Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding

Wenwen Cheng,David P Olson,Henriette Frikke-Schmidt,Desiree Gordian,Warren Pan,Ermelinda Ndoka,Andrew Mackinnon,Simon S Evers,Christopher J Rhodes,Jonathan N Flak,Basma Khoury,Anthony H Tsang,James L Trevaskis,Martin G Myers,Darleen A Sandoval,Randy J Seeley,Shuangcheng Wu,Karen J Roelofs ,Ian E Gonzalez ,So‐Ichiro Fukada ,Jeffrey Adams ,Clémence Blouet

doi:10.1016/j.cmet.2019.12.012

Abstract

SummaryTo understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating CalcrNTS neurons decreased food intake and body weight but (unlike neighboring CckNTS cells) failed to promote aversion, revealing that CalcrNTS neurons mediate a non-aversive suppression of food intake. While both CalcrNTS and CckNTS neurons decreased feeding via projections to the PBN, CckNTS cells activated aversive CGRPPBN cells while CalcrNTS cells activated distinct non-CGRP PBN cells. Hence, CalcrNTS cells suppress feeding via non-aversive, non-CGRP PBN targets. Additionally, silencing CalcrNTS cells blunted food intake suppression by gut peptides and nutrients, increasing food intake and promoting obesity. Hence, CalcrNTS neurons define a hindbrain system that participates in physiological energy balance and suppresses food intake without activating aversive systems.

Highlights

Obesity affects over one-third of the adult population in developed countries, leading to diabetes, cardiovascular disease, and other conditions that cause substantial morbidity and mortality
CalcrLepRbKO mice exhibited unchanged salmon calcitonin (sCT)-stimulated FOS-IR in the arcuate nucleus (ARC) (Figures S1B and S1C), and we detected increased sCT-stimulated FOS in the paraventricular hypothalamic nucleus (PVH) of CalcrSim1KO mice despite decreased PVH Calcr expression in CalcrSim1KO mice (Figures S1D and S1E). These findings suggest that most sCT-stimulated FOS in the ARC and PVH is mediated indirectly and that PVH calcitonin receptor (CALCR)
While we found that ThNTS activation failed to promote a conditioned taste aversion (CTA), activating ThNTS cells only weakly suppressed food intake compared to CalcrNTS cells; we continued to focus on CalcrNTS neurons to understand NTS cells that mediate the non-aversive suppression of food intake

Summary

Introduction

Obesity affects over one-third of the adult population in developed countries, leading to diabetes, cardiovascular disease, and other conditions that cause substantial morbidity and mortality (https://www.cdc.gov/obesity/data/adult.html).

Results

Discussion

Conclusion