A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila.
A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila.
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DOI：
10.1016/j.cmet.2016.12.013
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发表时间：
2017-01-10
期刊：
影响因子：
29
通讯作者：
Zhong Y
中科院分区：
文献类型：
--
作者：
Beshel J;Dubnau J;Zhong Y
瘦素是一种典型的脂肪源性“饱腹激素”，在体重调节中具有公认的作用。在这里，我们描述了一个功能保守的模型，遗传诱导的肥胖果蝇，通过操纵苍蝇瘦素类似物未配对1（upd 1）。出乎意料的是，细胞类型特异性敲除揭示了大脑中的upd 1，而不是脂肪组织，介导了肥胖相关的特征。扰乱果蝇脑源性upd 1基因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，体重增加。这些作用是由表达果蝇神经肽F的神经元上的无圆顶受体介导的，神经肽F是促食欲的哺乳动物神经肽Y同系物。体内双光子成像显示upd 1和domeless抑制了进食动物的这种享乐信号。沿着这一中枢回路的操作也会产生对致肥胖条件的超敏反应，强调生物易感性和环境在超重和肥胖流行中的关键相互作用。我们提出脂肪和脑源性upd/瘦素可能通过不同的神经回路控制不同的体重调节功能。
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 2-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.