Blunted Vagal Cocaine- and Amphetamine-Regulated Transcript Promotes Hyperphagia and Weight Gain

Shin J Lee; Jean-Philippe Krieger; Macarena Vergara; Danielle Quinn; Molly McDougle; Alan de Araujo; Rebecca Darling; Benjamin Zollinger; Seth Anderson; Annabeth Pan; Emilie J Simonnet; Angelica Pignalosa; Myrtha Arnold; Arashdeep Singh; Wolfgang Langhans; Helen E Raybould; Guillaume de Lartigue

doi:10.1016/j.celrep.2020.01.045

Blunted Vagal Cocaine- and Amphetamine-Regulated Transcript Promotes Hyperphagia and Weight Gain

Cell Rep. 2020 Feb 11;30(6):2028-2039.e4. doi: 10.1016/j.celrep.2020.01.045.

Authors

Shin J Lee¹, Jean-Philippe Krieger², Macarena Vergara³, Danielle Quinn⁴, Molly McDougle⁵, Alan de Araujo⁶, Rebecca Darling⁷, Benjamin Zollinger⁸, Seth Anderson⁸, Annabeth Pan⁸, Emilie J Simonnet⁷, Angelica Pignalosa¹, Myrtha Arnold¹, Arashdeep Singh³, Wolfgang Langhans¹, Helen E Raybould⁷, Guillaume de Lartigue⁹

Affiliations

¹ Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.
² Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland; Department of Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
³ Department of Pharmacodynamics, Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA.
⁴ The John B. Pierce Laboratory, New Haven, CT, USA.
⁵ Department of Pharmacodynamics, Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA; The John B. Pierce Laboratory, New Haven, CT, USA.
⁶ Department of Pharmacodynamics, Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA; The John B. Pierce Laboratory, New Haven, CT, USA; Yale University, New Haven, CT, USA.
⁷ Anatomy, Physiology and Cell Biology Department School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
⁸ The John B. Pierce Laboratory, New Haven, CT, USA; Yale University, New Haven, CT, USA.
⁹ Department of Pharmacodynamics, Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA; The John B. Pierce Laboratory, New Haven, CT, USA; Yale University, New Haven, CT, USA. Electronic address: gdelartigue@ufl.edu.

Abstract

The vagus nerve conveys gastrointestinal cues to the brain to control eating behavior. In obesity, vagally mediated gut-brain signaling is disrupted. Here, we show that the cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide synthesized proportional to the food consumed in vagal afferent neurons (VANs) of chow-fed rats. CART injection into the nucleus tractus solitarii (NTS), the site of vagal afferent central termination, reduces food intake. Conversely, blocking endogenous CART action in the NTS increases food intake in chow-fed rats, and this requires intact VANs. Viral-mediated Cartpt knockdown in VANs increases weight gain and daily food intake via larger meals and faster ingestion rate. In obese rats fed a high-fat, high-sugar diet, meal-induced CART synthesis in VANs is blunted and CART antibody fails to increase food intake. However, CART injection into the NTS retains its anorexigenic effect in obese rats. Restoring disrupted VAN CART signaling in obesity could be a promising therapeutic approach.

Keywords: NTS; cholecystokinin; diet-induced obesity; food intake; ingestion; neuropeptide; nodose ganglia; nucleus tractus solitarii; vagal afferent neurons; vagus nerve.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Hyperphagia / genetics*
Male
Nerve Tissue Proteins / metabolism*
Rats
Vagus Nerve / drug effects*
Weight Gain / genetics*

Substances

Nerve Tissue Proteins
cocaine- and amphetamine-regulated transcript protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding