To understand hindbrain pathways involved in the control of food intake, we initially defined markers for distinct subsets of nucleus tractus solitarius (NTS) neurons that respond to food intake, including those that express calcitonin receptor (Calcr), leptin receptor (LepRb), or cholecystokinin (CCK). While the chemogenetic activation of each of these NTS populations decreased short- and long-term food intake and body weight, only CCKNTS cells activated aversive CGRP-containing neurons of the parabrachial nucleus (CGRPPBN cells) and promoted a conditioned taste aversion. Indeed, the combined activation of CalcrNTS+LepRbNTS (LCNTS) cells provoked a stronger and more durable suppression of food intake and body weight than any single population but failed to promote aversive responses. Thus, while CCKNTS cells provoke aversive anorexia, CalcrNTS and LepRbNTS cells cooperatively suppress food intake without engaging aversive systems. To understand the roles for these NTS neurons in the physiologic control of food intake and energy balance, we chronically silenced them and examined food intake and energy balance. We found that silencing any single NTS population not only interfered with the response to gut peptide-mimetics, but also increased food intake and body weight, and that high-calorie food accentuated this effect. Additionally, simultaneously silencing multiple populations further increased food intake and body weight, promoting greater adiposity. These findings not only reveal the importance of both aversive and non-aversive brainstem circuits for the control of long-term energy balance, but also identify multiple synergistic hindbrain circuits that non-aversively suppress feeding. These non-aversive systems represent ideal targets for the potential treatment of obesity and associated metabolic diseases.

Disclosure

W.C. Cheng: None. E. Ndoka: None. B. Maerz: None. K.J. Roelofs: None. C.J. Rhodes: Employee; Self; AstraZeneca. R.J. Seeley: Consultant; Self; Ionis Pharmaceuticals, Inc., Kintai, Kintai, Novo Nordisk A/S, Sanofi, Scohia Pharma Inc. Research Support; Self; AstraZeneca, Novo Nordisk A/S, Pfizer Inc. Stock/Shareholder; Self; Redesign Health. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S. D. Olson: Research Support; Self; MedImmune, Inc, Novo Nordisk A/S. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc.

Funding

American Diabetes Association (1-16-PDF-021 to W.C.C.)

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