Myokines, bioactive peptides released by skeletal muscle, have emerged as crucial regulators of metabolic and protective pathways in peripheral tissues, particularly in combating oxidative stress and inflammation. Their plasma concentration significantly increases following exercise, offering valuable insights into the role of physical activity in preventing sarcopenia and mitigating metabolic diseases, including obesity, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). This review focuses on discussing the roles of specific myokines in activating intracellular signaling pathways within the liver, which confer protection against steatosis and lipid peroxidation. We detail the mechanism underlying lipid peroxidation and highlight the liver’s antioxidant defenses, such as glutathione (GSH) and glutathione peroxidase 4 (GPX4), which are pivotal in reducing ferroptosis. Furthermore, we provide an in-depth analysis of key myokines, including myostatin, brain-derived neurotrophic factor (BDNF), and irisin, among others, and their potential impact on liver function. Finally, we discuss the molecular mechanisms through which these myokines influence oxidate stress and lipid metabolism, emphasizing their capacity to modulate antioxidant responses in the liver. Finally, we underscore the therapeutic potential of exercise as a non-pharmacological intervention to enhance myokine release, thereby preventing the progression of MASD through improved hepatic antioxidant defenses. This review represents a comprehensive perspective on the intersection of exercise, myokine biology, and liver health.

Betaine-homocysteine methyltransferase (BHMT) catalyzes the transfer of methyl groups from betaine to homocysteine (Hcy), producing methionine and dimethylglycine. In this work, we characterize Bhmt wild type (Bhmt-WT) and knockout (Bhmt-KO) mice that were fully backcrossed to a C57Bl6/J background. Consistent with our previous findings, Bhmt-KO mice had decreased body weight, fat mass, and adipose tissue weight compared to WT. Histological analyses and gene expression profiling indicate that adipose browning was activated in KO mice and contributed to the adipose atrophy observed. BHMT is not expressed in adipose tissue but is abundant in liver; thus, a signal must originate from the liver that modulates adipose tissue. We found that, in Bhmt-KO mice, homocysteine-induced endoplasmic reticulum (ER) stress is associated with activation of the hepatic transcription factor cyclic AMP response element binding protein (CREBH), and an increase in hepatic and plasma concentrations of fibroblast growth factor 21 (FGF21), which is known to induce adipose browning. Our data indicate that the deletion of a single gene in one-carbon metabolism modifies adipose biology and energy metabolism. Future studies could focus on identifying if functional polymorphisms in BHMT result in a similar adipose atrophy phenotype.

Choline availability regulates neural progenitor cell proliferation and differentiation in the developing cerebral cortex. Here, we investigated the molecular mechanism underlying this process and demonstrated that choline regulates the transcription factor SOX4 in neural progenitor cells. Specifically, we found that low choline intake during neurogenesis reduces SOX4 protein levels, causing the downregulation of EZH2, a histone methyltransferase. Importantly, we demonstrate that low choline is not involved in SOX4 protein degradation rate and established that protein reduction is caused by aberrant expression of a microRNA (miR-129-5p). To confirm the role of miR-129-5p, we conducted gain-of-function and loss-of-function assays in neural progenitor cells and demonstrated that directly altering miR-129-5p levels could affect SOX4 protein levels. We also observed that the reduction in SOX4 and EZH2 led to decreased global levels of H3K27me3 in the developing cortex, contributing to reduced proliferation and precocious differentiation. For the first time, to our knowledge, we demonstrate that a nutrient, choline, regulates a master transcription factor and its downstream targets, providing a novel insight into the role of choline in brain development.

Although choline was established as an essential nutrient over three decades ago, critical questions remain about how choline regulates brain, liver, and cardiometabolic health across the lifespan. This Perspective summarizes emerging insights presented at the Future Directions in Choline Symposium: A Tribute to Steven H. Zeisel, which outlined three converging areas of research: (i) choline-dependent mechanisms in neurodevelopment and cognition, (ii) the link between choline metabolism and obesity, and (iii) the role of trimethylamine N-oxide (TMAO) in cardiovascular disease. Evidence from clinical and preclinical studies confirms that maternal choline intake is critical for neurogenesis, cognition, and visual system development, and that higher choline availability buffers the fetal brain against environmental and psychosocial stressors. Choline supplementation improves cognitive outcomes in fetal alcohol spectrum disorder and mitigates neurodegenerative pathology in Alzheimer’s models. In cardiometabolic health, recent data challenge the interpretation of TMAO as a causal toxin, positioning it instead as a marker of renal function. Moving forward, the field must develop validated biomarkers of choline adequacy in free-living populations, harmonize intervention protocols, and define context-specific requirements across obesity, pregnancy, and glucagon-like peptide-1 (GLP-1)-based therapy use. These efforts will refine dietary recommendations and solidify choline’s role in lifelong brain and metabolic health.

Extensive evidence demonstrates that prenatal nutrition is crucial for adequate fetal development. Specifically, maternal choline intake plays a significant role in gene expression, epigenetics, and cell membrane formation. Preclinical models have shown that maternal dietary intake improves the development of the cerebral cortex and hippocampus. This review focuses on the role of prenatal choline intake and discusses its potential role in neurodevelopmental disorders especially since choline has emerged as a promising coadjutant to mitigate cognitive and developmental disorders. However, more evidence regarding timing, dosage, and molecular mechanisms is needed. In this review, we discuss the impact of prenatal choline availability, evidence from current models, and gaps to address in how choline may impact the symptomology and manifestation of Rett syndrome, fragile X syndrome, and Down syndrome. Our ultimate goal is to highlight the importance of choline for maternal health and its potential beneficial impact on neurodevelopmental disorders.

Myokines are peptides released by the skeletal muscle that exert effects on peripheral tissues, activating metabolic or protective pathways against oxidative stress and inflammation. Many myokines increase their plasma levels after exercise, providing new insights into the role of physical activity in combating sarcopenia and preventing metabolic diseases, such as obesity, diabetes, and metabolic dysfunction associated with steatotic liver disease (MASLD). This review aims to discuss the roles of specific myokines in activating intracellular pathways in the liver to protect against steatosis and lipoperoxidation in MASLD. The progression of liver disease from steatosis to cirrhosis is partially driven by ferroptosis, an iron-dependent form of cell death linked to oxidative stress and lipoperoxidation. Exercise-induced myokines, such as irisin, have been shown to upregulate antioxidant enzymes such as glutathione (GSH) and glutathione peroxidase 4 (GPX4), which are crucial in reducing ferroptosis in hepatic tissues. This review provides a comprehensive perspective on the protective effects of myokines in the liver, particularly against lipid peroxidation and ferroptosis in MASLD, and highlights exercise as a therapeutic strategy to prevent the progression of this liver pathology.