GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells Natália da Silva Lima, Alba Cabaleiro, Eva Novoa, Cristina Riobello, Patrick J. Knerr, et al. Cellular and Molecular Life Sciences, 2024 The use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HSCs). For this, human hepatocyte and HSCs lines, as well as primary human hepatocytes and HSCs treated with Liraglutide, Acyl-GIP or the GLP-1/GIP dual agonist (MAR709) were used. We show that the concentrations of each compound, which were effective in insulin release, did not induce discernible alterations in either hepatocytes or HSCs. In hepatocytes displaying elevated fatty acid content after the treatment with oleic acid and palmitic acid, none of the three compounds reduced lipid concentration. Similarly, in HSCs activated with transforming growth factor-β (TGFb), Liraglutide, Acyl-GIP and MAR709 failed to ameliorate the elevated expression of fibrotic markers. The three compounds were also ineffective in phosphorylating CREB, which mediates insulinotropic actions, in both hepatocytes and HSCs. These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control.
Hypothalamic actions of estrogens in the regulation of energy and glucose homeostasis I González-García, Y Xu Reviews in Endocrine and Metabolic Disorders, 1-13 , 2025 2025 Citations: 3
Defective Olfactomedin-2 connects adipocyte dysfunction to obesity A Lluch, J Latorre, I Espadas, N Oliveras-Cañellas, JM Moreno-Navarrete, ... Nature Communications 16 (1), 7154 , 2025 2025 Citations: 2
JNK1 in SF1 neurons regulates the central action of thyroid hormones on hepatic lipid metabolism I Fernández-González, O Freire-Agulleiro, V Ferreira, M Silveira-Loureiro, ... Molecular Metabolism 98, 102170 , 2025 2025 Citations: 5
Neuroprotective effect of small extracellular vesicle-mediated targeting of AMPKα2 in cerebral ischemia A Ouro, A Rodríguez-Díaz, T López-González, D Romaus-Sanjurjo, ... Metabolism 167, 156160 , 2025 2025 Citations: 9
SF1-specific deletion of the energy sensor AMPKγ2 induces obesity O Freire-Agulleiro, A Estevez-Salguero, V Ferreira, CL Holleman, ... Molecular Metabolism 92, 102091 , 2025 2025 Citations: 5
Ceramides in the central control of metabolism M López, C Diéguez, M Tena-Sempere, I González-García Trends in Endocrinology & Metabolism 36 (1), 11-14 , 2025 2025 Citations: 9
GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells N da Silva Lima, A Cabaleiro, E Novoa, C Riobello, PJ Knerr, Y He, ... Cellular and Molecular Life Sciences 81 (1), 468 , 2024 2024 Citations: 29
HDAC5 controls a hypothalamic STAT5b-TH axis, the sympathetic activation of ATP-consuming futile cycles and adult-onset obesity in male mice RE Contreras, T Gruber, I González-García, SC Schriever, M De Angelis, ... Molecular Metabolism 90, 102033 , 2024 2024 Citations: 2
Protocol for ovariectomy and estradiol replacement in mice M Luengo-Mateos, A González-Vila, AMT Caldas, AM Alasaoufi, ... STAR protocols 5 (1) , 2024 2024 Citations: 29
Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance NRV Dragano, E Milbank, R Haddad-Tóvolli, P Garrido-Gil, E Nóvoa, ... Molecular metabolism 79, 101840 , 2024 2024 Citations: 24
High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling T Gruber, F Lechner, C Murat, RE Contreras, E Sanchez-Quant, V Miok, ... Cell reports 42 (10) , 2023 2023 Citations: 24
Astrocytic GABA in LHA is an obesity ‘thermostat’ I González-García, C García-Cáceres Nature Metabolism 5 (9), 1454-1455 , 2023 2023
Fezolinetant for menopausal hot flashes and night sweats I González-García, M López Trends in pharmacological sciences 44 (9), 635-636 , 2023 2023 Citations: 4
CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst S Zagmutt, P Mera, I González-García, K Ibeas, MM Romero, A Obri, ... Biology of sex Differences 14 (1), 14 , 2023 2023 Citations: 14
Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1 I González-García, E García-Clavé, A Cebrian-Serrano, O Le Thuc, ... Cell metabolism 35 (3), 438-455. e7 , 2023 2023 Citations: 62
Diet triggers specific responses of hypothalamic astrocytes in time and region dependent manner LM Lutomska, V Miok, N Krahmer, I González García, T Gruber, O Le Thuc, ... Glia 70 (11), 2062-2078 , 2022 2022 Citations: 34
An updated view on human neonatal thermogenesis I Gonzalez-Garcia, A Urisarri, R Nogueiras, C Dieguez, ML Couce, ... Nature Reviews Endocrinology 18 (5), 263-264 , 2022 2022 Citations: 3
