Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance

被引：12

作者：

Dragano, Nathalia R. V. ^{[1
,2
,3
,10
,11
]}

Milbank, Edward ^{[1
,2
,12
]}

Haddad-Tovolli, Roberta ^{[4
]}

Garrido-Gil, Pablo ^{[5
,6
]}

Novoa, Eva ^{[1
,2
]}

Fondevilla, Marcos F. ^{[1
,2
]}

Capelli, Valentina ^{[1
,2
]}

Zanesco, Ariane Maria ^{[3
]}

Solon, Carina ^{[3
]}

Morari, Joseane ^{[3
]}

Pires, Leticia ^{[3
]}

Estevez-Salguero, Anxela ^{[1
,2
]}

Beiroa, Daniel ^{[1
,2
]}

Gonzalez-Garcia, Ismael ^{[1
,2
]}

Barca-Mayo, Olga ^{[1
]}

Dieguez, Carlos ^{[1
,2
]}

Nogueiras, Ruben ^{[1
,2
]}

Labandeira-Garcia, Jose L. ^{[5
,6
]}

Ulven, Elisabeth Rexen ^{[7
]}

Ulven, Trond ^{[7
]}

Claret, Marc ^{[4
,8
,9
]}

Velloso, Licio A. ^{[3
]}

Lopez, Miguel ^{[1
]}

机构：

[1] Univ Santiago De Compostela, Dept Physiol, CiMUS, Santiago De Compostela 15782, Spain

[2] CIBER Fisiopatol Obes & Nutr CIBEROBN, Santiago De Compostela 15706, Spain

[3] Univ Estadual Campinas, Obes & Comorbid Res Ctr, Lab Cell Signaling, Campinas, Brazil

[4] Inst Invest Biomed August Pi i Sunyer IDIBAPS, Neuronal Control Metab NeuCoMe Lab, Barcelona, Spain

[5] Univ Santiago De Compostela, Dept Morphol Sci, CiMUS, Santiago De Compostela, Spain

[6] CIBER Enfermedades Neurodegenerat CIBERNED, Santiago De Compostela 28029, Spain

[7] Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark

[8] CIBER Diabet & Enfermedades Metab Asociadas CIBERd, Barcelona 08036, Spain

[9] Univ Barcelona, Fac Med, Barcelona, Spain

[10] German Mouse Clin Neuherberg, Inst Expt Genet, Neuherberg, Germany

[11] German Ctr Diabet Res DZD Neuherberg, Neuherberg, Germany

[12] Univ Augsburg, Inst Theoret Med, Med Fac, Mol Cell Biol, Augsburg, Germany

来源：

MOLECULAR METABOLISM | 2024年 / 79卷

基金：

巴西圣保罗研究基金会; 欧洲研究理事会;

关键词：

Fatty acids; FFAR1/GPR40; Hypothalamus; POMC; Obesity; Food intake; Thermogenesis; THYROID-HORMONES; POMC NEURONS; GPR40; AMPK; AGONIST; OBESITY; CELLS; FFAR1; MICE; MASS;

D O I：

10.1016/j.molmet.2023.101840

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. m 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

引用

页数：13

共 50 条

[1] Multifaceted actions of melanin-concentrating hormone on mammalian energy homeostasis [J].

Al-Massadi, Omar ;

Dieguez, Carlos ;

Schneeberger, Marc ;

Lopez, Miguel ;

Schwaninger, Markus ;

Prevot, Vincent ;

Nogueiras, Ruben .

NATURE REVIEWS ENDOCRINOLOGY, 2021, 17 (12) :745-755

[2] Deletion of GPR40 Impairs Glucose-Induced Insulin Secretion In Vivo in Mice Without Affecting Intracellular Fuel Metabolism in Islets [J].

Alquier, Thierry ;

Peyot, Marie-Line ;

Latour, Martin G. ;

Kebede, Melkam ;

Sorensen, Christina M. ;

Gesta, Stephane ;

Kahn, C. Ronald ;

Smith, Richard D. ;

Jetton, Thomas L. ;

Metz, Thomas O. ;

Prentki, Marc ;

Poitout, Vincent .

