Indole is a major component of the bacterial exo-metabolome, and the mechanisms for its wide-ranging effects on bacterial physiology are biomedically significant although they remain poorly understood. Here, we determined how indole modulates the functions of a widely-conserved motility apparatus, the bacterial flagellum. Our experiments in Escherichia coli revealed that indole influences the rotation rates and reversals in the flagellum's direction of rotation via multiple mechanisms. At concentrations higher than 1 mM, indole decreased the membrane potential to dissipate the power available for the rotation of the motor that operates the flagellum. Below 1 mM, indole did not dissipate the membrane potential. Instead, experiments and modeling indicated that indole weakens cooperative protein interactions within the flagellar complexes to inhibit motility. The metabolite also induced reversals in the rotational direction of the motor to promote a weak chemotactic response, even when the chemotaxis response regulator, CheY, was lacking. Experiments further revealed that Indole does not require the transporter Mtr to cross the membrane and influence motor functions. Based on these findings, we propose that indole modulates intra- and inter-protein interactions in the cell to influence several physiological functions.

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WAT and mediate leptin-stimulated lipolysis is not surprising. However, Zeng and colleagues' study fills a gap in our understanding of precisely how organisms respond to an abundance of leptin. Their work also specifically demonstrates that sympathetic neurons projecting to WAT are a central trigger for leptin-mediated lipolysis. Of course, questions arise from these findings. Leptin is thought to signal through several brain areas 11 , but it remains unclear which neuronal networks sense increased blood leptin concentrations and control sympathetic relay stations to ultimately regulate lipolysis and fat mass. Notably, only half of the nerve fibres found in WAT expressed tyrosine hydroxylase, and the authors did not analyse the other half, nor the characteristics of the fat cells that the neurons innervate. Although their identities remain elusive, these neurons and fat cells hold the potential for further exciting discoveries. Future experiments should define the key brain areas that control sympathetic traffic to WAT and the molecular circuitry that controls lipolysis downstream of these effectors. Zeng et al. estimated that tyrosinehydroxylase-expressing neurons envelop between 3 and 12% of fat cells, a relatively sparse coverage. Nonetheless, the fact that optogenetic activation markedly increased lipolysis indicates that catecholamine signalling through neuro-adipose junctions has an important role in the control of lipid homeostasis. Given that leptin resistance is a common feature of obesity, it is to be hoped that this study will fuel further dissections of the brain-fat axis. It might also open a door to assessing the therapeutic potential of controlling catecholamine signalling in fat. ■

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