Multiple NTS neuron populations cumulatively suppress food intake
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eLife assessment:
Interoceptive signals from internal organs activate neurons in the nucleus tractus solitarius (NTS) to help maintain homeostasis. The authors of this paper use gain-of-function and loss-of-function experiments to examine three distinct NTS neuronal populations, individually and in combination, and find that activating (or inhibiting) combinations of these neurons have more robust effects on food intake and body weight than activating (or inhibiting) them individually. The results of this paper are convincing and solid but do not provide mechanistic insights.
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Abstract
Several discrete groups of feeding-regulated neurons in the nucleus of the solitary tract ( nucleus tractus solitarius ; NTS) suppress food intake, including avoidance-promoting neurons that express Cck (NTS Cck cells) and distinct Lepr - and Calcr -expressing neurons (NTS Lepr and NTS Calcr cells, respectively) that suppress food intake without promoting avoidance. To test potential synergies among these cell groups, we manipulated multiple NTS cell populations simultaneously. We found that activating multiple sets of NTS neurons (e.g. NTS Lepr plus NTS Calcr [NTS LC ], or NTS LC plus NTS Cck [NTS LCK ]) suppressed feeding more robustly than activating single populations. While activating groups of cells that include NTS Cck neurons promoted conditioned taste avoidance (CTA), NTS LC activation produced no CTA despite abrogating feeding. Thus, the ability to promote CTA formation represents a dominant effect but activating multiple non-aversive populations augments the suppression of food intake without provoking avoidance. Furthermore, silencing multiple NTS neuron groups augmented food intake and body weight to a greater extent than silencing single populations, consistent with the notion that each of these NTS neuron populations plays crucial and cumulative roles in the control of energy balance. We found that silencing NTS LCK neurons failed to blunt the weight-loss response to vertical sleeve gastrectomy (VSG) and that feeding activated many non-NTS LCK neurons, however, suggesting that as-yet undefined NTS cell types must make additional contributions to the restraint of feeding.
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Author Response
Reviewer #1 (Public Review):
The authors provide compelling evidence that the activation of distinct populations of NTS neurons provides stronger decreases in eating/body weight when co-activated. Avoidance is not necessarily linked to the extent of the effects but seems to depend on specific neurons which when activated, not only reduce eating but also induce avoidance reactions. The results of this study provide strong data promoting multi-targeted approaches to reduce eating and body weight in obesity. Interestingly, none of the pathways identified is necessary for the weight-reducing effect of vertical sleeve gastrectomy. Future studies will hopefully shed light on the type of neurotransmitters released by these distinct populations of NTS neurons.
We thank the reviewer for these helpful and supportive comments.
Author Response
Reviewer #1 (Public Review):
The authors provide compelling evidence that the activation of distinct populations of NTS neurons provides stronger decreases in eating/body weight when co-activated. Avoidance is not necessarily linked to the extent of the effects but seems to depend on specific neurons which when activated, not only reduce eating but also induce avoidance reactions. The results of this study provide strong data promoting multi-targeted approaches to reduce eating and body weight in obesity. Interestingly, none of the pathways identified is necessary for the weight-reducing effect of vertical sleeve gastrectomy. Future studies will hopefully shed light on the type of neurotransmitters released by these distinct populations of NTS neurons.
We thank the reviewer for these helpful and supportive comments.
Reviewer #2 (Public Review):
Prior results established that Lepr, Calcr, and Cck neurons are non-overlapping neuronal populations in the NTS that individually suppress food intake when activated. This paper examines the consequences of activating or inhibiting two or three of these populations simultaneously. Activating two or three populations inhibits food intake a body weight more than each individually. Activation of Lepr and/or Calcr neurons is not aversive based on the conditioned taste aversion test, whereas activating all three is aversive by this test, indicating that aversion due to Cck neurons activation is dominant. Vertical sleeve gastrectomy (VSG) causes weight loss, but inhibiting each of these neurons individual or all three of them does not prevent weight loss. Overall, this paper provides a solid set of results but does not provide mechanistic insight into any of the phenomena examined.
We have now added data demonstrating differences in the activation of FOS-IR in the downstream targets of our NTS neuron types, alone or in combination (new Figure 6). Our findings reveal that each population (NTSLepr, NTSCalcr, and NTSCck) activates an at least partially distinct set of neurons and that only NTSCck cells activate the known aversive PBN CGRP cells. These data suggest that the cumulative effects mediated by each of these NTS populations stem in part from their ability to activate at least partly distinct populations of downstream neurons.
Unfortunately, it is outside of the scope of this manuscript (and the realm of the currently possible) to define the neurons that mediate the response to VSG, and we have now reorganized the manuscript to clarify that our VSG data (along with the feeding-induced FOS-IR data) serve to reveal that additional populations of neurons (other than NTSLCK cells) must contribute to the restraint of feeding.
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eLife assessment:
Interoceptive signals from internal organs activate neurons in the nucleus tractus solitarius (NTS) to help maintain homeostasis. The authors of this paper use gain-of-function and loss-of-function experiments to examine three distinct NTS neuronal populations, individually and in combination, and find that activating (or inhibiting) combinations of these neurons have more robust effects on food intake and body weight than activating (or inhibiting) them individually. The results of this paper are convincing and solid but do not provide mechanistic insights.
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Reviewer #1 (Public Review):
The authors provide compelling evidence that the activation of distinct populations of NTS neurons provides stronger decreases in eating/body weight when co-activated. Avoidance is not necessarily linked to the extent of the effects but seems to depend on specific neurons which when activated, not only reduce eating but also induce avoidance reactions. The results of this study provide strong data promoting multi-targeted approaches to reduce eating and body weight in obesity. Interestingly, none of the pathways identified is necessary for the weight-reducing effect of vertical sleeve gastrectomy. Future studies will hopefully shed light on the type of neurotransmitters released by these distinct populations of NTS neurons.
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Reviewer #2 (Public Review):
Prior results established that Lepr, Calcr, and Cck neurons are non-overlapping neuronal populations in the NTS that individually suppress food intake when activated. This paper examines the consequences of activating or inhibiting two or three of these populations simultaneously. Activating two or three populations inhibits food intake a body weight more than each individually. Activation of Lepr and/or Calcr neurons is not aversive based on the conditioned taste aversion test, whereas activating all three is aversive by this test, indicating that aversion due to Cck neurons activation is dominant. Vertical sleeve gastrectomy (VSG) causes weight loss, but inhibiting each of these neurons individual or all three of them does not prevent weight loss. Overall, this paper provides a solid set of results but …
Reviewer #2 (Public Review):
Prior results established that Lepr, Calcr, and Cck neurons are non-overlapping neuronal populations in the NTS that individually suppress food intake when activated. This paper examines the consequences of activating or inhibiting two or three of these populations simultaneously. Activating two or three populations inhibits food intake a body weight more than each individually. Activation of Lepr and/or Calcr neurons is not aversive based on the conditioned taste aversion test, whereas activating all three is aversive by this test, indicating that aversion due to Cck neurons activation is dominant. Vertical sleeve gastrectomy (VSG) causes weight loss, but inhibiting each of these neurons individual or all three of them does not prevent weight loss. Overall, this paper provides a solid set of results but does not provide mechanistic insight into any of the phenomena examined.
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