Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation

Edward Milbank; Nathalia R.V. Dragano; Ismael González-García; Marcos Rios Garcia; Verónica Rivas-Limeres; Liliana Perdomo; Grégory Hilairet; Francisco Ruiz-Pino; Patricia Mallegol; Donald A. Morgan; Ramón Iglesias-Rey; Cristina Contreras; Luisa Vergori; Juan Cuñarro; Begoña Porteiro; Aleix Gavaldà-Navarro; Rebecca Oelkrug; Anxo Vidal; Juan Roa; Tomás Sobrino; Francesc Villarroya; Carlos Diéguez; Rubén Nogueiras; Cristina García-Cáceres; Manuel Tena-Sempere; Jens Mittag; M. Carmen Martínez; Kamal Rahmouni; Ramaroson Andriantsitohaina; Miguel López

doi:10.1038/s42255-021-00467-8

Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation

Edward Milbank, Nathalia R.V. Dragano, Ismael González-García, Marcos Rios Garcia, Verónica Rivas-Limeres, Liliana Perdomo, Grégory Hilairet, Francisco Ruiz-Pino, Patricia Mallegol, Donald A. Morgan, Ramón Iglesias-Rey, Cristina Contreras, Luisa Vergori, Juan Cuñarro, Begoña Porteiro, Aleix Gavaldà-Navarro, Rebecca Oelkrug, Anxo Vidal, Juan Roa, Tomás SobrinoFrancesc Villarroya, Carlos Diéguez, Rubén Nogueiras, Cristina García-Cáceres, Manuel Tena-Sempere, Jens Mittag, M. Carmen Martínez, Kamal Rahmouni, Ramaroson Andriantsitohaina^*, Miguel López^*

^*Korrespondierende/r Autor/-in für diese Arbeit

80 Zitate (Scopus)

Abstract

Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown adipose tissue (BAT) thermogenesis. Here, we show that body weight of obese mice can be reduced by intravenous injection of small extracellular vesicles (sEVs) delivering a plasmid encoding an AMPKα1 dominant negative mutant (AMPKα1-DN) targeted to VMH-SF1 neurons. The beneficial effect of SF1-AMPKα1-DN-loaded sEVs is feeding-independent and involves sympathetic nerve activation and increased UCP1-dependent thermogenesis in BAT. Our results underscore the potential of sEVs to specifically target AMPK in hypothalamic neurons and introduce a broader strategy to manipulate body weight and reduce obesity.

Originalsprache	Englisch
Zeitschrift	Nature Metabolism
Jahrgang	3
Ausgabenummer	10
Seiten (von - bis)	1415-1431
Seitenumfang	17
ISSN	2522-5812
DOIs	https://doi.org/10.1038/s42255-021-00467-8
Publikationsstatus	Veröffentlicht - 10.2021

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The research leading to these results has received funding from the Xunta de Galicia (R.N. grant no. 2016-PG057, M.L. grant no. 2016-PG068); EuroNanoMed III (R.A. and M.L. grant no. EURONANOMED2019-050/ENAMEP); Junta de Andalucía (M.T.-S. grant no. P12-FQM-01943); Ministerio de Ciencia y Universidades cofunded by the FEDER Program of EU (C.D. grant no. BFU2017-87721; M.T.-S. grant no. BFU2014-57581-P, R.N. grant no. BFU2015-70664R; M.L. grant no. RTI2018–101840-B-I00 and grant no. BFU2015-70454-REDT/Adipoplast); USA National Institutes of Health (K.R. grant no. HL084207); the German Research Foundation (DFG) (grant nos. MI1242/3-2 to J.M. and OE723/2-1 to R.O.); the USA Department of Veterans Affairs (K.R. grant no. I01BX004249); The University of Iowa Fraternal Order of Eagles Diabetes Research Center (K.R.); European Research Council ERC (C.G.-C. STG grant AstroNeuroCrosstalk no. 757393); Atresmedia Corporación (R.N. and M.L. grant no. 2017-PO004) and ‘la Caixa’ Foundation (grant no. ID 100010434), under grant agreement no. LCF/PR/HR19/52160022 (M.L.). E.M. was the recipient of a Predoctoral Fellowship of the Nanofar Erasmus Mundus Program. I.G.-G. is the recipient of a fellowship from Alexander von Humboldt Foundation (ref. 3.3, ESP-1206916-HFST-P) and European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie actions (grant no. 842080, H2020-MSCA-IF-2018). T.S. is the recipient of a research contract from the Miguel Servet Program (CPII17/00027, Instituto de Salud Carlos III). The CiMUS is supported by the Xunta de Galicia (grant no. 2016-2019, ED431G/05). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. INSERM U1063 is supported by the Institut National de Santé et Recherche Médicale and Université d’Angers. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper. We thank S. Recoquillon and M. Wertheimer for technical assistance. The TEM analysis was performed in the Service Commun d’Imageries et d’Analyses Microscopiques of University of Angers. We thank SCAHU staff (Université d’Angers) for taking care of animals. The PET–CT analysis was performed in the Molecular Imaging Unit of the Department of Nuclear Medicine of USC.

