Short-term high-fat diet alters behavior, peripheral metabolism, and brain mitochondrial function in Swiss mice

Abstract

Understanding the temporal dynamics of high-fat diets (HFD) effects on behavior and metabolism is crucial for comprehending their negative impact on organisms. This study investigated the short-term effects (15, 25, and 35 days) of HFD in Swiss mice. Our findings revealed distinct behavioral and metabolic changes throughout the treatment. After 15 days of HFD, mice exhibited impaired exploratory habituation and significant increases in visceral adipose mass, fasting glucose levels, and glucose intolerance. Extending the diet to 25 days intensified the metabolic effects, resulting in compromised acquisition of recognition memory, increased body mass gain, and elevated plasma total cholesterol and triglyceride levels. After 35 days of HFD, these effects were further intensified and accompanied by anxiogenic-like responses in the open field test. Additionally, we observed a positive correlation between metabolic changes and behavioral impairments alongside prefrontal cortex mitochondrial dysfunction. In conclusion, our study reveals the temporal dynamics of behavioral and metabolic changes induced by short-term HFD in Swiss mice, highlighting the relationship between metabolic dysfunction and behavioral impairments. These findings pave the way for future research to unravel the underlying mechanisms and develop strategies to counteract the detrimental effects of HFD on behavior and metabolism.

Key words
high-fat diet; metabolism; behavior; memory; mice

INTRODUCTION

Excessive and prolonged consumption of hypercaloric diets, rich in lipids and sugars, has consistently been associated with a substantial elevation in the risk of developing chronic diseases such as obesity, diabetes, hypertension, cardiovascular disease, and certain cancers (Edwardson et al. 2012, Lutsey et al. 2008). A significant association between these diets and cognitive, emotional, and behavioral impairment development has also been observed (Nousen et al. 2014, Skilton et al. 2007).

High-fat diet (HFD) consumption in rodents is associated with the proliferation of adipose tissue and several related conditions, including hyperglycemia (Braga et al. 2021), insulin resistance (Soltis et al. 2017), dyslipidemia (Moreira et al. 2014), and hypertension (Wilde et al. 2000). Collectively, these factors explain the increased risk of developing type 2 diabetes mellitus observed in individuals affected by obesity or those with prolonged consumption of energy-rich, nutritionally deficient diets (Marshall & Bessesen 2002). Moreover, a significant body of evidence indicates that HFD-induced behavioral and cognitive impairments in rodents are likely mediated by oxidative stress (Langley et al. 2020), neuroinflammation (Thirumangalakudi et al. 2008), mitochondrial dysfunction (Miotto et al. 2018), cholinergic dysfunction (Machado et al. 2018, Moreira et al. 2014), reduced neurogenesis, synaptic dysfunction, and other mechanisms (Stranahan et al. 2011).

Chronic consumption of a HFD is associated with disrupted redox homeostasis across several tissues in mice, including the brain (de Oliveira et al. 2013, Mancini et al. 2021). For instance, previous studies indicated a dysregulation of the glutathione system, characterized by reduced levels of glutathione and impaired activities of the enzymes glutathione reductase and glutathione peroxidase (Morrison et al. 2010, Wang et al. 2020). Moreover, HFD-induced perturbations in the redox system directly affect brain mitochondrial function, including the hippocampus and prefrontal cortex (Pintana et al. 2012, Yuzefovych et al. 2013, Mancini et al. 2021), brain areas associated with cognitive processes related to learning, memory, and emotional regulation.

While most studies on the effects of HFD consumption on behavioral and metabolic impairments focus on extended exposure durations (e.g., months), emerging research suggests that even brief periods of HFD exposure can significantly influence critical physiological functions, including behavior and cognition (Ji et al. 2019, de Paula et al. 2021). Considering the significant impact of HFD consumption on human health, evaluating the temporal progression of metabolic and behavioral effects resulting from short-term HFD intake in rodents will aid in understanding the underlying mechanisms and developing effective therapeutic strategies to mitigate health disturbances associated with HFD consumption. Considering this, the primary hypothesis of the present study is that HFD-induced metabolic alterations precede and correlate positively with the emergence of behavioral alterations. Consequently, we investigated the short-term effects (15, 25, and 35 days) of HFD in Swiss mice.

