Metabolic syndrome (MetS)1 affects 20-25% of the global population and includes conditions like obesity, type 2 diabetes, and systemic metabolic inflammation, leading to severe diseases and increased premature mortality.
In a recent review published in the Gene Expression, researchers looked at (Epi)genetic aspects of metabolic syndrome pathogenesis in relation to brain-derived neurotrophic factor expression, explaining that the hypothalamus, crucial for regulating eating behaviour, plays a pivotal role in Metabolic syndrome (MetS) development. Psychoneurotic disorders and MetS are interconnected, highlighting the brain's significant role in the syndrome's progression. MetS is also linked to cancer development, likely due to hypothalamic dysfunction.
According to the study, inflammation and hypothalamic alterations can trigger MetS. Animal studies show that a high-fat diet (HFD) in mothers causes hypothalamic inflammation and gliosis in offspring, leading to metabolic dysregulation. This disrupts the blood-brain barrier (BBB), allowing inflammatory mediators and fatty acids to affect foetal hypothalamus development, altering neuronal communication and promoting obesity and insulin resistance.
Maternal and paternal obesity can epigenetically reprogramme offspring, affecting their metabolic health. Maternal HFD exposure increases inflammatory gene expression and alters neuronal signalling in offspring, with female offspring being more susceptible to metabolic disorders. Paternal obesity also influences offspring through epigenetic modifications, contributing to metabolic dysfunctions.
Todosenko et al. explained that a maternal hypercaloric diet affects lipid metabolism and the endogenous cannabinoid system in the hypothalamus of adult offspring, leading to sex-specific metabolic responses. This diet increases the expression of lipid metabolism-related genes and cannabinoid receptors, disrupting normal metabolic processes and contributing to obesity and other metabolic disorders.
Developmental programming during critical periods can permanently alter hypothalamic structure and function, predisposing individuals to metabolic disorders later in life. Epigenetic mechanisms, such as DNA methylation and histone modifications, mediate these long-lasting effects. miRNAs1, crucial for hypothalamic development and function, are influenced by maternal diet.
Key hypothalamic signalling pathways, like the Notch signalling pathway and POMC1 neurons, are disrupted by maternal obesity, leading to altered neuronal development and metabolic dysfunction. The researchers concluded that understanding these epigenetic and developmental mechanisms provides insights into potential therapeutic targets for preventing and managing metabolic disorders.
