MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect

A glucose-lowering medication that acts by a different mechanism than metformin, or other approved diabetes medications, can supplement monotherapies when patients fail to meet blood glucose goals. We examined the actions underlying the effects of an insulin sensitizer, tolimidone (MLR-1023) and inv...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Candida J. Rebello, Ann A. Coulter, Andrew G. Reaume, Weina Cong, Luke A. Cusimano, Frank L. Greenway
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	MLR-1023 menthol beige fat UCP1 thermogenesis insulin sensitivity Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/4516d1342a1f4ef69cc538ba787de368
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:4516d1342a1f4ef69cc538ba787de368
record_format	dspace
spelling	oai:doaj.org-article:4516d1342a1f4ef69cc538ba787de3682021-11-25T18:40:08ZMLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect10.3390/ph141111961424-8247https://doaj.org/article/4516d1342a1f4ef69cc538ba787de3682021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1196https://doaj.org/toc/1424-8247A glucose-lowering medication that acts by a different mechanism than metformin, or other approved diabetes medications, can supplement monotherapies when patients fail to meet blood glucose goals. We examined the actions underlying the effects of an insulin sensitizer, tolimidone (MLR-1023) and investigated its effects on body weight. Diet-induced obesity (CD1/ICR) and type 2 diabetes (db/db) mouse models were used to study the effect of MLR-1023 on metabolic outcomes and to explore its synergy with menthol. We also examined the efficacy of MLR-1023 alone in a clinical trial (NCT02317796), as well as in combination with menthol in human adipocytes. MLR-1023 produced weight loss in humans in four weeks, and in mice fed a high-fat diet it reduced weight gain and fat mass without affecting food intake. In human adipocytes from obese donors, the upregulation of Uncoupling Protein 1, Glucose (UCP)1, adiponectin, Glucose Transporter Type 4 (GLUT4), Adipose Triglyceride Lipase (ATGL), Carnitine palmitoyltransferase 1 beta (CPT1β), and Transient Receptor Potential Melastin (TRPM8) mRNA expression suggested the induction of thermogenesis. The TRPM8 agonist, menthol, potentiated the effect of MLR-1023 on the upregulation of genes for energy expenditure and insulin sensitivity in human adipocytes, and reduced fasting blood glucose in mice. The amplification of the thermogenic program by MLR-1023 and menthol in the absence of adrenergic activation will likely be well-tolerated, and bears investigation in a clinical trial.Candida J. RebelloAnn A. CoulterAndrew G. ReaumeWeina CongLuke A. CusimanoFrank L. GreenwayMDPI AGarticleMLR-1023mentholbeige fatUCP1thermogenesisinsulin sensitivityMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1196, p 1196 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	MLR-1023 menthol beige fat UCP1 thermogenesis insulin sensitivity Medicine R Pharmacy and materia medica RS1-441
spellingShingle	MLR-1023 menthol beige fat UCP1 thermogenesis insulin sensitivity Medicine R Pharmacy and materia medica RS1-441 Candida J. Rebello Ann A. Coulter Andrew G. Reaume Weina Cong Luke A. Cusimano Frank L. Greenway MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect
description	A glucose-lowering medication that acts by a different mechanism than metformin, or other approved diabetes medications, can supplement monotherapies when patients fail to meet blood glucose goals. We examined the actions underlying the effects of an insulin sensitizer, tolimidone (MLR-1023) and investigated its effects on body weight. Diet-induced obesity (CD1/ICR) and type 2 diabetes (db/db) mouse models were used to study the effect of MLR-1023 on metabolic outcomes and to explore its synergy with menthol. We also examined the efficacy of MLR-1023 alone in a clinical trial (NCT02317796), as well as in combination with menthol in human adipocytes. MLR-1023 produced weight loss in humans in four weeks, and in mice fed a high-fat diet it reduced weight gain and fat mass without affecting food intake. In human adipocytes from obese donors, the upregulation of Uncoupling Protein 1, Glucose (UCP)1, adiponectin, Glucose Transporter Type 4 (GLUT4), Adipose Triglyceride Lipase (ATGL), Carnitine palmitoyltransferase 1 beta (CPT1β), and Transient Receptor Potential Melastin (TRPM8) mRNA expression suggested the induction of thermogenesis. The TRPM8 agonist, menthol, potentiated the effect of MLR-1023 on the upregulation of genes for energy expenditure and insulin sensitivity in human adipocytes, and reduced fasting blood glucose in mice. The amplification of the thermogenic program by MLR-1023 and menthol in the absence of adrenergic activation will likely be well-tolerated, and bears investigation in a clinical trial.
format	article
author	Candida J. Rebello Ann A. Coulter Andrew G. Reaume Weina Cong Luke A. Cusimano Frank L. Greenway
author_facet	Candida J. Rebello Ann A. Coulter Andrew G. Reaume Weina Cong Luke A. Cusimano Frank L. Greenway
author_sort	Candida J. Rebello
title	MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect
title_short	MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect
title_full	MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect
title_fullStr	MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect
title_full_unstemmed	MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect
title_sort	mlr-1023 treatment in mice and humans induces a thermogenic program, and menthol potentiates the effect
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4516d1342a1f4ef69cc538ba787de368
work_keys_str_mv	AT candidajrebello mlr1023treatmentinmiceandhumansinducesathermogenicprogramandmentholpotentiatestheeffect AT annacoulter mlr1023treatmentinmiceandhumansinducesathermogenicprogramandmentholpotentiatestheeffect AT andrewgreaume mlr1023treatmentinmiceandhumansinducesathermogenicprogramandmentholpotentiatestheeffect AT weinacong mlr1023treatmentinmiceandhumansinducesathermogenicprogramandmentholpotentiatestheeffect AT lukeacusimano mlr1023treatmentinmiceandhumansinducesathermogenicprogramandmentholpotentiatestheeffect AT franklgreenway mlr1023treatmentinmiceandhumansinducesathermogenicprogramandmentholpotentiatestheeffect
_version_	1718410829170212864

MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect

Ejemplares similares