MATERIALS AND METHODS

Animals

Experiments were conducted on 3-month-old male Swiss mice (Mus musculus) obtained from the animal facility of Universidade Federal de Santa Catarina (UFSC, Florianópolis, Brazil). They were housed in groups of eight mice per cage in a temperature-controlled room (23 ± 1 °C) and maintained on a 12-hour light cycle (lights on at 6:00 a.m.). The mice had ad libitum access to both food and water. All animal procedures strictly adhered to the Brazilian Federal Law on Animal Experimentation (Law 11.794 of 2008) and received approval from the Committee on Animal Use in Research (CEUA) of UFSC (Protocol 1793080916).

Experimental design

This study utilized 3-month-old male Swiss mice, randomly allocated by weight to four experimental groups (n = 8 per group). The first group received a standard diet (SD; Nuvilab CR1, Nuvital; Quimtia Nutrientes SA, Colombo, PR, Brazil) for 35 days. A second group was subjected to a high-fat diet (HFD) containing 61 kJ% saturated fat (Pragsoluções Biociências, Jáu, SP, Brazil) for the same 35-day period (see Table SI in Supplementary Material for details on diets composition). Two additional groups were included in the study. One group was given the SD for 20 days and the HFD for 15 days. The second comparative group received the SD for 10 days and the HFD for 25 days. After 31 days, the mice underwent behavioral tests, including the open field (days 31-33) and the object recognition task (day 34). Subsequently, on the 35th day, following six hours of food deprivation, a glucose tolerance test (GTT) was conducted. On the following day, following another six-hour food deprivation period, the mice were anesthetized via intraperitoneal administration of ketamine-xylazine. A cardiac puncture was then employed to collect blood samples to evaluate plasma cholesterol and triglyceride levels. Concurrently, visceral adipose tissue was meticulously excised and weighed with precision. The body weight of the animals was measured weekly throughout the experimental protocol.

In a separate experimental setting, mice were divided into two groups and fed either a SD or a HFD for 35 days (n = 7 per group). Following the 35-day dietary intervention, the animals were euthanized through inhalation of isoflurane (5%), followed by cervical dislocation. Subsequently, their frontal cortex brains were meticulously dissected to perform a high-resolution respirometry assay.

Behavioral tests

All behavioral assessments were carried out by an experimenter who remained blinded to the respective experimental groups. The experiments were conducted during the light phase of the animals’ circadian cycle within a controlled environment. This environment was maintained at 23°C, with humidity levels ranging from approximately 40 to 60%. Furthermore, the experimental area was illuminated with low-intensity lighting (~15 lx). All mazes and objects employed in the behavioral tests underwent thorough cleaning with 10% ethanol solution between each test session.

Open Field Test

In this experimental paradigm, animals were allowed free exploration in a box measuring 50 cm x 50 cm x 40 cm in volume, with a daily exposure of 5 minutes each over three consecutive days. The following behavioral parameters were assessed: total crossings, which reflect locomotor activity and exploratory habituation, and the time spent in the center of the apparatus. The time spent in the center is related to emotionality, considering the inherent aversiveness of this area for the animal (Bolivar et al. 2000, Prut et al. 2003).

Object Recognition Test

To evaluate short-term recognition memory, we employed the object recognition test. This protocol involves a 5-minute training session, followed by a 5-minute test session after a 30-minute interval. During the training session, the animals were exposed to two objects with identical color, shape, and texture properties. In this session, the animals are expected to explore both objects with equal frequency and duration. In the subsequent test session, the animals are reintroduced to the context. Here, they encounter a familiar object, which was present during the training session, and a novel object. The novel object distinguishes itself by varying color, shape, and texture from the objects encountered in the training session. During this session, a higher frequency and longer duration of exploratory behaviors are expected to be directed toward the novel object. This inclination towards the novel object is rooted in animals’ inherent preference for novelty. Mice displaying limited exploration activity (total object interaction lasting ≤ 2 s) were excluded from the experiment. A recognition index was calculated using the formula: (T novel × 100)/(T novel + T familiar), wherein T novel represents the duration of exploration directed at the novel object and T familiar denotes the time exploring the familiar object (Vogel-Ciernia & Wood 2014).

