scholarly journals Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

2020 ◽  
Author(s):  
Paul V. Sabatini ◽  
Henriette Frikke-Schmidt ◽  
Joe Arthurs ◽  
Desiree Gordian ◽  
Anita Patel ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Food Intake ◽  
Taste Aversion ◽  
Conditioned Taste Aversion ◽  
Mechanisms Of Action ◽  
Parabrachial Nucleus ◽  
Gastric Physiology ◽  
Anorexigenic Peptide ◽  
Artificial Activation ◽  
Meal Ingestion

AbstractTo determine the function and mechanisms of action for hindbrain neurons that express GFRAL, the receptor for the anorexigenic peptide, GDF-15, we generated Gfralcre and conditional GfralCreERT mice. While signals of infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons, the artificial activation of GfralCre- expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). Additionally, activation of the smaller population of GFRAL neurons captured by the GfralCreERT allele decreased gastric emptying and produced a CTA without suppressing food intake, suggesting that GFRAL neurons primarily modulate gastric physiology and stimulate aversive responses. GFRAL neurons most strongly innervated the parabrachial nucleus (PBN), where they targeted CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated, pathophysiologic signals to the aversive suppression of nutrient uptake and absorption.

scholarly journals SUN-269 Activation of GFRAL Neurons Decreases Food Intake via Aversive Pathways

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Paul Sabatini ◽  
Henriette Frikke-Schmidt ◽  
Alan Rupp ◽  
Desiree Gordian ◽  
Martin Myers Jr ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Food Intake ◽  
Conditioned Taste Aversion ◽  
Area Postrema ◽  
Mechanisms Of Action ◽  
Parabrachial Nucleus ◽  
Peptide Mimetics ◽  
Solitary Tract ◽  
Promising Candidate ◽  
Anorexigenic Peptide

Abstract Growth and differentiation factor 15 (GDF15), an anorexigenic peptide that represents a promising candidate for anti-obesity treatment, acts via GDNF Family Receptor Alpha Like (GFRAL), which is expressed almost exclusively on a subset of neurons in the area postrema (AP). To determine the function and mechanisms of action for GFRAL neurons, we generated Gfralcre and conditional GfralCreERT mice. Although their chemogenetic (DREADD-mediated) activation promoted FOS in a variety of brainstem, hypothalamic, and limbic nuclei, GFRAL neurons projected only to the nucleus of the solitary tract (NTS) and the parabrachial nucleus (PBN), where they innervated and activated aversive/anorexigenic GCRP-expressing cells. Tetanus-toxin-mediated silencing of PBN CGRP neurons abrogated the aversive and anorexic effects of GDF15. Furthermore, while non-gastrointestinal (GI) stimuli (e.g., GDF15 and LPS, but not feeding or gut peptide mimetics) activated GFRAL neurons, chemogenetically activating these cells decreased gastric emptying, suppressed feeding, and promoted a conditioned taste aversion. These findings suggest that GFRAL neurons link non-GI anorexigenic signals to the control of gut physiology and to the aversive suppression of food intake. Additionally, because the chemogenetic activation of GFRAL neurons suppressed food intake more strongly than GDF15 in lean mice, additional modes of activating GFRAL neurons may augment the anorectic potential of GDF15.

scholarly journals GFRAL-expressing neurons suppress food intake via aversive pathways

2021 ◽  
Vol 118 (8) ◽  
pp. e2021357118
Author(s):  
Paul V. Sabatini ◽  
Henriette Frikke-Schmidt ◽  
Joe Arthurs ◽  
Desiree Gordian ◽  
Anita Patel ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Area Postrema ◽  
Mechanisms Of Action ◽  
Parabrachial Nucleus ◽  
Potential Treatment ◽  
Exciting Opportunity ◽  
Wide Range ◽  
Restricted Expression Pattern ◽  
Meal Ingestion

The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α–like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre-expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non–meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.

Two novel paradigms for the simultaneous assessment of conditioned taste aversion and food intake effects of anorexic agents

2003 ◽  
Vol 79 (4-5) ◽  
pp. 761-766 ◽  
Author(s):  
S BENOIT ◽  
E AIR ◽  
K WILMER ◽  
P MESSERSCHMIDT ◽  
K HODGE ◽  
...  
Keyword(s):  
Food Intake ◽  
Taste Aversion ◽  
Conditioned Taste Aversion ◽  
Simultaneous Assessment

2116 C-fos expression in the parabrachial nucleus after acquisition of conditioned taste aversion in the rat

1993 ◽  
Vol 18 ◽  
pp. S230
Author(s):  
Takashi Yamamoto ◽  
Tsuyoshi Shimura ◽  
Noritaka Sako ◽  
Norimi Ozaki ◽  
Nobuyuki Sakai ◽  
...  
Keyword(s):  
Taste Aversion ◽  
Conditioned Taste Aversion ◽  
Parabrachial Nucleus ◽  
Fos Expression

scholarly journals Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight

2008 ◽  
Vol 294 (2) ◽  
pp. R352-R361 ◽  
Author(s):  
Susan Aja ◽  
Leslie E. Landree ◽  
Amy M. Kleman ◽  
Susan M. Medghalchi ◽  
Aravinda Vadlamudi ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Fatty Acid ◽  
Food Intake ◽  
Taste Aversion ◽  
Conditioned Taste Aversion ◽  
Fatty Acid Synthase ◽  
Intraperitoneal Administration ◽  
Carnitine Palmitoyl Transferase ◽  
Dose Dependent

Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified. We administered compounds that target FAS or CPT-1 to mice by single icv bolus and examined acute and prolonged effects on feeding and body weight. C75 decreased food intake rapidly and potently at all doses (1–56 nmol) and dose dependently inhibited intake on day 1. Dose-dependent weight loss on day 1 persisted through 4 days of postinjection monitoring. The FAS inhibitor cerulenin produced dose-dependent (560 nmol) hypophagia for 1 day, weight loss for 2 days, and weight regain to vehicle control by day 3. The CPT-1 inhibitor etomoxir (32, 320 nmol) did not alter overall day 1 feeding. However, etomoxir attenuated the hypophagia produced by C75, indicating that CPT-1 stimulation is important for C75's effect. A novel compound, C89b, was characterized in vitro as a selective stimulator of CPT-1 that does not affect fatty acid synthesis. C89b (100, 320 nmol) decreased feeding in mice for 3 days and produced persistent weight loss for 6 days without producing conditioned taste aversion. Similarly, intraperitoneal administration decreased feeding and body weight without producing conditioned taste aversion. These results suggest a role for brain CPT-1 in the regulation of energy balance and implicate CPT-1 stimulation as a pharmacological approach to weight loss.

Dietary fibers reduce food intake by satiation without conditioned taste aversion in mice

2013 ◽  
Vol 110-111 ◽  
pp. 13-19 ◽  
Author(s):  
Rojo Rasoamanana ◽  
Patrick C. Even ◽  
Nicolas Darcel ◽  
Daniel Tomé ◽  
Gilles Fromentin
Keyword(s):  
Food Intake ◽  
Taste Aversion ◽  
Conditioned Taste Aversion ◽  
Reduce Food Intake ◽  
Dietary Fibers

Glutamate in the parabrachial nucleus of rats during conditioned taste aversion

2000 ◽  
Vol 887 (2) ◽  
pp. 413-417 ◽  
Author(s):  
Edita Bielavska ◽  
Ivan Miksik ◽  
Jiri Krivanek
Keyword(s):  
Taste Aversion ◽  
Conditioned Taste Aversion ◽  
Parabrachial Nucleus
Sign in / Sign up

Export Citation Format

Share Document