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SDG 3 – Gesundheit und Wohlergehen

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Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

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2.22-17 Endokrinologie, Diabetologie, Metabolismus

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10.1038/s42255-021-00467-8

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SFB/TRR 296 LocoTact: Lokale Kontrolle der Schilddrüsenhormonwirkung
Führer-Sakel, D. (Sprecher*in), Mittag, J. (Stellv. Sprecher*in, Co-Sprecher*in), Kühnen, P. (Stellv. Sprecher*in, Co-Sprecher*in), Heuer, H. (Projektleiter*in (PI)), Schwaninger, M. (Projektleiter*in (PI)), Müller-Fielitz, H. (Projektleiter*in (PI)), Bechmann, I. (Projektleiter*in (PI)), Biebermann, H. (Projektleiter*in (PI)), Müller, T. (Projektleiter*in (PI)), Pfluger, P. (Projektleiter*in (PI)), Krude, H. (Projektleiter*in (PI)), Schülke-Gerstenfeld, M. (Projektleiter*in (PI)), Cirkel, A. (Projektleiter*in (PI)), Münte, T. (Projektleiter*in (PI)), Kleinschnitz, C. (Projektleiter*in (PI)), Langhauser, F. (Projektleiter*in (PI)), Engel, D. R. (Projektleiter*in (PI)), Möller, L. (Projektleiter*in (PI)), Kaiser, F. (Projektleiter*in (PI)), Oster, H. (Projektleiter*in (PI)), Kirchner, H. (Projektleiter*in (PI)), Spranger, J. (Projektleiter*in (PI)), Tacke, F. (Projektleiter*in (PI)), Wirth, E. K. (Projektleiter*in (PI)), Köhrle, J. (Projektleiter*in (PI)), Schomburg, L. (Projektleiter*in (PI)), Lange, C. M. (Projektleiter*in (PI)), Zwanziger, D. (Projektleiter*in (PI)), Mayerl, S. (Projektleiter*in (PI)), Stachelscheid, H. (Projektleiter*in (PI)), Opitz, R. (Projektleiter*in (PI)), Prasuhn, J. (Projektleiter*in (PI)), Lorenz, K. (Projektleiter*in (PI)), Köster, J. (Projektleiter*in (PI)), Mai, K. (Projektleiter*in (PI)), Püngel, T. (Projektleiter*in (PI)), Obermayer, B. (Projektleiter*in (PI)) & Rehwald, S. (Projektleiter*in (PI))
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Milbank, E., Dragano, N. R. V., González-García, I., Garcia, M. R., Rivas-Limeres, V., Perdomo, L., Hilairet, G., Ruiz-Pino, F., Mallegol, P., Morgan, D. A., Iglesias-Rey, R., Contreras, C., Vergori, L., Cuñarro, J., Porteiro, B., Gavaldà-Navarro, A., Oelkrug, R., Vidal, A., Roa, J., ... López, M. (2021). Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation. Nature Metabolism, 3(10), 1415-1431. https://doi.org/10.1038/s42255-021-00467-8

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title = "Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation",

abstract = "Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown adipose tissue (BAT) thermogenesis. Here, we show that body weight of obese mice can be reduced by intravenous injection of small extracellular vesicles (sEVs) delivering a plasmid encoding an AMPKα1 dominant negative mutant (AMPKα1-DN) targeted to VMH-SF1 neurons. The beneficial effect of SF1-AMPKα1-DN-loaded sEVs is feeding-independent and involves sympathetic nerve activation and increased UCP1-dependent thermogenesis in BAT. Our results underscore the potential of sEVs to specifically target AMPK in hypothalamic neurons and introduce a broader strategy to manipulate body weight and reduce obesity.",