Biochemical analysis

The glucose tolerance test (GTT) was conducted through intraperitoneal administration of D- (+)-glucose (2 g/kg of body weight; Sigma Aldrich, St Louis, MO) in mice following a 6-hour fast. Blood glucose levels were measured from the tail tip at baseline and 15, 30, 60, and 120 minutes using a glucometer (Accu-check, Roche Diagnostics). On the subsequent day, following six hours of food deprivation, mice were anesthetized with xylazine/ketamine. Blood samples were collected from the heart and promptly centrifuged at 1000 x g, and the resulting plasma samples were stored at -80°C. Total cholesterol and triglyceride levels were measured using an enzymatic kit, following the manufacturer’s instructions (Bioclin, Belo Horizonte, MG, Brazil). The results are expressed in mg/dL.

Mitochondrial oxygen consumption

Mitochondrial oxygen consumption rate (OCR) within cerebral cortex homogenate (2 mg/ml) was quantified using high-resolution respirometry (Oxygraph-2k, OROBOROS Instruments, Innsbruck, Austria). The measurements were conducted at 37°C, following the procedure outlined in Mancini et al. (2021). After dissection, the freshly obtained frontal cortex tissue was weighed and homogenized (2 mg/ml of fresh tissue) using a glass homogenizer. This procedure was carried out in 500 μl of Buffer, composed of sucrose (320 mM), EGTA (1 mM), MgCl₂ (4 mM), KH₂PO₄ (5 mM), and Tris HCl (10 mM). The prepared homogenate was kept on ice for immediate utilization. Before each experiment and per the equipment’s instructions, air calibration was meticulously conducted. The acquisition and subsequent data analysis were performed using DatLab software 5.0 (OROBOROS Instruments, Innsbruck, Austria). According to the substrate-uncoupler-inhibitor titration (SUIT) protocol (Klop et al. 2013), after stabilization and basal OCR determination, the OCR associated with the LEAK state was obtained by adding pyruvate (5 mM) and malate (0.5 mM). LEAK respiration compensates for proton leak, proton slip, and cation cycling before adding ADP. The OCR associated with ATP production of complex I and complex II (complexes I and II–phosphorylating) was then determined by adding 2 steps of ADP (0.5 mM and 1 mM) and succinate (10 mM). In this last step, after the addition of rotenone (0,5uM) and antimycin (2,5uM), the residual O₂ consumption rate (Rox) represents the consumption of extramitochondrial O₂, i.e., the consumption by other organelles and cellular biochemical processes independent of the mitochondria (Mancini et al. 2021)

Standard behavioral and metabolic Z-score

To standardize the data, simple mathematical techniques were employed to normalize each individual raw metabolic and behavioral data to the control groups’ mean within each experimental cohort, thus integrating data into a single value called the metabolic and neurobehavioral z-scores. Their values were obtained by subtracting the average observations in a population from an individual raw value and dividing this difference by the population standard deviation, as described previously (Zemdegs et al. 2016). This type of normalization allows data on different scales to be compared. The neurobehavioral z-score encompassed parameters derived from the open field test (total crossings and time spent in the center) and the object recognition test (recognition index during the test session). Conversely, the metabolic z-score integrated variables such as body mass variation, visceral adipose mass, plasma triglyceride and cholesterol levels, glycemia, and area under the curve for blood glucose.

Statistics

Data are expressed as the mean ± standard error of the mean. All data were checked for normal distribution by using the Shapiro-Wilk test. Statistical differences among the experimental groups were evaluated using a one-way analysis of variance (ANOVA), followed by post-hoc Dunnet tests for multiple comparisons. A repeated-measures ANOVA was applied to analyze the glucose-tolerance curve. The degree of correlation between metabolic and behavioral scores was assessed using Pearson’s correlation test. One-sample t-tests were conducted for the novel object recognition task to determine deviations from the expected 50% (random investigation) recognition index. The accepted significance level was set up at p < 0.05 for all analyses. Statistical assessments were carried out using the GraphPad Prism 5.0 software package.

