Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons.

Perez CI, Luis-Islas J, Lopez A, Diaz X, Molina O, Arroyo B, Moreno MG, Lievana EG, Fonseca E, Castañeda-Hernández G, Gutierrez R

PloS one24 Apr 2024Cited by 4 (Europe PMC)

PMID38656972PMCIDPMC11042726DOI10.1371/journal.pone.0300544PepBankPUB-38656972

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Summary

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study11

10 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In rats, tesofensine induced greater weight loss in obese animals than lean animals.
In plain wordsIn rats, tesofensine caused more weight loss in obese rats than lean rats.
Peptide
Tesofensine
Outcome
IncreaseWeight loss in obese versus lean rats
Study
ratn: not reported in source
rats
Comparator
Lean rats
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH.
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697201
02AnimalAnimal study (in vivo)Mechanism
In rats, tesofensine differentially modulated lateral hypothalamic neuronal ensembles and population activity.
In plain wordsIn rats, tesofensine changed activity patterns in the lateral hypothalamus.
Peptide
Tesofensine
Outcome
MixedLateral hypothalamic neuronal activity
Study
ratn: not reported in source
rats
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH.
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697202
03AnimalAnimal study (in vivo)Mechanism
In transgenic mice, tesofensine inhibited a subset of lateral hypothalamic GABAergic neurons.
In plain wordsIn mice, tesofensine reduced activity in some GABAergic neurons in the lateral hypothalamus.
Peptide
Tesofensine
Outcome
DecreaseLH GABAergic neuron activity
Study
mousen: not reported in source
Vgat-ChR2 and Vgat-IRES-cre transgenic mice
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons,
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697203
04AnimalAnimal study (in vivo)Mechanism
In transgenic mice, tesofensine reduced the ability of lateral hypothalamic GABAergic neurons to promote feeding.
In plain wordsIn mice, tesofensine reduced the ability of these hypothalamic neurons to promote eating.
Peptide
Tesofensine
Outcome
DecreaseNeuron-driven feeding behavior
Study
mousen: not reported in source
Vgat-ChR2 and Vgat-IRES-cre transgenic mice
Outcome group
Appetite and food intake · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior,
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697204
05AnimalAnimal study (in vivo)Safety outcome
In the rodent study, tesofensine caused few, if any, head-weaving stereotypies at therapeutic doses, unlike phentermine.
In plain wordsIn rodents, tesofensine caused few, if any, head-weaving movements at therapeutic doses, unlike phentermine.
Peptide
Tesofensine
Outcome
DecreaseHead-weaving stereotypy
Study
mice and ratsn: not reported in source
rodent study
Comparator
Phentermine
Outcome group
Adverse events · Nervous system and cognition
Studied dose
therapeutic dosesAs given in this study (mice and rats).
Source sentences
Summary
Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses.
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697206
06AnimalAnimal study (in vivo)Efficacy outcome
In the rodent study, tesofensine prolonged weight loss induced by 5-HTP.
In plain wordsIn rodents, adding tesofensine prolonged weight loss induced by 5-HTP.
Peptide
Tesofensine
Outcome
IncreaseDuration of 5-HTP-induced weight loss
Study
mice and ratsn: not reported in source
rodent study
Comparator
5-HTP without tesofensine
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss.
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697207
07AnimalAnimal study (in vivo)Efficacy outcome
In the rodent study, tesofensine blocked body weight rebound after 5-HTP-induced weight loss.
In plain wordsIn rodents, tesofensine prevented weight regain after weight loss induced by 5-HTP.
Peptide
Tesofensine
Outcome
DecreaseBody weight rebound
Study
mice and ratsn: not reported in source
rodent study
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss.
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697208
08AnimalAnimal study (in vivo)Mechanism
In rats tested with sucrose, tesofensine-associated appetite suppression was independent of taste aversion.
In plain wordsIn rats, tesofensine suppressed appetite independently of taste aversion in sucrose tests.
Peptide
Tesofensine
Outcome
Not applicableTaste aversion and appetite suppression
Study
ratn: not reported in source
rats
Outcome group
Appetite and food intake · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose.
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697209
09AnimalAnimal study (in vivo)Mechanism
In rats tested with sucrose, tesofensine did not directly affect sweetness perception.
In plain wordsIn rats, tesofensine did not directly change sucrose sweetness perception.
Peptide
Tesofensine
Outcome
No significant changeSweetness perception
Study
ratn: not reported in source
rats
Outcome group
Appetite and food intake · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose.
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697210
10AnimalAnimal study (in vivo)Mechanism
In rats, tesofensine did not directly affect sucrose palatability.
In plain wordsIn rats, tesofensine did not directly change how palatable sucrose was.
Peptide
Tesofensine
Outcome
No significant changeSucrose palatability
Study
ratn: not reported in source
rats
Outcome group
Appetite and food intake · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose.
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
Show in the study text Report a problemFND-3865697211

Studies that did not test the peptide alone1

In this study, Tesofensine was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Tesofensine.

11AnimalNot a test of Tesofensine aloneAnimal study (in vivo)Mechanism
In transgenic mice, chemogenetic silencing of LH GABAergic neurons enhanced tesofensine-associated food suppression.
In plain wordsIn mice, engineered silencing of these hypothalamic neurons increased food suppression associated with tesofensine.
Peptide
Tesofensine
Outcome
IncreaseFood suppression with chemogenetic neuronal silencing
Study
mousen: not reported in source
Vgat-ChR2 and Vgat-IRES-cre transgenic mice
Outcome group
Appetite and food intake · Metabolic and weight
Source sentences
Summary
In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects.
1 context sentence(design, population, supporting numbers)
Summary · context
Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH).
In this study, Tesofensine was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tesofensine.
Show in the study text Report a problemFND-3865697205

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
21 Oct 2026, 15:58 UTC
Study results updated
Version 1
21 Oct 2026, 12:50 UTC
First added · source update from Europe PMC

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