Genistein stimulates fatty acid oxidation in a leptin receptor-independent manner through the JAK2-mediated phosphorylation and activation of AMPK in skeletal muscle

• Published in: Biochimica et biophysica acta Vol. 1841; no. 1; pp. 132 - 140
• Main Authors: Palacios-González, Berenice, Zarain-Herzberg, Angel, Flores-Galicia, Isabel, Noriega, Lilia G., Alemán-Escondrillas, Gabriela, Zariñan, Teresa, Ulloa-Aguirre, Alfredo, Torres, Nimbe, Tovar, Armando R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2014
• Subjects: AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Anticarcinogenic Agents - pharmacology; Cell Line; Enzyme Activation - drug effects; Enzyme Activation - genetics; Fatty acid oxidation; Fatty Acids - genetics; Fatty Acids - metabolism; Genistein; Genistein - pharmacology; JAK2; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Male; Mice; Muscle Fibers, Skeletal - metabolism; Myoblasts, Skeletal - metabolism; Oxidation-Reduction - drug effects; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation - drug effects; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Leptin - genetics; Receptors, Leptin - metabolism; Skeletal muscle; Soy protein; Transcription Factors - genetics; Transcription Factors - metabolism; FFA; Fatty acid oxidation; PLC; Genistein; CAMKKβ; CPT1; UCP3; SREBP1c; LEPR; JAK2; SP; ACC; Epac1; PDE4; PPARα; SIRT1; Skeletal muscle; PPARδ; Soy protein; FAO; SCD; 007; AMPK; AICAR; ObR; HF; stearoyl-CoA desaturase-1; 5′-adenosine monophosphate-activated protein kinase; free fatty acids; Janus kinase 2; phosphodiesterases; Ca(2+)/calmodulin-dependent protein kinase kinase β; cAMP-regulated guanine nucleotide exchange factor; phospholipase C; sirtuin 1; uncoupling carrier protein 3; carnitine palmitoyl transferase-1; leptin receptor; peroxisome proliferator-activated receptor-α; high fat; acetyl CoA carboxylase; 8-(4-chlorophenylthio)-2-Omethyladenosine-3,5-cAMP; 5-amino 4-imidazolecarboxamide ribose; sterol regulatory element binding protein-1c; peroxisome proliferator activated receptor-δ PGC-1α, PPAR-γ coactivator-1α
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2013.08.018

Obesity is a public health problem that contributes to the development of insulin resistance, which is associated with an excessive accumulation of lipids in skeletal muscle tissue. There is evidence that soy protein can decrease the ectopic accumulation of lipids and improves insulin sensitivity; however, it is unknown whether soy isoflavones, particularly genistein, can stimulate fatty acid oxidation in the skeletal muscle. Thus, we studied the mechanism by which genistein stimulates fatty acid oxidation in the skeletal muscle. We showed that genistein induced the expression of genes of fatty acid oxidation in the skeletal muscle of Zucker fa/fa rats and in leptin receptor (ObR)-silenced C2C12 myotubes through AMPK phosphorylation. Furthermore, the genistein-mediated AMPK phosphorylation occurred via JAK2, which was possibly activated through a mechanism that involved cAMP. Additionally, the genistein-mediated induction of fatty acid oxidation genes involved PGC1α and PPARδ. As a result, we observed that genistein increased fatty acid oxidation in both the control and silenced C2C12 myotubes, as well as a decrease in the RER in mice, suggesting that genistein can be used in strategies to decrease lipid accumulation in the skeletal muscle. •Genistein increases fatty acid oxidation in skeletal muscle through an increase in AMPK phosphorylation via JAK2.•Genistein activates AMPK in skeletal muscle, independent of leptin receptor.•Genistein is able to prevent lipotoxicity in skeletal muscle.