Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects

Inês Mahú,Ana I Domingos,Miguel López,Nadiya Kubasova,Imogen Morris,Carolina Temporão,Benjamin Jenkins,Albert Koulman,Carlos Cordeiro,Vitka Gres,Elsa Seixas,Tiago Rodrigues,Raquel Mendes,Ana M Sebastião,Yolanda Sanz,Eva Rial-Pensado,Francisco Corzana,Marta Olivares,Sandra H Vaz,Adelaide Fernandes ,Noelia Martínez-Sánchez ,Mafalda M A Pereira ,Pedro M S D Cal ,Gonçalo J L Bernardes ,M Felizardo

doi:10.1016/j.cmet.2020.04.013

Abstract

SummaryAnti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.

Highlights

Anti-obesity drugs in the amphetamine (AMPH) class, such as FDA-approved phentermine, are highly efficacious therapeutic compounds approved for common obesity (Cooke and Bloom, 2006; Melnikova and Wages, 2006)
No direct evidence exists regarding the in vivo origin of any cardiovascular side effects or whether a cardioneutral anti-obesity effect could result if AMPH is excluded from the brain
To directly activate sympathetic neurons. To bridge this literature gap, we utilized both electrophysiology and intracellular calcium ([Ca2+]i) imaging to probe the effects of AMPH on the excitability of neurons isolated from superior cervical ganglia (SCG)

Summary

Introduction

Anti-obesity drugs in the amphetamine (AMPH) class, such as FDA-approved phentermine, are highly efficacious therapeutic compounds approved for common obesity (Cooke and Bloom, 2006; Melnikova and Wages, 2006). The potent anti-obesity action of this class of drugs is reportedly mediated by a stimulant action in the brain that suppresses appetite and promotes hyperkinesia (Cooke and Bloom, 2006; Heal et al, 2013; Melnikova and Wages, 2006). Their anti-obesity effects are unparalleled, these drugs are addictive, and drive cardiovascular side effects, such as tachycardia and hypertension. It is so far unclear whether these side effects originate peripherally or centrally in the brain. No direct evidence exists regarding the in vivo origin of any cardiovascular side effects or whether a cardioneutral anti-obesity effect could result if AMPH is excluded from the brain

Methods

Results

Discussion

Conclusion