Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

Veronica Pena-Leon; Cintia Folgueira; Silvia Barja-Fernández; Raquel Pérez-Lois; Natália Da Silva Lima; Marion Martin; Violeta Heras; Sara Martinez-Martinez; Paola Valero; Cristina Iglesias; Mannon Duquenne; Omar Al-Massadi; Daniel Beiroa; Yara Souto; Miguel Fidalgo; Rasika Sowmyalakshmi; Diana Guallar; Juan Cunarro; Cecilia Castelao; Ana Senra; Patricia González-Saenz; Rocío Vázquez-Cobela; Rosaura Leis; Guadalupe Sabio; Helge Mueller-Fielitz; Markus Schwaninger; Miguel López; Sulay Tovar; Felipe F Casanueva; Emmanuel Valjent; Carlos Diéguez; Vincent Prevot; Rubén Nogueiras; Luisa M Seoane

doi:10.1038/s42255-022-00602-z

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

Veronica Pena-Leon, Cintia Folgueira, Silvia Barja-Fernández, Raquel Pérez-Lois, Natália Da Silva Lima, Marion Martin, Violeta Heras, Sara Martinez-Martinez, Paola Valero, Cristina Iglesias, Mannon Duquenne, Omar Al-Massadi, Daniel Beiroa, Yara Souto, Miguel Fidalgo, Rasika Sowmyalakshmi, Diana Guallar, Juan Cunarro, Cecilia Castelao, Ana SenraPatricia González-Saenz, Rocío Vázquez-Cobela, Rosaura Leis, Guadalupe Sabio, Helge Mueller-Fielitz, Markus Schwaninger, Miguel López, Sulay Tovar, Felipe F Casanueva, Emmanuel Valjent, Carlos Diéguez, Vincent Prevot, Rubén Nogueiras, Luisa M Seoane

Institute of Experimental and Clinical Pharmacology and Toxicology

Abstract

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

Original language	English
Journal	Nature Metabolism
Volume	4
Issue number	7
Pages (from-to)	901-917
Number of pages	17
ISSN	2522-5812
DOIs	https://doi.org/10.1038/s42255-022-00602-z
Publication status	Published - 07.2022

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

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

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10.1038/s42255-022-00602-z

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Pena-Leon, V., Folgueira, C., Barja-Fernández, S., Pérez-Lois, R., Da Silva Lima, N., Martin, M., Heras, V., Martinez-Martinez, S., Valero, P., Iglesias, C., Duquenne, M., Al-Massadi, O., Beiroa, D., Souto, Y., Fidalgo, M., Sowmyalakshmi, R., Guallar, D., Cunarro, J., Castelao, C., ... Seoane, L. M. (2022). Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21. Nature Metabolism, 4(7), 901-917. https://doi.org/10.1038/s42255-022-00602-z

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title = "Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21",

abstract = "Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.",

author = "Veronica Pena-Leon and Cintia Folgueira and Silvia Barja-Fern{\'a}ndez and Raquel P{\'e}rez-Lois and {Da Silva Lima}, Nat{\'a}lia and Marion Martin and Violeta Heras and Sara Martinez-Martinez and Paola Valero and Cristina Iglesias and Mannon Duquenne and Omar Al-Massadi and Daniel Beiroa and Yara Souto and Miguel Fidalgo and Rasika Sowmyalakshmi and Diana Guallar and Juan Cunarro and Cecilia Castelao and Ana Senra and Patricia Gonz{\'a}lez-Saenz and Roc{\'i}o V{\'a}zquez-Cobela and Rosaura Leis and Guadalupe Sabio and Helge Mueller-Fielitz and Markus Schwaninger and Miguel L{\'o}pez and Sulay Tovar and Casanueva, {Felipe F} and Emmanuel Valjent and Carlos Di{\'e}guez and Vincent Prevot and Rub{\'e}n Nogueiras and Seoane, {Luisa M}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = jul,

doi = "10.1038/s42255-022-00602-z",

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Pena-Leon, V, Folgueira, C, Barja-Fernández, S, Pérez-Lois, R, Da Silva Lima, N, Martin, M, Heras, V, Martinez-Martinez, S, Valero, P, Iglesias, C, Duquenne, M, Al-Massadi, O, Beiroa, D, Souto, Y, Fidalgo, M, Sowmyalakshmi, R, Guallar, D, Cunarro, J, Castelao, C, Senra, A, González-Saenz, P, Vázquez-Cobela, R, Leis, R, Sabio, G, Mueller-Fielitz, H , Schwaninger, M, López, M, Tovar, S, Casanueva, FF, Valjent, E, Diéguez, C, Prevot, V, Nogueiras, R & Seoane, LM 2022, 'Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21', Nature Metabolism, vol. 4, no. 7, pp. 901-917. https://doi.org/10.1038/s42255-022-00602-z

TY - JOUR

T1 - Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

AU - Pena-Leon, Veronica

AU - Folgueira, Cintia

AU - Barja-Fernández, Silvia

AU - Pérez-Lois, Raquel

AU - Da Silva Lima, Natália

AU - Martin, Marion

AU - Heras, Violeta

AU - Martinez-Martinez, Sara

AU - Valero, Paola

AU - Iglesias, Cristina

AU - Duquenne, Mannon

AU - Al-Massadi, Omar

AU - Beiroa, Daniel

AU - Souto, Yara

AU - Fidalgo, Miguel

AU - Sowmyalakshmi, Rasika

AU - Guallar, Diana

AU - Cunarro, Juan

AU - Castelao, Cecilia

AU - Senra, Ana

AU - González-Saenz, Patricia

AU - Vázquez-Cobela, Rocío

AU - Leis, Rosaura

AU - Sabio, Guadalupe

AU - Mueller-Fielitz, Helge

AU - Schwaninger, Markus

AU - López, Miguel

AU - Tovar, Sulay

AU - Casanueva, Felipe F

AU - Valjent, Emmanuel

AU - Diéguez, Carlos

AU - Prevot, Vincent

AU - Nogueiras, Rubén

AU - Seoane, Luisa M

PY - 2022/7

Y1 - 2022/7

N2 - Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

AB - Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

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JO - Nature Metabolism

JF - Nature Metabolism

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ER -

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

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