Olfactomedin 2 deficiency protects against diet-induced obesity I González-García, Ó Freire-Agulleiro, N Nakaya, FJ Ortega, P Garrido-Gil, ... Metabolism 129, 155122 , 2022 2022 Citations: 18
Synaptotagmin-13 is a neuroendocrine marker in brain, intestine and pancreas M Tarquis-Medina, K Scheibner, I González-García, A Bastidas-Ponce, ... International Journal of Molecular Sciences 22 (22), 12526 , 2021 2021 Citations: 10
Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation E Milbank, NRV Dragano, I González-García, MR Garcia, ... Nature metabolism 3 (10), 1415-1431 , 2021 2021 Citations: 92
MOST CITED SCHOLAR PUBLICATIONS
Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK PBM de Morentin, I González-García, L Martins, R Lage, ... Cell metabolism 20 (1), 41-53 , 2014 2014 Citations: 519
Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance C Contreras, I González-García, N Martínez-Sánchez, P Seoane-Collazo, ... Cell reports 9 (1), 366-377 , 2014 2014 Citations: 271
Hypothalamic AMPK-ER stress-JNK1 axis mediates the central actions of thyroid hormones on energy balance N Martinez-Sanchez, P Seoane-Collazo, C Contreras, L Varela, ... Cell metabolism 26 (1), 212-229. e12 , 2017 2017 Citations: 264
A functional link between AMPK and orexin mediates the effect of BMP8B on energy balance L Martins, P Seoane-Collazo, C Contreras, I González-García, ... Cell reports 16 (8), 2231-2242 , 2016 2016 Citations: 156
Reduction of hypothalamic endoplasmic reticulum stress activates browning of white fat and ameliorates obesity C Contreras, I González-García, P Seoane-Collazo, N Martínez-Sánchez, ... Diabetes 66 (1), 87-99 , 2017 2017 Citations: 129
Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys A Ortega-Molina, E Lopez-Guadamillas, JA Mattison, SJ Mitchell, ... Cell metabolism 21 (4), 558-570 , 2015 2015 Citations: 110
Estradiol regulates energy balance by ameliorating hypothalamic ceramide-induced ER stress I González-García, C Contreras, A Estevez-Salguero, F Ruíz-Pino, ... Cell Reports 25 (2), 413-423. e5 , 2018 2018 Citations: 98
Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation E Milbank, NRV Dragano, I González-García, MR Garcia, ... Nature metabolism 3 (10), 1415-1431 , 2021 2021 Citations: 92
Ferritin regulates organismal energy balance and thermogenesis B Blankenhaus, F Braza, R Martins, P Bastos-Amador, I González-García, ... Molecular metabolism 24, 64-79 , 2019 2019 Citations: 76
Glucagon, GLP-1 and thermogenesis I González-García, E Milbank, C Diéguez, M López, C Contreras International journal of molecular sciences 20 (14), 3445 , 2019 2019 Citations: 64
Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1 I González-García, E García-Clavé, A Cebrian-Serrano, O Le Thuc, ... Cell metabolism 35 (3), 438-455. e7 , 2023 2023 Citations: 62
Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats PB Martinez de Morentin, R Lage, I González-García, F Ruíz-Pino, ... Endocrinology 156 (3), 947-960 , 2015 2015 Citations: 61
Insulin action on astrocytes: From energy homeostasis to behaviour I González‐García, T Gruber, C García‐Cáceres Journal of neuroendocrinology 33 (4), e12953 , 2021 2021 Citations: 59
Olanzapine depot exposure in male rats: dose-dependent lipogenic effects without concomitant weight gain J Fernø, KM Ersland, IH Duus, I González-García, KO Fossan, RK Berge, ... European Neuropsychopharmacology 25 (6), 923-932 , 2015 2015 Citations: 50
BMP8 and activated brown adipose tissue in human newborns A Urisarri, I González-García, Á Estévez-Salguero, MP Pata, E Milbank, ... Nature Communications 12 (1), 5274 , 2021 2021 Citations: 49
Estradiol regulation of brown adipose tissue thermogenesis I González-García, M Tena-Sempere, M López Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity … , 2017 2017 Citations: 49
Hypothalamic astrocytes as a specialized and responsive cell population in obesity I González-García, C García-Cáceres International journal of molecular sciences 22 (12), 6176 , 2021 2021 Citations: 42
mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol I González-García, PBM de Morentin, Á Estévez-Salguero, C Contreras, ... Journal of Endocrinology 238 (3), 177-186 , 2018 2018 Citations: 36
Hypothalamic lipids: key regulators of whole body energy balance I González-García, J Fernø, C Diéguez, R Nogueiras, M López Neuroendocrinology 104 (4), 398-411 , 2017 2017 Citations: 36
Diet triggers specific responses of hypothalamic astrocytes in time and region dependent manner LM Lutomska, V Miok, N Krahmer, I González García, T Gruber, O Le Thuc, ... Glia 70 (11), 2062-2078 , 2022 2022 Citations: 34