RESULTS

There were no significant differences in the initial body mass of the animals between the groups (one-way ANOVA, F (3, 28) = 0.7672, p > 0.05) (Fig 1a). However, one-way ANOVA indicated a significant effect of diet on body mass gain [F (3, 28) = 28.71, p < 0.0001] (Fig 1b). Post hoc comparisons revealed a significantly higher body mass gain in HFD-fed mice over the 25- and 35-day periods compared to the SD group (p < 0.0001). Additionally, a significant effect of diet on visceral adipose tissue mass was identified [F (3, 28) = 27.81, p < 0.0001] (Fig 1c). The post hoc analyses indicated elevated visceral adipose tissue mass in HFD-fed mice during the 15, 25, and 35-day intervals compared to the SD group (p < 0.001).

Figure 1
a) At the beginning of the experiment, no significant differences in body mass were observed among the groups (p > 0.05, n = 8). b) Animals fed a high-fat diet (HFD) for 25 and 35 days exhibited significant increases in body mass (p < 0.0001****, n = 8). c) All groups on a HFD showed a significant increase in visceral adipose tissue mass compared to the standard diet (SD) group (p < 0.0001, n = 8). Data are expressed as mean ± SE.

One-way ANOVA did not reveal any differences in spontaneous locomotion during either the initial session [F (3, 28) = 0.5743, p > 0.05; Fig 2a] or the subsequent day session [F (3, 28) = 0.5721, p > 0.05; Fig 2b] of the open field test. Conversely, the one-way ANOVA revealed a significant effect of diet during the third-day session [F (3, 28) = 4.154, p < 0.05] (Fig 2c). Post hoc comparisons revealed increased total crossings within the apparatus among HFD-fed mice over the 15-, 25-, and 35-day periods, relative to the SD group (p < 0.05).

Figure 2
a) On the first day and b) the second day of exposure to the open field, no significant differences in locomotion were detected among the groups (p > 0.05). c) By the third day, mice on the SD diet exhibited significantly reduced locomotion compared to those on the HFD (p < 0.05*, n = 8). d) On the first day of the open field test, the group fed with HFD for 35 days spent significantly less time exploring the center of the apparatus (p < 0.01**, n = 8). e) During the training session, all groups showed no significant deviation from the 50% object exploration threshold (p > 0.05), indicating no specific object preference. f) In the test session, animals fed with HFD for 25 and 35 days did not differ significantly from the 50% object exploration threshold (p < 0.05*, p < 0.01**, n = 8). Data are presented as mean ± SE.

Emotionality was assessed by quantifying the duration the animals spent in the central region of the apparatus on the first day of open-field exposure. The one-way ANOVA indicated a significant diet effect [F (3, 28) = 3.743, p < 0.05] concerning center time. Post hoc comparisons indicated a significant reduction in the time spent within the central area of the open field apparatus after 35 days of HFD exposure (p < 0.05) (Fig 2d).

During the training session in the object recognition test, no significant difference in the object recognition index was observed (t-test against a hypothetical value of 50%, p > 0.05; Fig 2e), indicating that animals across all experimental groups displayed no innate preference for the objects. In the test session, the groups subjected to HFD for 25 and 35 days spent significantly less time exploring the new object than the control group (t-test against a hypothetical value of 50%, p > 0.05; Fig 2f), indicating recognition memory impairments.

