TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding.

Autor:	Dedic N; Sumitomo Pharma America, Inc., Marlborough, MA, USA. Electronic address: nina.dedic@us.sumitomo-pharma.com., Wang L; Sumitomo Pharma America, Inc., Marlborough, MA, USA., Hajos-Korcsok E; Sumitomo Pharma America, Inc., Marlborough, MA, USA., Hecksher-Sørensen J; Gubra ApS, Hørsholm, Denmark., Roostalu U; Gubra ApS, Hørsholm, Denmark., Vickers SP; Sygnature Discovery, Nottingham, UK., Wu S; Department of Psychiatry, New York State Psychiatric Institute (NYSPI), Columbia University, NY, New York City, USA., Anacker C; Department of Psychiatry, New York State Psychiatric Institute (NYSPI), Columbia University, NY, New York City, USA., Synan C; Sumitomo Pharma America, Inc., Marlborough, MA, USA., Jones PG; Sumitomo Pharma America, Inc., Marlborough, MA, USA., Milanovic S; Sumitomo Pharma America, Inc., Marlborough, MA, USA., Hopkins SC; Sumitomo Pharma America, Inc., Marlborough, MA, USA., Bristow LJ; Sumitomo Pharma America, Inc., Marlborough, MA, USA., Koblan KS; Sumitomo Pharma America, Inc., Marlborough, MA, USA.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2024 Feb; Vol. 80, pp. 101883. Date of Electronic Publication: 2024 Jan 16.
DOI:	10.1016/j.molmet.2024.101883
Abstrakt:	Objective: Metabolic Syndrome, which can be induced or exacerbated by current antipsychotic drugs (APDs), is highly prevalent in schizophrenia patients. Recent preclinical and clinical evidence suggest that agonists at trace amine-associated receptor 1 (TAAR1) have potential as a new treatment option for schizophrenia. Intriguingly, preclinical tudies have also identified TAAR1 as a novel regulator of metabolic control. Here we evaluated the effects of three TAAR1 agonists, including the clinical development candidate ulotaront, on body weight, metabolic parameters and modulation of neurocircuits implicated in homeostatic and hedonic feeding. Methods: Effects of TAAR1 agonists (ulotaront, RO5166017 and/or RO5263397) on body weight, food intake and/or metabolic parameters were investigated in rats fed a high-fat diet (HFD) and in a mouse model of diet-induced obesity (DIO). Body weight effects were also determined in a rat and mouse model of olanzapine-, and corticosterone-induced body weight gain, respectively. Glucose tolerance was assessed in lean and diabetic db/db mice and fasting plasma glucose and insulin examined in DIO mice. Effects on gastric emptying were evaluated in lean mice and rats. Drug-induced neurocircuit modulation was evaluated in mice using whole-brain imaging of c-fos protein expression. Results: TAAR1 agonists improved oral glucose tolerance by inhibiting gastric emptying. Sub-chronic administration of ulotaront in rats fed a HFD produced a dose-dependent reduction in body weight, food intake and liver triglycerides compared to vehicle controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in HFD rats switched to ulotaront or RO5263397 treatment compared to those switched to vehicle. Chronic ulotaront administration also reduced body weight and improved glycemic control in DIO mice, and normalized corticosterone-induced body weight gain in mice. TAAR1 activation increased neuronal activity in discrete homeostatic and hedonic feeding centers located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures. Conclusion: The current data demonstrate that TAAR1 agonists, as a class, not only lack APD-induced metabolic liabilities but can reduce body weight and improve glycemic control in rodent models. The underlying mechanisms likely include TAAR1-mediated peripheral effects on glucose homeostasis and gastric emptying as well as central regulation of energy balance and food intake. Competing Interests: Declaration of competing interest ND, LW, PGJ, CS, SM, SCH, LJB and KSK are employees of Sumitomo Pharma America, Inc (formerly Sunovion Pharmaceuticals). EHK was an employee of Sunovion Pharmaceuticals at the time the studies were conducted. JHS and UR are employees of Gubra ApS. SPV is an employee of Sygnature Discovery. CA has received investigator-initiated research funding from Sumitomo Pharma America, Inc. (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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