Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 101840 |
| Tidsskrift | Molecular Metabolism |
| Vol/bind | 79 |
| Antal sider | 13 |
| ISSN | 2212-8778 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
The research leading to these results has received funding from the Xunta de Galicia (OBM: ED431F 2020/009 and ED431C 2023/28; RN: 2016-PG057); Ministerio de Ciencia e Innovación co-funded by the FEDER Program of EU (IGG: PID2022-141115NA-I00; OBM: PID2019-109556RB-I00; PID2022-138436OB-I00; CD: PID2020-116628GB-I00; RN: RTI2018-099413-B-I00 and RED2018-102379-T; ML: RTI2018-101840-B-I00, PID2021-128145NB-I00 and PDC2022-133958-I00); European Research Council (ERC Synergy Grant-2019-WATCH-810331); Innovation Fund Denmark (TU: ANFA, 5133-00007B); Lundbeck Foundation (ERU: R307-2018-2950); “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/HR19/52160022 (ML) and São Paulo Research Foundation (FAPESP–2013/07607-8). OBM and IGG are supported by Ramón y Cajal Awards (IGG: RYC2021-031225-I; OBM: RYC2018-026293-I) from the Ministerio de Ciencia e Innovación of Spain. CiMUS was supported by the Xunta de Galicia (2016–2019, ED431G/05). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
The research leading to these results has received funding from the Xunta de Galicia (OBM: ED431F 2020/009 and ED431C 2023/28; RN: 2016-PG057); Ministerio de Ciencia e Innovación co-funded by the FEDER Program of EU (IGG: PID2022-141115NA-I00 ; OBM: PID2019-109556RB-I00 ; PID2022-138436OB-I00 ; CD: PID2020-116628GB-I00 ; RN: RTI2018-099413-B-I00 and RED2018-102379-T ; ML: RTI2018-101840-B-I00 , PID2021-128145NB-I00 and PDC2022-133958-I00 ); European Research Council (ERC Synergy Grant- 2019-WATCH-810331 ); Innovation Fund Denmark (TU: ANFA, 5133-00007B ); Lundbeck Foundation (ERU: R307-2018-2950 ); “la Caixa” Foundation (ID 100010434 ), under agreement LCF/PR/HR19/52160022 (ML) and São Paulo Research Foundation (FAPESP– 2013/07607-8 ). OBM and IGG are supported by Ramón y Cajal Awards (IGG: RYC2021-031225-I ; OBM: RYC2018-026293-I ) from the Ministerio de Ciencia e Innovación of Spain . CiMUS was supported by the Xunta de Galicia (2016–2019, ED431G/05 ). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2023 The Author(s)
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