One-way ANOVA revealed a significant effect of diet on basal glucose levels [F (3, 28) = 8.792, p < 0.0005] (Fig 3a). Further exploration through post hoc comparisons revealed elevated fasting glucose levels in HFD-fed mice over the 15, 25, and 35-day periods, compared to the SD group (p < 0.005). Moreover, a two-way ANOVA with repeated measures revealed significant main effects of diet [F (3, 28) = 13.26, p < 0.0001], repetition [F (3.229, 90.40) = 259.8, p < 0.0001], and diet by repetition interaction [F (12, 112) = 8.640, p < 0.0001] on the glucose tolerance test (mg/dL). Further post hoc comparisons revealed significant increases in glucose levels in HFD-fed mice during the 15, 25, and 35-day spans compared to the SD group, specifically at 30, 60, and 120 minutes following glucose challenge (p < 0.05; Fig 3b). Moreover, there was a significant diet effect [F (3, 28) = 43.66, p < 0.0001] concerning the AUC (Fig 3C), derived from the blood glucose levels represented in Fig 3b. Subsequent post hoc comparisons revealed a significant increase in the AUC among HFD-fed mice throughout the 15, 25, and 35-day intervals, compared to the SD group (p < 0.0001; Fig 3c).

Figure 3
a) Regardless of the duration of the diet, all HFD-fed groups exhibited significantly higher basal fasting glucose levels compared to the SD group (p < 0.05, n = 8). b) Glucose tolerance curve. c) The area under the glucose tolerance curve showed that all HFD-fed groups had greater glucose intolerance than the SD group (p < 0.05, n = 8). d) Groups fed with HFD for 25 and 35 days had significantly elevated triglyceride concentrations compared to the SD group (ANOVA p < 0.05, post-hoc Dunnett). e) Animals on HFD for 25 and 35 days showed a significant increase in total plasma cholesterol levels compared to the SD group (ANOVA p < 0.05, post-hoc Dunnett). Data are presented as mean ± SE.

One-way ANOVA analysis indicated a significant effect of diet on plasma total cholesterol levels [F (3, 28) = 7.855, p < 0.005]. The post hoc comparisons revealed a significant rise in plasma cholesterol concentration following 25 and 35 days of HFD exposure compared to the SD group (p < 0.05; Fig 3d). Similarly, one-way ANOVA analysis indicated a significant diet effect [F (3, 28) = 13.18, p < 0.0001] on plasma triglyceride concentrations. Subsequent post-hoc comparisons revealed elevated plasma triglyceride concentration among HFD-fed mice over the 25 and 35-day periods, compared to the SD group (p < 0.05; Fig 3e).

Furthermore, metabolic and neurobehavioral z-scores were established by normalizing each raw data point to the control’s group mean and integrating all parameters into a single value. One-way ANOVA analysis indicated a significant effect of diet on the neurobehavioral z-score [F (3, 28) = 7.173, p < 0.001). The post hoc comparisons indicated a higher neurobehavioral z-score among HFD-fed mice over the 15, 25, and 35-day spans, in comparison to the SD group (p < 0.005; Fig 4a). Similarly, the one-way ANOVA analysis indicated a significant diet effect [F (3, 28) = 48.64, p < 0.0001] concerning the metabolic z-score. The post hoc comparisons indicated higher metabolic z-score in HFD-fed mice throughout the 15, 25, and 35-day intervals compared to the SD group (p < 0.05; Fig 4b). Finally, a significant positive correlation between the metabolic and neurobehavioral z-scores was observed in the HFD-induced obesity model (Pearson r = 0.40; p < 0.05; Fig 4c).

Figure 4
a) Animals on the high-fat diet for 15, 25 and 35 days showed a significant increase in the behavioral z-score (p < 0.005). b) Animals subjected to HFD for 15, 25, and 35 days exhibited significantly higher metabolic z-scores than the SD group (p < 0.00005****, n = 8). c) A weak positive correlation was observed between the behavioral z-score and the metabolic z-score (p < 0.05*, r = 0.40, n = 8). Data are presented as mean ± SE.

To assess the impact of HFD on bioenergetics, mitochondrial physiology was evaluated in mice exposed to HFD for 35 days (Figs 5a-d). Figures 5a and 5c show that basal and maximal oxygen consumption were impaired in HFD-fed mice, while Figure 5d shows increased non-mitochondrial oxygen consumption in HFD-fed mice.

