A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila

Publication date: 10 January 2017
Source:Cell Metabolism, Volume 25, Issue 1
Author(s): Jennifer Beshel, Josh Dubnau, Yi Zhong
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.

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Teaser

Beshel and colleagues show that upd1, a mammalian leptin homolog, is expressed in the fly brain and that upd1 deletion in neurons, but not in fat tissue, increases food cue attraction, food intake, weight, and sensitivity to obesogenic conditions. This neural circuit is functionally conserved with the mammalian leptin/NPY circuit.


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