Beshel Jennifer, Dubnau Josh, Zhong Yi
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cell Metab. 2017 Jan 10;25(1):208-217. doi: 10.1016/j.cmet.2016.12.013.
Leptin, a typically adipose-derived "satiety hormone," has a well-established role in weight regulation. Here we describe a functionally conserved model of genetically induced obesity in Drosophila by manipulating the fly leptin analog unpaired 1 (upd1). Unexpectedly, cell-type-specific knockdown reveals upd1 in the brain, not the adipose tissue, mediates obesity-related traits. Disrupting brain-derived upd1 in flies leads to all the hallmarks of mammalian obesity: increased attraction to food cues, increased food intake, and increased weight. These effects are mediated by domeless receptors on neurons expressing Drosophila neuropeptide F, the orexigenic mammalian neuropeptide Y homolog. In vivo two-photon imaging reveals upd1 and domeless inhibit this hedonic signal in fed animals. Manipulations along this central circuit also create hypersensitivity to obesogenic conditions, emphasizing the critical interplay between biological predisposition and environment in overweight and obesity prevalence. We propose adipose- and brain-derived upd/leptin may control differing features of weight regulation through distinct neural circuits.
瘦素是一种典型的源自脂肪组织的“饱腹感激素”，在体重调节中具有既定作用。在此，我们通过操纵果蝇瘦素类似物未配对蛋白1（upd1），描述了一种在果蝇中基因诱导肥胖的功能保守模型。出乎意料的是，细胞类型特异性敲低显示，大脑而非脂肪组织中的upd1介导了肥胖相关特征。破坏果蝇大脑来源的upd1会导致哺乳动物肥胖的所有特征：对食物线索的吸引力增加、食物摄入量增加和体重增加。这些效应由表达果蝇神经肽F（促食欲的哺乳动物神经肽Y同源物）的神经元上的无穹窿受体介导。体内双光子成像显示，在进食的动物中，upd1和无穹窿会抑制这种享乐信号。沿着这条中枢回路进行的操作也会导致对致肥胖条件的超敏反应，强调了生物学易感性与环境在超重和肥胖流行中的关键相互作用。我们提出，脂肪和大脑来源的upd/瘦素可能通过不同的神经回路控制体重调节的不同特征。
