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Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome

Loss of KBTBD2 in all tissues causes the teeny phenotype, characterized by insulin resistance with late failure of insulin production, severe hyperglycemia/diabetes, lipodystrophy, hepatosteatosis, and growth retardation. KBTBD2 maintains insulin sensitivity in adipocytes by restricting the abundanc...

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Autores principales: Zhang, Zhao, Gallagher, Thomas, Scherer, Philipp E., Beutler, Bruce
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260979/
https://www.ncbi.nlm.nih.gov/pubmed/32381739
http://dx.doi.org/10.1073/pnas.2000118117
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author Zhang, Zhao
Gallagher, Thomas
Scherer, Philipp E.
Beutler, Bruce
author_facet Zhang, Zhao
Gallagher, Thomas
Scherer, Philipp E.
Beutler, Bruce
author_sort Zhang, Zhao
collection PubMed
description Loss of KBTBD2 in all tissues causes the teeny phenotype, characterized by insulin resistance with late failure of insulin production, severe hyperglycemia/diabetes, lipodystrophy, hepatosteatosis, and growth retardation. KBTBD2 maintains insulin sensitivity in adipocytes by restricting the abundance of p85α. However, the possible physiological contribution or contributions of KBTBD2 have not yet been examined in other tissues. Here we show that mice with an adipocyte-specific knockout of Kbtbd2 accumulate p85α in white and brown adipose tissues, causing insulin resistance, moderate rather than severe hyperglycemia, sustained hyperinsulinemia without late failure of insulin production, and lipodystrophy leading to ectopic lipid accumulation in the liver. Adipocyte-extrinsic insulin resistance was observed in liver and muscle. None of these abnormalities were observed in liver- or muscle-specific Kbtbd2 knockout mice. Mice with Kbtbd2 knockout in adipocytes, liver, and muscle all showed normal growth, suggesting that KBTBD2 may be necessary to ensure IGF1 signaling in other tissues, notably bone. While much of the teeny phenotype results from loss of KBTBD2 in adipocytes, some features are adipocyte-extrinsic.
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spelling pubmed-72609792020-06-08 Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome Zhang, Zhao Gallagher, Thomas Scherer, Philipp E. Beutler, Bruce Proc Natl Acad Sci U S A Biological Sciences Loss of KBTBD2 in all tissues causes the teeny phenotype, characterized by insulin resistance with late failure of insulin production, severe hyperglycemia/diabetes, lipodystrophy, hepatosteatosis, and growth retardation. KBTBD2 maintains insulin sensitivity in adipocytes by restricting the abundance of p85α. However, the possible physiological contribution or contributions of KBTBD2 have not yet been examined in other tissues. Here we show that mice with an adipocyte-specific knockout of Kbtbd2 accumulate p85α in white and brown adipose tissues, causing insulin resistance, moderate rather than severe hyperglycemia, sustained hyperinsulinemia without late failure of insulin production, and lipodystrophy leading to ectopic lipid accumulation in the liver. Adipocyte-extrinsic insulin resistance was observed in liver and muscle. None of these abnormalities were observed in liver- or muscle-specific Kbtbd2 knockout mice. Mice with Kbtbd2 knockout in adipocytes, liver, and muscle all showed normal growth, suggesting that KBTBD2 may be necessary to ensure IGF1 signaling in other tissues, notably bone. While much of the teeny phenotype results from loss of KBTBD2 in adipocytes, some features are adipocyte-extrinsic. National Academy of Sciences 2020-05-26 2020-05-07 /pmc/articles/PMC7260979/ /pubmed/32381739 http://dx.doi.org/10.1073/pnas.2000118117 Text en Copyright © 2020 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Zhang, Zhao
Gallagher, Thomas
Scherer, Philipp E.
Beutler, Bruce
Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome
title Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome
title_full Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome
title_fullStr Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome
title_full_unstemmed Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome
title_short Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome
title_sort tissue-specific disruption of kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260979/
https://www.ncbi.nlm.nih.gov/pubmed/32381739
http://dx.doi.org/10.1073/pnas.2000118117
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