Obesity is a risk factor for various neurological diseases and can affect behavior, cognition, and mood. In 2020, the World Health Organization reported that 1.9 billion adults were overweight [body mass index (BMI) ≥25 kg m−2] and 650 million adults been obese [body mass index (BMI) ≥30 kg m−2] since 1975. High-fat diet (HFD) causes nutritional excess and promotes obesity.

Studies have shown that obesity caused by HFD is negatively related to cognitive function and that people with obesity are more susceptible to cognitive impairment than others. The mechanism of HFD-induced cognitive impairment is complex and includes inflammation (Tan and Norhaizan, 2019), peripheral nervous system and brain insulin resistance (Sa-Nguanmoo et al., 2017), impaired glucose metabolism, increased oxidative stress, and mitochondrial function disorders. These abnormalities may cause pathological changes in brain cognitive impairment.

Nevertheless, the detailed mechanism linking hyperlipidemia to neuronal damage is still not understood, and suitable drugs that can delay or prevent the progression of cognitive dysfunction are not available. Because of the lack of effective treatment strategies, cognitive impairment cannot be delayed or reversed. In most cases, cholinesterase inhibitors, excitatory amino acid receptor antagonists, or others are used to treat cognitive impairment, although these drugs negligibly delay cognitive impairment. Fortunately, increasing evidence has shown that abnormal glucose and lipid metabolism may initiate cognitive dysfunction (Sedky, 2021). Therefore, strategies to improve insulin-induced signal transduction are important for maintaining the steady state of glucose and lipid metabolism.

Insulin receptor substrate 1 (IRS1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3-β) is the most important signal pathway to regulate blood glucose levels (Cheng et al., 2009; Prasad et al., 2013). GSK3β is a key downstream factor of AKT, and its activity is negatively regulated by AKT (Balaraman et al., 2006, 2006de la Monte and Wands, 2005). AKT can cause GSK3β mediated apoptosis and inhibition of glycogen synthase. Relevant studies have confirmed that IRS1/PI3K/AKT/GSK-3β signaling pathway can reduce insulin resistance (Yan et al., 2019; Zuo et al., 2019). In addition, IRS1/PI3K/AKT/GSK-3β signaling pathway also affects adipogenesis by regulating sterol regulatory element-binding transcription factor (Yan et al., 2019). Persistent hyperlipidemia in the body can destroy the integrity of the blood-brain barrier and increase its permeability. Cholesterol metabolism disorders occur when peripheral cholesterol enters the brain, which causes oxidative stress, mitochondrial dysfunction to lipid peroxidation (Dias et al., 2014).

Ferulic acid (FA) is a natural phenolic acid and one of the main cinnamic acid derivatives (Mattila and Kumpulainen, 2002). Many studies have shown that it possesses anti-inflammatory (Zhang et al., 2018), antioxidant (Zduńska et al., 2018), and cardioprotective properties. Certain studies have reported its potential use in the treatment of cognitive dysfunction (Luan et al., 2013; Stefani and Rigacci, 2013). However, although it regulates glucose and lipid metabolism in hyperlipidemia, its exact role and the mechanism whereby it maintains body homeostasis remain unclear. Furthermore, considering the important role of AKT in glucose and lipid metabolism, determining whether FA can affect AKT is crucial.

FA may exert antioxidant and anti-apoptotic effects via the IRS1/PI3K/AKT/GSK-3β pathway, thereby delaying the cognitive function deficit caused by hyperlipidemia. Thus, we hypothesized that FA may delay this process by modulating these reactions. In the current study, we investigated the therapeutic effects and underlying mechanisms of FA in HFD-induced mice and palmitic acid (PA)-induced neuronal cell hyperlipidemia models. Experimental design for mice was shown in Fig. 1.