Figure 5
a) Basal oxygen consumption rate (OCR), b) OCR associated with LEAK, c) OCR associated with ATP synthesis, and d) extramitochondrial O2 consumption rate in the frontal cortex of animals fed with HFD for 35 days (p < 0.00005, n = 7). Data are expressed as mean ± SE.

DISCUSSION

This study provides insights into short-term exposure to a HFD on mice’s behavior, metabolism, and mitochondrial function. After 15 days of diet, the animals exhibited mild behavioral changes related to exploratory habituation. They also showed signs of hyperglycemia, glucose intolerance, and increased adipose mass compared to the SD group. By day 25, the mice displayed recognition memory impairments, hypercholesterolemia, hypertriglyceridemia, and significant weight gain. Emotional impairments were observed at the 35-day mark. Additionally, an additional experimental set revealed mitochondrial dysfunction in the frontal cortex of HFD-fed mice after 35 days.

Previous research has demonstrated that a HFD can lead to a substantial weight gain in mice. Licholai et al. (2018) found that HFD causes a spontaneous increase in daily caloric intake, which is linked to weight gain on an individual level, affecting overall mass balance and promoting obesity (Braga et al. 2021, Licholai et al. 2018, Lutz & Woods 2007). Additionally, all groups of mice fed a HFD exhibited a noteworthy visceral adipose tissue mass increase. Accumulating evidence supports this finding, suggesting that adipose tissue growth precedes most dietary effects (Engin & Engin 2017, Gepstein & Weiss 2019).

Our research has shown that a HFD can lead to hyperglycemia and reduced glucose tolerance in mice, consistent with previous studies by our group (Braga et al. 2021). One significant mechanism explaining the impact of high-fat diets on glucose metabolism is their ability to decrease the expression of glucose transporters type 4 (GLUT4), particularly in skeletal muscle and adipose tissue (Ikemoto et al. 1995). This reduction results in decreased glucose uptake by muscle fibers in response to insulin, leading to higher blood glucose levels, glucose intolerance, and insulin resistance (Hribal et al. 2002). Overfeeding on a HFD also increases hepatic glucose production, further exacerbating elevated blood sugar levels (Brøns et al. 2009).

After 25 days of consuming a HFD, dyslipidemia was observed, characterized by a significant increase in plasma triglyceride and cholesterol levels. Elevated plasma lipids are linked to increased activation of pro-inflammatory pathways, which may inhibit insulin action across various tissues (Samuel et al. 2010). The increase in lipid levels is attributed to heightened circulation of absorbed dietary lipids and their hepatic distribution (Soltis et al. 2017).

Prior research has produced conflicting results regarding the effects of a HFD on the exploration and locomotion of animals undergoing the open field test, with some studies showing increased locomotor activity (Mancini et al. 2021) and others indicating decreased performance (Wong et al. 2015). Our study observed no differences on the first day of the animal’s exposure to the experiment arena. However, mice subjected to a HFD for any duration exhibited significantly higher locomotion levels by the third day than those on a SD. This behavior change may be attributed to impaired spatial habituation learning, as evidenced by documented spatial memory impairments in animals on a HFD (Valladolid-Acebes et al. 2011), as well as the absence of notable locomotion differences among the groups on the first day of testing.

The open-field test evaluated potential emotional effects arising from the exploration-aversion conflict. Notably, mice on a HFD for 35 days showed a significant reduction in the time spent in the central area on the first day of exposure to the open field compared to the SD group. This suggests a characteristic anxious response in HFD-fed mice, as supported by various studies (Gainey et al. 2016, Pini et al. 2017, Zemdegs et al. 2016). Previous research highlights the role of inflammation as a crucial factor influencing emotional outcomes linked to dietary patterns. For instance, the work by Noronha et al. (2019) showed that a nine-week HFD protocol increased anxiety-like defensive behavioral responses in rats, which was accompanied by increased proinflammatory cytokine expression, including IL-6 in the amygdala and hypothalamus and TNF-alpha in the amygdala. In this regard, it is possible that the level of inflammation within the first 25 days of HFD may not be sufficient to cause such changes at the amygdala system level.

