Obesity is one of the major public health problems because it substantially increases the risk of many diseases, including neurodegenerative disorders (Medina-Remón et al., 2018). Obesity-related neurodegenerative disease is mainly mediated by chronic low-grade inflammation, increased oxidative stress, and neuronal mitochondrial dysfunction (Tanaka et al., 2020; Volkow et al., 2013). These effects contribute to breakdown of the blood-brain barrier, and neuronal cell death, consequently leading to cognitive impairment (Chunchai et al., 2020; Saiyasit et al., 2020).

Caloric restriction and exercise are recognized as behavioral modification methods to attenuate obesity (Institute of Medicine Subcommittee on Military Weight, M, 2004). Importantly, these two strategies can reduce the risks of obesity-related neurodegenerative diseases (Cassilhas et al., 2016). Prior studies in obese animals showed that either caloric restriction or exercise notably led to better cognitive performance via the improvement of neuronal metabolism, anti-neuroinflammation, antioxidative capacity, neurogenesis, and synaptic plasticity (Cremonini et al., 2019; Fontana et al., 2021; Lynch et al., 2013). Unfortunately, only approximately 20% of obese individuals can maintain their weight loss after dietary restriction and physical activity (Wing and Hill, 2001; Wing and Phelan, 2005). In other words, most of people who manage to lose weight eventually regain it. This is frequently due to a starvation-induced increase in appetite and a decreased energy expenditure with weight loss (Müller et al., 2016; Myers et al., 2019). Long-term caloric restriction and an exercise regime for an entire life are notoriously extremely challenging (Foreyt and Poston 2nd, 1999), whereas weight maintenance following short-term caloric restriction and exercise seem to be the more practical behavioral modification strategies to attenuate obesity-related neurodegeneration in the long term. However, the effects of long-term caloric restriction or exercise, and weight maintenance following short-term caloric restriction or exercise on neuroprotection in HFD-induced obesity have never been compared.

In addition to caloric restriction or exercise, untrained fitness is another factor that exerts a neuroprotective effect in obesity (Henriksson et al., 2020; Oktay et al., 2017). Untrained fitness refers to the ability of the circulatory and respiratory systems to deliver oxygen to skeletal muscle during physical activity (Raghuveer et al., 2020). Interestingly, previous meta-analyses have confirmed that untrained fitness is highly determined by genetics, and therefore untrained fitness levels vary greatly between individuals (Schutte et al., 2016; Zadro et al., 2017). Numerous clinical studies demonstrated that untrained fitness was positively related to cortical thickness, hippocampal functional connectivity, and cognitive function in obese subjects (Marks et al., 2011; Mora-Gonzalez et al., 2019; Mora-Gonzalez et al., 2021; Rodriguez-Ayllon et al., 2020). In animals, it has been shown that genetically bred rats with higher untrained fitness level had better hippocampal structural plasticity and less hippocampal inflammation than those of their low- untrained fitness counterparts (Mäkinen et al., 2021). Nonetheless, the neuroprotective effects of higher untrained fitness have never been compared between the normal condition, HFD-induced obesity, and cases of HFD-induced obesity receiving caloric restriction or exercise in the long and short term. Indeed, the interplay between untrained fitness, HFD-induced obesity, and caloric restriction or exercise has never been determined.

Our study aimed to compare the effect of long-term caloric restriction or exercise and weight maintenance following short-term caloric restriction or exercise on the amelioration of brain impairment in HFD-fed rats. To identify the neuroprotective effect of higher untrained fitness level in the obese condition, we also compared the correlations between baseline untrained fitness level and a variety of brain parameters in obese rats, both with and without caloric restriction or exercise. We anticipated that our results would contribute to the new guidelines for assisting the neuroprotection in obese patients. Furthermore, we anticipated that our findings regarding the benefit of higher untrained fitness on neuroprotection will contribute to the development of novel medications that directly target an enhancement of untrained fitness level.