiological role of the NPY system and the action sites has been difficult largely because of the complexity of mammalian models.NPY family molecules have been found in diverse organisms (8-10). Neuropeptide F (NPF) is the sole member of the NPY family in the Drosophila genome, and its action is mediated by G protein-coupled seven-transmembrane receptors related to mammalian NPY receptors (11). Both NPY and NPF are present prominently, although...

Background:The autocrine regulatory effects of apelin on self-remodeling of adipose tissue are not known. Results: Apelin enhances not only the differentiation and metabolic activity of brown adipocytes but also the browning of white adipocytes. Conclusion: Apelin-APJ signaling promotes adipose tissue browning. Significance: Apelin signaling may serve as a potential therapeutic target for obesity and associated metabolic diseases.

Enhancing brown fat activity and promoting white fat browning are attractive therapeutic strategies for treating obesity and associated metabolic disorders. To provide a comprehensive picture of the gene regulatory network in these processes, we conducted a series of transcriptome studies by RNA sequencing (RNA-seq) and quantified the mRNA and long noncoding RNA (lncRNA) changes during white fat browning (chronic cold exposure, beta-adrenergic agonist treatment, and intense exercise) and brown fat activation or inactivation (acute cold exposure or thermoneutrality, respectively). mRNA–lncRNA coexpression networks revealed dynamically regulated lncRNAs to be largely embedded in nutrient and energy metabolism pathways. We identified a brown adipose tissue–enriched lncRNA, lncBATE10, that was governed by the cAMP-cAMP response element-binding protein (Creb) axis and required for a full brown fat differentiation and white fat browning program. Mechanistically, lncBATE10 can decoy Celf1 from Pgc1α, thereby protecting Pgc1α mRNA from repression by Celf1. Together, these studies provide a comprehensive data framework to interrogate the transcriptomic changes accompanying energy homeostasis transition in adipose tissue.

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Brown adipose tissue (BAT) is specialized to burn lipids for heat generation as a natural defense against cold and obesity. Previous studies established microRNAs (miRNAs) as essential regulators of brown adipocyte differentiation, but whether miRNAs are required for the feature maintenance of mature brown adipocytes remains unknown. To address this question, we ablated Dgcr8, a key regulator of the miRNA biogenesis pathway, in mature brown as well as in white adipocytes. Adipose tissue–specific Dgcr8 knockout mice displayed enlarged but pale interscapular brown fat with decreased expression of genes characteristic of brown fat and were intolerant to cold exposure. Primary brown adipocyte cultures in vitro confirmed that miRNAs are required for marker gene expression in mature brown adipocytes. We also demonstrated that miRNAs are essential for the browning of subcutaneous white adipocytes in vitro and in vivo. Using this animal model, we performed miRNA expression profiling analysis and identified a set of BAT-specific miRNAs that are upregulated during brown adipocyte differentiation and enriched in brown fat compared with other organs. We identified miR-182 and miR-203 as new regulators of brown adipocyte development. Taken together, our study demonstrates an essential role of miRNAs in the maintenance as well as in the differentiation of brown adipocytes.

Human antigen R (HuR) is an essential regulator of RNA metabolism, but its function in metabolism remains unclear. This study identifies HuR as a major repressor during adipogenesis. Knockdown and overexpression of HuR in primary adipocyte culture enhances and inhibits adipogenesis in vitro, respectively. Fat-specific knockout of HuR significantly enhances adipogenic gene program in adipose tissues, accompanied by a systemic glucose intolerance and insulin resistance. HuR knockout also results in depot-specific phenotypes: it can repress myogenesis program in brown fat, enhance inflammation program in epidydimal white fat and induce browning program in inguinal white fat. Mechanistically, HuR may inhibit adipogenesis by recognizing and modulating the stability of hundreds of adipocyte transcripts including Insig1, a negative regulator during adipogenesis. Taken together, our work establishes HuR as an important posttranscriptional regulator of adipogenesis and provides insights into how RNA processing contributes to adipocyte development.

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Edited by Ulrike KutayKeywords: AID Alternative splicing RBM5 U2AF a b s t r a c t Alternative splicing is involved in functional regulation of the mutagenic enzyme activationinduced cytidine deaminase (AID). However, the molecular basis for AID splicing regulation remains undefined. Using a mini-gene-based screen in HeLa cells, we found that overexpression of RNA binding motif protein 5 (RBM5, or LUCA-15/H37) significantly promoted AID exon 4 skipping by suppressing the splicing of intron 3. The inhibitive effect of RBM5 on intron 3 splicing required a weak 3 0 -splice site (ss). Indicative of the underlying mechanism, RBM5 interfered with the binding of U2AF65 to the polypyrimidine tract at the 3 0 -ss in vitro. Our findings thus not only shed lights on the regulatory mechanism of AID exon 4 skipping, but also provide new insights into how RBM5 functions in splicing regulation.