Short-term recognition memory was also adversely impacted in the groups exposed to an HFD for 25 and 35 days. These animals failed to acquire the novel object recognition task, indicating compromised recognition memory formation. In this context, glucose intolerance was observed before impairments in recognition memory arose. These results suggest that glucose intolerance emerges before the most relevant cognitive changes and may be related to imbalances in metabolic regulation and insulin signaling, which can also directly impact nervous tissue and behavior (Ma et al. 2015, Neergaard et al. 2017). Insulin signaling and blood glucose regulation also function as signals in the nervous system. Neurons respond to insulin, and its action is essential in various synaptic plasticity processes, such as modulating glutamatergic receptors (Lee et al. 2016). Higher plasma cholesterol levels are also associated with cognitive impairment and emotional changes (Schreurs 2010). In animal models, hypercholesterolemia is linked to impairments in various cognitive and behavioral tests, as well as neurochemical changes such as increased activity of the acetylcholinesterase enzyme, neurotransmitter dysfunction, and impaired plasticity systems (Ghodke et al. 2012, Machado et al. 2018, Moreira et al. 2014). A positive correlation between behavioral and metabolic z-scores was observed, indicating that a more pronounced metabolic impact corresponds to a more significant behavioral impact (Zemdegs et al. 2016).

Numerous lines of evidence support a connection between mitochondrial dysfunction and oxidative stress with cognitive and emotional impairments (Knott et al. 2008, Duan et al. 2021, Tripathi et al. 2021). Thus, in another round of experiments, our study sought to evaluate whether the behavioral changes were associated with mitochondrial dysfunction in the frontal cortex, a critical brain region for cognition and emotion. We focused on the effects of 35 days of dieting, during which we noticed more significant behavioral changes. Our findings reveal that 35 days of HFD triggered mitochondrial dysfunction in the frontal cortex, evidenced by reduced ATP production and increased reactive oxygen species generation. We also observed an elevated basal oxygen consumption rate in the cerebral cortical tissue of mice on the HFD compared to those on a regular diet. Collectively, the HFD induced a metabolic state characterized by diminished efficiency, leading to heightened production of reactive species and reduced ATP generation. Such metabolic efficiency is typically associated with neurotoxicity (Langley et al. 2020) and impairment of neuronal plasticity (Pintana et al. 2012). This interplay of factors may underlie the behavioral alterations observed in this study. For instance, mitochondrial dysfunction is associated with inflammation and other energy-dependent disturbances, where the production of reactive oxygen species exceeds the physiological antioxidant protective activity, leading to cellular oxidative damage (Schmitt & Gaspar 2023). Future research could delve deeper into the temporal progression of short-term HFD effects and further explore the influence of brain metabolism and mitochondrial function on behavior and cognition.

CONCLUSIONS

Our research unveils the temporal dynamics of behavioral and metabolic changes triggered by short-term HFD in Swiss mice. The increase in adipose tissue and the onset of glucose intolerance preceded more pronounced behavioral and cognitive changes within 15 days of HFD exposure. Cognitive functions were impacted by day twenty-five, coinciding with the emergence of dyslipidemia characterized by elevated levels of triglycerides and cholesterol in the bloodstream. By day thirty-five of HFD consumption, an anxiogenic effect was observed, indicating a disruption in emotional processing. The alterations in mitochondrial functions within the frontal cortex of animals exposed to 35 days of HFD consumption suggest a correlation between brain impact and behavioral perturbations.

SUPPLEMENTARY MATERIAL

Table SI.

ACKNOWLEDGMENTS

Grants from Brazilian funding agencies financially supported this research: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Universal 424799/2018-9), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Proex), Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (2021TR000342). E.L.G.M. and A.S.L. are recipients of a research productivity fellowship from the CNPq. We used Grammarly (https://www.grammarly.com/) to detect grammatical errors and obtain suggestions for improving the readability and clarity of the manuscript.

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Publication Dates

• Publication in this collection
  09 Dec 2024
• Date of issue
  2024

History

• Received
  15 Aug 2024
• Accepted
  3 Oct 2024