Maresin 1 Regulates Hepatic FGF21 in Diet‐Induced Obese Mice and in Cultured Hepatocytes

Abstract

ScopeTo study the effects of Maresin 1 (MaR1), a docosahexaenoic‐acid‐derived lipid mediator, on fibroblast growth factor 21 (FGF21) production and to characterize the tissue‐specific regulation of Fgf21 and its signaling pathway in liver, skeletal muscle, and white adipose tissue (WAT).Methods and resultsDiet‐induced obese (DIO) mice are treated with MaR1 (50 µg kg−1, 10 days, oral gavage) and serum FGF21 levels and liver, muscle and WAT Fgf21, β‐Klotho, Fgfr1, Egr1, and cFos mRNA expression are evaluated. Additionally, MaR1 effects are tested in mouse primary hepatocytes, HepG2 human hepatocytes, C2C12 myotubes, and 3T3‐L1 adipocytes. In DIO mice, MaR1 decreases circulating FGF21 levels and HFD‐induced hepatic Fgf21 mRNA expression. MaR1 increases hepatic β‐Klotho, Egr1, and cFos in DIO mice. In WAT, MaR1 counteracts the HFD‐induced downregulation of Fgf21, Fgfr1, and β‐Klotho. In muscle, MaR1 does not modify Fgf21 but promoted Fgfr1 expression. In mouse primary hepatocytes, MaR1 decreases Fgf21 expression and downregulated Pparα mRNA levels. In HepG2 cells, MaR1 reverses the increased production of FGF21 and the downregulation of FGFR1, Β‐KLOTHO, EGR1, and cFOS induced by palmitate. Preincubation with a PPARα antagonist prevents MaR1 effects on FGF21 secretion.ConclusionThe ability of MaR1 to modulate FGF21 can contribute to its beneficial metabolic effects.

Effects of Long-Term DHA Supplementation and Physical Exercise on Non-Alcoholic Fatty Liver Development in Obese Aged Female Mice

“…Real-time PCR was performed using the Touch Real-Time PCR System (C1000 + CFX384, BIO-RAD, Hercules, CA, USA). Expression of fatty acid synthase (Fas), Srebp1c, stearoyl-coenzyme A desaturase 1 (Scd1), Dgat2, hormone sensitive lipase (Hsl), acylcoenzyme A oxidase (Acox), carnitine palmitoyltransferase 1a (Cpt1a), Ppara, autophagy-related gene 5 (Atg5), autophagy-related gene 7 (Atg7), Xbp1, Ern1, monocyte chemoattractant protein-1 (Mcp-1), tumor necrosis factor alpha (Tnfα), interleukin-6 (Il-6), and Toll-like receptor 4 (Tlr4) genes were determined using predesigned Taqman ® Assays-on-Demand (Applied Biosystems, CA, USA) or by Power SYBR Green PCR Master Mix (BIO-RAD) [45,46]. Primers were designed with Primer-Blast software (National Center for Biotechnology Information, Bethesda, MD, USA; https://www.ncbi.nlm.nih.gov/tools/primer-blast).…”

Effects of Maresin 1 (MaR1) on Colonic Inflammation and Gut Dysbiosis in Diet-Induced Obese Mice

“…After this period, the control group ( n = 7) received a daily oral gavage of the vehicle (100 μL of saline solution with 0.1% ethanol) for 10 days. Additionally, the DIO mice were assigned to two subgroups that received a daily oral gavage of the vehicle ( n = 8) or MaR1 ( n = 8) (50 μg/kg body weight; Cayman, Ann Arbor, Michigan, USA) for 10 days [ 28 ] On the last day of treatment, fresh faeces were collected and immediately frozen at −80 °C for future DNA extraction and metagenomics analyses. Once the treatment was concluded, animals were sacrificed after 12 h of fasting.…”

“…Recent studies have also shown the effectiveness of MaR1 to regulate gastrointestinal tract functions. In this way, MaR1 has been shown to ameliorate liver steatosis in nonalcoholic fatty liver disease (NAFLD) animal models, inducing fatty acid oxidation genes and regulating autophagy and endoplasmic reticulum stress [26][27][28][29][30]. In mice with dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid-induced colitis, MaR1 reduced leukocyte infiltration, inhibited neutrophil migration, and reduced the levels of the following proinflammatory cytokines: IL-1β, TNF-α, IL-6, and INF-γ.…”

Specialized Proresolving Mediators for Therapeutic Interventions Targeting Metabolic and Inflammatory Disorders

“…Furthermore, MaR1 was observed to directly affect hepatocytes by increasing AMPK phosphorylation, and ultimately decreasing lipid accumulations and endoplasmic reticulum stress ( Rius et al ., 2017 ; Jung et al ., 2018 ). In addition, MaR1 modulated the expression of fibroblast growth factor 21 (FGF21), a key growth factor in systemic metabolism, in cultured hepatocytes ( Martinez-Fernandez et al ., 2019 ). In a previous study, nuclear receptor RORα was identified as an important regulator of liver macrophage polarization to induce an anti-inflammatory M2 phenotype in NASH ( Han et al ., 2017 ).…”

“…Furthermore, MaR1 treatment in diet-induced obesity mice regulated FGF21 and its production in hepatocytes, resulting in improved glucose metabolism and insulin sensitivity. In addition, it reversed the HFD-induced downregulation of FGF21, FGFR1, and β-Klotho in white adipose tissue ( Martinez-Fernandez et al ., 2019 ). In another study with a similar mouse model, MaR1 treatment improved anti-inflammatory effects by reducing the levels of pro-inflammatory agents IL-1β and TNF-α in colonic mucosa of obese mice ( Leon et al ., 2020 ).…”