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

Institute of Endocrinology and Diabetes

35 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

Research Areas and Centers

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

DFG Research Classification Scheme

2.22-17 Endocrinology, Diabetology, Metabolism

UN SDGs

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

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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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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",

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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 - 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

AU - Roa, Juan

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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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

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CRC/Transregio 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

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

Other files and links

Fingerprint

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CRC/Transregio TRR 296 LocoTact: Local control of TH action

Cite this