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Milbank, E.* ; Dragano, N.R.V.* ; Gonzales 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.* ; 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.*

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

Nat. Metab. 3, 1415-1431 (2021)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Brown Adipose-tissue; Steroidogenic Factor-1; Thyroid-hormones; Energy-balance; Gt1-7 Cells; Ampk; Thermogenesis; Health; Mechanisms; Secretion

ISSN (print) / ISBN 2522-5812

e-ISSN 2522-5812

Journal Nature metabolism

Quellenangaben Volume: 3, Issue: 10, Pages: 1415-1431

Publisher Springer

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)

Grants Department of Veterans Affairs | Office of Academic Affiliations, Department of Veterans Affairs (OAA, VA)
"la Caixa" Foundation (Caixa Foundation)
Conselleria de Cultura, Educacion e Ordenacion Universitaria, Xunta de Galicia (Ministry of Culture, Education and University Planning, Government of Galicia)
Ministerio de Economia y Competitividad (Ministry of Economy and Competitiveness)
EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
Deutsche Forschungsgemeinschaft (German Research Foundation)