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Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancrea...

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Autores principales: Mukherjee, Sandip, Haubner, Jake, Chakraborty, Anutosh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144392/
https://www.ncbi.nlm.nih.gov/pubmed/32204420
http://dx.doi.org/10.3390/molecules25061403
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author Mukherjee, Sandip
Haubner, Jake
Chakraborty, Anutosh
author_facet Mukherjee, Sandip
Haubner, Jake
Chakraborty, Anutosh
author_sort Mukherjee, Sandip
collection PubMed
description In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans.
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spelling pubmed-71443922020-04-13 Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases Mukherjee, Sandip Haubner, Jake Chakraborty, Anutosh Molecules Review In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans. MDPI 2020-03-19 /pmc/articles/PMC7144392/ /pubmed/32204420 http://dx.doi.org/10.3390/molecules25061403 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Mukherjee, Sandip
Haubner, Jake
Chakraborty, Anutosh
Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases
title Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases
title_full Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases
title_fullStr Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases
title_full_unstemmed Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases
title_short Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases
title_sort targeting the inositol pyrophosphate biosynthetic enzymes in metabolic diseases
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144392/
https://www.ncbi.nlm.nih.gov/pubmed/32204420
http://dx.doi.org/10.3390/molecules25061403
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