author = "Edward Milbank and Dragano, \{Nathalia R.V.\} and Ismael Gonz{\'a}lez-Garc{\'i}a and Garcia, \{Marcos Rios\} and Ver{\'o}nica Rivas-Limeres and Liliana Perdomo and Gr{\'e}gory Hilairet and Francisco Ruiz-Pino and Patricia Mallegol and Morgan, \{Donald A.\} and Ram{\'o}n Iglesias-Rey and Cristina Contreras and Luisa Vergori and Juan Cu{\~n}arro and Bego{\~n}a Porteiro and Aleix Gavald{\`a}-Navarro and Rebecca Oelkrug and Anxo Vidal and Juan Roa and Tom{\'a}s Sobrino and Francesc Villarroya and Carlos Di{\'e}guez and Rub{\'e}n Nogueiras and Cristina Garc{\'i}a-C{\'a}ceres and Manuel Tena-Sempere and Jens Mittag and \{Carmen Mart{\'i}nez\}, M. and Kamal Rahmouni and Ramaroson Andriantsitohaina and Miguel L{\'o}pez",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = oct,

doi = "10.1038/s42255-021-00467-8",

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Milbank, E, Dragano, NRV, González-García, I, Garcia, MR, Rivas-Limeres, V, Perdomo, L, Hilairet, G, Ruiz-Pino, F, Mallegol, P, Morgan, DA, Iglesias-Rey, R, Contreras, C, Vergori, L, Cuñarro, J, Porteiro, B, Gavaldà-Navarro, A, Oelkrug, R, Vidal, A, Roa, J, Sobrino, T, Villarroya, F, Diéguez, C, Nogueiras, R, García-Cáceres, C, Tena-Sempere, M, Mittag, J, Carmen Martínez, M, Rahmouni, K, Andriantsitohaina, R & López, M 2021, 'Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation', Nature Metabolism, Jg. 3, Nr. 10, S. 1415-1431. https://doi.org/10.1038/s42255-021-00467-8

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T1 - Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation

AU - Milbank, Edward

AU - Dragano, Nathalia R.V.

AU - González-García, Ismael

AU - Garcia, Marcos Rios

AU - Rivas-Limeres, Verónica

AU - Perdomo, Liliana

AU - Hilairet, Grégory

AU - Ruiz-Pino, Francisco

AU - Mallegol, Patricia

AU - Morgan, Donald A.

AU - Iglesias-Rey, Ramón

AU - Contreras, Cristina

AU - Vergori, Luisa

AU - Cuñarro, Juan

AU - Porteiro, Begoña

AU - Gavaldà-Navarro, Aleix

AU - Oelkrug, Rebecca

AU - Vidal, Anxo

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AU - Sobrino, Tomás

AU - Villarroya, Francesc

AU - Diéguez, Carlos

AU - Nogueiras, Rubén

AU - García-Cáceres, Cristina

AU - Tena-Sempere, Manuel

AU - Mittag, Jens

AU - Carmen Martínez, M.

AU - Rahmouni, Kamal

AU - Andriantsitohaina, Ramaroson

AU - López, Miguel

PY - 2021/10

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N2 - Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown adipose tissue (BAT) thermogenesis. Here, we show that body weight of obese mice can be reduced by intravenous injection of small extracellular vesicles (sEVs) delivering a plasmid encoding an AMPKα1 dominant negative mutant (AMPKα1-DN) targeted to VMH-SF1 neurons. The beneficial effect of SF1-AMPKα1-DN-loaded sEVs is feeding-independent and involves sympathetic nerve activation and increased UCP1-dependent thermogenesis in BAT. Our results underscore the potential of sEVs to specifically target AMPK in hypothalamic neurons and introduce a broader strategy to manipulate body weight and reduce obesity.

AB - Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown adipose tissue (BAT) thermogenesis. Here, we show that body weight of obese mice can be reduced by intravenous injection of small extracellular vesicles (sEVs) delivering a plasmid encoding an AMPKα1 dominant negative mutant (AMPKα1-DN) targeted to VMH-SF1 neurons. The beneficial effect of SF1-AMPKα1-DN-loaded sEVs is feeding-independent and involves sympathetic nerve activation and increased UCP1-dependent thermogenesis in BAT. Our results underscore the potential of sEVs to specifically target AMPK in hypothalamic neurons and introduce a broader strategy to manipulate body weight and reduce obesity.

UR - https://www.scopus.com/pages/publications/85117683847

U2 - 10.1038/s42255-021-00467-8

DO - 10.1038/s42255-021-00467-8

M3 - Journal articles

C2 - 34675439

AN - SCOPUS:85117683847

SN - 2522-5812

VL - 3

SP - 1415

EP - 1431

JO - Nature Metabolism

JF - Nature Metabolism

IS - 10

ER -

Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation

Abstract

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