DIABETES, 2009, 58 (11) :2607-2615

[3] Respiratory uncoupling lowers blood pressure through a leptin-dependent mechanism in genetically obese mice [J].

Bernal-Mizrachi, C ;

Weng, S ;

Li, B ;

Nolte, LA ;

Feng, C ;

Coleman, T ;

Holloszy, JO ;

Semenkovich, CF .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2002, 22 (06) :961-968

[4] The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids [J].

Briscoe, CP ;

Tadayyon, M ;

Andrews, JL ;

Benson, WG ;

Chambers, JK ;

Eilert, MM ;

Ellis, C ;

Elshourbagy, NA ;

Goetz, AS ;

Minnick, DT ;

Murdock, PR ;

Sauls, HR ;

Shabon, U ;

Spinage, LD ;

Strum, JC ;

Szekeres, PG ;

Tan, KB ;

Way, JM ;

Ignar, DM ;

Wilson, S ;

Muir, AI .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (13) :11303-11311

[5] Obesity-programmed mice are rescued by early genetic intervention [J].

Bumaschny, Viviana F. ;

Yamashita, Miho ;

Casas-Cordero, Rodrigo ;

Otero-Corchon, Veronica ;

de Souza, Flavio S. J. ;

Rubinstein, Marcelo ;

Low, Malcolm J. .

JOURNAL OF CLINICAL INVESTIGATION, 2012, 122 (11) :4203-4212

[6] A molecular census of arcuate hypothalamus and median eminence cell types [J].

Campbell, John N. ;

Macosko, Evan Z. ;

Fenselau, Henning ;

Pers, Tune H. ;

Lyubetskaya, Anna ;

Tenen, Danielle ;

Goldman, Melissa ;

Verstegen, Anne M. J. ;

Resch, Jon M. ;

McCarroll, Steven A. ;

Rosen, Evan D. ;

Lowell, Bradford B. ;

Tsai, Linus T. .

NATURE NEUROSCIENCE, 2017, 20 (03) :484-496

[7] Hypothalamic CB1 Cannabinoid Receptors Regulate Energy Balance in Mice [J].

Cardinal, Pierre ;

Bellocchio, Luigi ;

Clark, Samantha ;

Cannich, Astrid ;

Klugmann, Matthias ;

Lutz, Beat ;

Marsicano, Giovanni ;

Cota, Daniela .

ENDOCRINOLOGY, 2012, 153 (09) :4136-4143

[8] Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists: Mesylpropoxy Appendage Lowers Lipophilicity and Improves ADME Properties [J].

Christiansen, Elisabeth ;

Due-Hansen, Maria E. ;

Urban, Christian ;

Grundmann, Manuel ;

Schroeder, Ralf ;

Hudson, Brian D. ;

Milligan, Graeme ;

Cawthorne, Michael A. ;

Kostenis, Evi ;

Kassack, Matthias U. ;

Ulven, Trond .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (14) :6624-6628

[9] Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean [J].

Clapham, JC ;

Arch, JRS ;

Chapman, H ;

Haynes, A ;

Lister, C ;

Moore, GBT ;

Piercy, V ;

Carter, SA ;

Lehner, I ;

Smith, SA ;

Beeley, LJ ;

Godden, RJ ;

Herrity, N ;

Skehel, M ;

Changani, KK ;

Hockings, PD ;

Reid, DG ;

Squires, SM ;

Hatcher, J ;

Trail, B ;

Latcham, J ;

Rastan, S ;

Harper, AJ ;

Cadenas, S ;

Buckingham, JA ;

Brand, MD ;

Abuin, A .

NATURE, 2000, 406 (6794) :415-418

[10] Reduction of Hypothalamic Endoplasmic Reticulum Stress Activates Browning of White Fat and Ameliorates Obesity [J].

Contreras, Cristina ;

Gonzalez-Garcia, Ismael ;

Seoane-Collazo, Patricia ;

Martinez-Sanchez, Noelia ;

Linares-Pose, Laura ;

Rial-Pensado, Eva ;

Ferno, Johan ;

Tena-Sempere, Manuel ;

Casals, Nuria ;

Dieguez, Carlos ;

Nogueiras, Ruben ;

Lopez, Miguel .

DIABETES, 2017, 66 (01) :87-99

← 1 2 3 4 5 →