Hypothalamic leptin action is mediated by histone deacetylase 5

Dhiraj G Kabra; Katrin Pfuhlmann; Cristina García-Cáceres; Sonja C Schriever; Veronica Casquero García; Adam Fiseha Kebede; Esther Fuente-Martin; Chitrang Trivedi; Kristy Heppner; N Henriette Uhlenhaut; Beata Legutko; Uma D Kabra; Yuanqing Gao; Chun-Xia Yi; Carmelo Quarta; Christoffer Clemmensen; Brian Finan; Timo D Müller; Carola W Meyer; Marcelo Paez-Pereda; Kerstin Stemmer; Stephen C Woods; Diego Perez-Tilve; Robert Schneider; Eric N Olson; Matthias H Tschöp; Paul T Pfluger

doi:10.1038/ncomms10782

Hypothalamic leptin action is mediated by histone deacetylase 5

Dhiraj G Kabra, Katrin Pfuhlmann, Cristina García-Cáceres, Sonja C Schriever, Veronica Casquero García, Adam Fiseha Kebede, Esther Fuente-Martin, Chitrang Trivedi, Kristy Heppner, N Henriette Uhlenhaut, Beata Legutko, Uma D Kabra, Yuanqing Gao, Chun-Xia Yi, Carmelo Quarta, Christoffer Clemmensen, Brian Finan, Timo D Müller, Carola W Meyer, Marcelo Paez-PeredaKerstin Stemmer, Stephen C Woods, Diego Perez-Tilve, Robert Schneider, Eric N Olson, Matthias H Tschöp, Paul T Pfluger

34 Citationer (Scopus)

Abstract

Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.

Originalsprog	Engelsk
Artikelnummer	10782
Tidsskrift	Nature Communications
Vol/bind	7
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms10782
Status	Udgivet - 29 feb. 2016
Udgivet eksternt	Ja

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10.1038/ncomms10782Licens: CC BY

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Kabra, D. G., Pfuhlmann, K., García-Cáceres, C., Schriever, S. C., Casquero García, V., Kebede, A. F., Fuente-Martin, E., Trivedi, C., Heppner, K., Uhlenhaut, N. H., Legutko, B., Kabra, U. D., Gao, Y., Yi, C.-X., Quarta, C., Clemmensen, C., Finan, B., Müller, T. D., Meyer, C. W., ... Pfluger, P. T. (2016). Hypothalamic leptin action is mediated by histone deacetylase 5. Nature Communications, 7, Artikel 10782. https://doi.org/10.1038/ncomms10782

Kabra, DG, Pfuhlmann, K, García-Cáceres, C, Schriever, SC, Casquero García, V, Kebede, AF, Fuente-Martin, E, Trivedi, C, Heppner, K, Uhlenhaut, NH, Legutko, B, Kabra, UD, Gao, Y, Yi, C-X, Quarta, C, Clemmensen, C, Finan, B, Müller, TD, Meyer, CW, Paez-Pereda, M, Stemmer, K, Woods, SC, Perez-Tilve, D, Schneider, R, Olson, EN, Tschöp, MH & Pfluger, PT 2016, 'Hypothalamic leptin action is mediated by histone deacetylase 5', Nature Communications, bind 7, 10782. https://doi.org/10.1038/ncomms10782

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title = "Hypothalamic leptin action is mediated by histone deacetylase 5",

abstract = "Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.",

keywords = "Animals, Blood Glucose, Cell Line, Gene Expression Regulation, Gene Knockdown Techniques, Glucose Tolerance Test, Histone Deacetylases, Hypothalamus, Infusions, Intraventricular, Insulin Resistance, Laser Capture Microdissection, Leptin, Male, Melanocyte-Stimulating Hormones, Mice, Mice, Inbred Strains, Mice, Knockout, Neurons, Rats, Rats, Wistar, Journal Article, Research Support, Non-U.S. Gov't",

author = "Kabra, {Dhiraj G} and Katrin Pfuhlmann and Cristina Garc{\'i}a-C{\'a}ceres and Schriever, {Sonja C} and {Casquero Garc{\'i}a}, Veronica and Kebede, {Adam Fiseha} and Esther Fuente-Martin and Chitrang Trivedi and Kristy Heppner and Uhlenhaut, {N Henriette} and Beata Legutko and Kabra, {Uma D} and Yuanqing Gao and Chun-Xia Yi and Carmelo Quarta and Christoffer Clemmensen and Brian Finan and M{\"u}ller, {Timo D} and Meyer, {Carola W} and Marcelo Paez-Pereda and Kerstin Stemmer and Woods, {Stephen C} and Diego Perez-Tilve and Robert Schneider and Olson, {Eric N} and Tsch{\"o}p, {Matthias H} and Pfluger, {Paul T}",

year = "2016",

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doi = "10.1038/ncomms10782",

language = "English",

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journal = "Nature Communications",

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T1 - Hypothalamic leptin action is mediated by histone deacetylase 5

AU - Kabra, Dhiraj G

AU - Pfuhlmann, Katrin

AU - García-Cáceres, Cristina

AU - Schriever, Sonja C

AU - Casquero García, Veronica

AU - Kebede, Adam Fiseha

AU - Fuente-Martin, Esther

AU - Trivedi, Chitrang

AU - Heppner, Kristy

AU - Uhlenhaut, N Henriette

AU - Legutko, Beata

AU - Kabra, Uma D

AU - Gao, Yuanqing

AU - Yi, Chun-Xia

AU - Quarta, Carmelo

AU - Clemmensen, Christoffer

AU - Finan, Brian

AU - Müller, Timo D

AU - Meyer, Carola W

AU - Paez-Pereda, Marcelo

AU - Stemmer, Kerstin

AU - Woods, Stephen C

AU - Perez-Tilve, Diego

AU - Schneider, Robert

AU - Olson, Eric N

AU - Tschöp, Matthias H

AU - Pfluger, Paul T

PY - 2016/2/29

Y1 - 2016/2/29

N2 - Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.

AB - Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.

KW - Animals

KW - Blood Glucose

KW - Cell Line

KW - Gene Expression Regulation

KW - Gene Knockdown Techniques

KW - Glucose Tolerance Test

KW - Histone Deacetylases

KW - Hypothalamus

KW - Infusions, Intraventricular

KW - Insulin Resistance

KW - Laser Capture Microdissection

KW - Leptin

KW - Male

KW - Melanocyte-Stimulating Hormones

KW - Mice

KW - Mice, Inbred Strains

KW - Mice, Knockout

KW - Neurons

KW - Rats

KW - Rats, Wistar

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ncomms10782

DO - 10.1038/ncomms10782

M3 - Journal article

C2 - 26923837

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10782

ER -

Hypothalamic leptin action is mediated by histone deacetylase 5

Abstract

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