Malnutrition during fetal and infant development [1] could lead to diseases in adulthood through epigenetic mechanisms known as “developmental programming” [2]. A growing body of evidence suggests that maternal overnutrition during pregnancy and lactation impairs hippocampus-dependent learning and memory processes [[3], [4], [5], [6]–7]. While fructose is a common sweetener in natural fruits and daily diet, maternal high fructose diet (HFD) has been associated with metabolic disorders in the offspring of later life, including cognitive dysfunction [[8], [9]–10], hypertension [11,12], and renal diseases [13]. However, the mechanism of maternal HFD-induced cognitive dysfunction remains largely unknown.

Maternal HFD during gestation and lactation induces microbiota dysbiosis in their offspring [14]. Butyrate, a four-carbon short-chain fatty acid (SCFA), is one of the major microbiota metabolites which is produced by dietary fiber fermentation and has beneficial effects on brain health [15]. Interestingly, butyrate promotes epigenetic remodeling by inhibiting histone deacetylases (HDACs) [16,17]. Of note, a previous study indicated that class II HDACs repress gene expression while G-protein-coupled receptors-activated class II HDACs are exported to cytoplasm from the nucleus to promote gene expression [18]. In particular, HDAC4, a class IIA HDAC, has been reported to regulate peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α, an upstream regulator of mitochondrial biogenesis) [19]. These lines of evidence raise a possibility that maternal HFD induces abnormal levels of butyrate and HDAC4 activity to deteriorate mitochondrial functions in the hippocampus. Nonetheless, the mediators and downstream effectors are elusive.

Three G protein-coupled receptors (GPR41, GPR43, and GPR109A) have been identified to respond to butyrate. In liver hepatocytes, the primary suppliers of blood glucose, butyrate has been documented to modulate gene expressions related to mitochondrial energy metabolism [20]. Mitochondria are central to energy metabolism to maintain cell functions, astrocyte-neuron metabolic coupling [21,22] and neuronal plasticity [23,24]. Mitochondrial biogenesis, a self‐renewal route of mitochondria, is critical for mitochondrial quality control to regulate cellular energy metabolism. Indeed, the impairment of mitochondrial bioenergetics has been demonstrated to damage hippocampal functions [[25], [26]–27]. Moreover, maternal HFD is known to suppress the metabolic function of hippocampal astrocytes [28]. Here, using a rodent model of maternal HFD during gestation and lactation, we examined the relationship between butyrate signaling, mitochondrial biogenesis, bioenergetics, and HDAC4 in the hippocampal tissue and astrocytes of the adult offspring.