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 Citations (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.

Original language	English
Article number	10782
Journal	Nature Communications
Volume	7
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms10782
Publication status	Published - 29 Feb 2016
Externally published	Yes

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms10782Licence: 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, [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, vol. 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.",

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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

Keywords

UN SDGs

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