Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance
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Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance. / Dragano, Nathalia R.V.; Milbank, Edward; Haddad-Tóvolli, Roberta; Garrido-Gil, Pablo; Nóvoa, Eva; Fondevilla, Marcos F.; Capelli, Valentina; Zanesco, Ariane Maria; Solon, Carina; Morari, Joseane; Pires, Leticia; Estevez-Salguero, Ánxela; Beiroa, Daniel; González-García, Ismael; Barca-Mayo, Olga; Diéguez, Carlos; Nogueiras, Ruben; Labandeira-García, José L.; Rexen Ulven, Elisabeth; Ulven, Trond; Claret, Marc; Velloso, Licio A.; López, Miguel.
In: Molecular Metabolism, Vol. 79, 101840, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance
AU - Dragano, Nathalia R.V.
AU - Milbank, Edward
AU - Haddad-Tóvolli, Roberta
AU - Garrido-Gil, Pablo
AU - Nóvoa, Eva
AU - Fondevilla, Marcos F.
AU - Capelli, Valentina
AU - Zanesco, Ariane Maria
AU - Solon, Carina
AU - Morari, Joseane
AU - Pires, Leticia
AU - Estevez-Salguero, Ánxela
AU - Beiroa, Daniel
AU - González-García, Ismael
AU - Barca-Mayo, Olga
AU - Diéguez, Carlos
AU - Nogueiras, Ruben
AU - Labandeira-García, José L.
AU - Rexen Ulven, Elisabeth
AU - Ulven, Trond
AU - Claret, Marc
AU - Velloso, Licio A.
AU - López, Miguel
N1 - Publisher Copyright: © 2023 The Author(s)
PY - 2024
Y1 - 2024
N2 - Objective: Free fatty acid receptor-1 (FFAR1) is a medium- and long-chain fatty acid sensing G protein-coupled receptor that is highly expressed in the hypothalamus. Here, we investigated the central role of FFAR1 on energy balance. Methods: Central FFAR1 agonism and virogenic knockdown were performed in mice. Energy balance studies, infrared thermographic analysis of brown adipose tissue (BAT) and molecular analysis of the hypothalamus, BAT, white adipose tissue (WAT) and liver were carried out. Results: Pharmacological stimulation of FFAR1, using central administration of its agonist TUG-905 in diet-induced obese mice, decreases body weight and is associated with increased energy expenditure, BAT thermogenesis and browning of subcutaneous WAT (sWAT), as well as reduced AMP-activated protein kinase (AMPK) levels, reduced inflammation, and decreased endoplasmic reticulum (ER) stress in the hypothalamus. As FFAR1 is expressed in distinct hypothalamic neuronal subpopulations, we used an AAV vector expressing a shRNA to specifically knockdown Ffar1 in proopiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) of obese mice. Our data showed that knockdown of Ffar1 in POMC neurons promoted hyperphagia and body weight gain. In parallel, these mice developed hepatic insulin resistance and steatosis. Conclusions: FFAR1 emerges as a new hypothalamic nutrient sensor regulating whole body energy balance. Moreover, pharmacological activation of FFAR1 could provide a therapeutic advance in the management of obesity and its associated metabolic disorders.
AB - Objective: Free fatty acid receptor-1 (FFAR1) is a medium- and long-chain fatty acid sensing G protein-coupled receptor that is highly expressed in the hypothalamus. Here, we investigated the central role of FFAR1 on energy balance. Methods: Central FFAR1 agonism and virogenic knockdown were performed in mice. Energy balance studies, infrared thermographic analysis of brown adipose tissue (BAT) and molecular analysis of the hypothalamus, BAT, white adipose tissue (WAT) and liver were carried out. Results: Pharmacological stimulation of FFAR1, using central administration of its agonist TUG-905 in diet-induced obese mice, decreases body weight and is associated with increased energy expenditure, BAT thermogenesis and browning of subcutaneous WAT (sWAT), as well as reduced AMP-activated protein kinase (AMPK) levels, reduced inflammation, and decreased endoplasmic reticulum (ER) stress in the hypothalamus. As FFAR1 is expressed in distinct hypothalamic neuronal subpopulations, we used an AAV vector expressing a shRNA to specifically knockdown Ffar1 in proopiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) of obese mice. Our data showed that knockdown of Ffar1 in POMC neurons promoted hyperphagia and body weight gain. In parallel, these mice developed hepatic insulin resistance and steatosis. Conclusions: FFAR1 emerges as a new hypothalamic nutrient sensor regulating whole body energy balance. Moreover, pharmacological activation of FFAR1 could provide a therapeutic advance in the management of obesity and its associated metabolic disorders.
KW - Fatty acids
KW - FFAR1/GPR40
KW - Food intake
KW - Hypothalamus
KW - Obesity
KW - POMC
KW - Thermogenesis
U2 - 10.1016/j.molmet.2023.101840
DO - 10.1016/j.molmet.2023.101840
M3 - Journal article
C2 - 38036170
AN - SCOPUS:85180594006
VL - 79
JO - Molecular Metabolism
JF - Molecular Metabolism
SN - 2212-8778
M1 - 101840
ER -
ID: 378768339