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^*

^*Corresponding author for this work

85 Citations (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.

Original language	English
Journal	Nature Metabolism
Volume	3
Issue number	10
Pages (from-to)	1415-1431
Number of pages	17
ISSN	2522-5812
DOIs	https://doi.org/10.1038/s42255-021-00467-8
Publication status	Published - 10.2021

Funding

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.

UN SDGs

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

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

2.22-17 Endocrinology, Diabetology, Metabolism

Access to Document

10.1038/s42255-021-00467-8

Cite this

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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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.",

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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, vol. 3, no. 10, pp. 1415-1431. https://doi.org/10.1038/s42255-021-00467-8

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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

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AU - García-Cáceres, Cristina

AU - Tena-Sempere, Manuel

AU - Mittag, Jens

AU - Carmen Martínez, M.

AU - Rahmouni, Kamal

AU - Andriantsitohaina, Ramaroson

AU - López, Miguel

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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.

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

Abstract

Funding

UN SDGs

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DFG Research Classification Scheme

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CRC/TRR 296 LocoTact: Local control of TH action

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

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

Other files and links

Fingerprint

Projects

CRC/TRR 296 LocoTact: Local control of TH action

Cite this