Obesity is defined as abnormal and excessive fat accumulation, and it is a risk factor for developing metabolic and neurodegenerative diseases and cognitive deficits. Obesity is caused by an imbalance in energy homeostasis resulting from increased caloric intake associated with a sedentary lifestyle. However, the entire physiopathology linking obesity with neurodegeneration and cognitive decline has not yet been elucidated. During the progression of obesity, adipose tissue undergoes immune, metabolic, and functional changes that induce chronic low-grade inflammation. It has been proposed that inflammatory processes may participate in both the peripheral disorders and brain disorders associated with obesity, including the development of cognitive deficits. In addition, mitochondrial dysfunction is related to inflammation and oxidative stress, causing cellular oxidative damage. Preclinical and clinical studies of obesity and metabolic disorders have demonstrated mitochondrial brain dysfunction. Since neuronal cells have a high energy demand and mitochondria play an important role in maintaining a constant energy supply, impairments in mitochondrial activity lead to neuronal damage and dysfunction and, consequently, to neurotoxicity. In this review, we highlight the effect of obesity and high-fat diet consumption on brain neuroinflammation and mitochondrial changes as a link between metabolic dysfunction and cognitive decline.

Consumption of high-fat diets (HFD) is associated with brain alterations, including changes in feeding behavior, cognitive decline, and dementia. Astrocytes play a role in HFD-induced neuroinflammation and brain dysfunction; however, this process is not entirely understood. We hypothesized that exposure to saturated fatty acids can compromise astrocyte viability and mitochondrial function. The C6 (astrocytes) cell line was treated with palmitate or stearate (200 µM and 400 µM) for 6 h. Cell viability, morphology, inflammatory markers, and oxidative stress were evaluated. To assess mitochondrial function, various parameters were measured (membrane potential, mass, respiration, and complex activities). We observed that 6 h of treatment with 400 µM palmitate decreased cell viability, and treatment with 200 µM palmitate changed the astrocyte morphology. Palmitate increased inflammatory markers (TNF-α and IL6) but did not induce oxidative stress. Palmitate significantly decreased the mitochondrial membrane potential and mitochondrial mass. Complex I activity also decreased in palmitate-treated cells; however, no changes were observed in mitochondrial respiration. In conclusion, palmitate, a saturated fatty acid, induces inflammation and impairs mitochondrial function, leading to reduced astrocytic cell viability and changes in cellular morphology. Our study provides valuable insights into the potential mechanisms underlying the relationship between saturated fatty acids, astrocytes, and mitochondrial function in obesity-related brain dysfunction.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, along with restricted and repetitive patterns of behavior, interests, or activities. ASD encompasses a wide spectrum of clinical presentations and functional impairments, ranging from mild to severe. Despite its prevalence, the underlying physiopathological mechanisms of ASD remain largely unknown, resulting in a lack of effective targeted therapeutic interventions, contributing to significant financial and emotional burdens on affected families and the healthcare system. Emerging evidence suggests that dysfunction in the tetrahydrobiopterin (BH4) pathway may impair the activity of monoaminergic and nitric oxide (NO)-dependent neurons in individuals with ASD. To explore this potential mechanism, we conducted a systematic review to analyze such impairments to gather information on whether the off-label use of BH4 could represent a novel pharmacological approach for managing ASD. Following the PRISMA 2020 guidelines, we systematically reviewed the literature from four databases: PubMed, Virtual Health Library, Cochrane Library, and SciELO, from January 1967 to December 2021. The quality of the included studies was assessed using the Newcastle–Ottawa scale. The inclusion criteria for this systematic review focused on identifying articles published in English that contained the following keywords, used in various combinations: autism, ASD, autism spectrum disorder, BH4, tetrahydrobiopterin, neopterin, NO, nitric oxide. The analysis was performed between December 2020 and December 2021. The collected data demonstrated that BH4 metabolism was altered in individuals with ASD. Lower levels of BH4 were reported in biological samples from ASD-affected individuals compared to age- and sex-matched controls. Additionally, neopterin levels were elevated in plasma and urine, but decreased in cerebrospinal fluid, while nitric oxide levels were consistently reported to be higher across studies. Treatment with BH4 has shown potential in improving ASD-related symptoms. The reported increase in neopterin in biological fluids indicates inflammation, while the reduction in BH4 levels suggests a potential shift in its metabolic role. Specifically, BH4 may be diverted from its primary role in neurotransmitter synthesis to function as an antioxidant or to perpetuate inflammation through NO production. Given that BH4 is a critical cofactor in monoaminergic neurotransmission, its dysfunction highlights the molecule's therapeutic potential. BH4, already FDA-approved for other conditions, emerges as a promising off-label candidate to alleviate ASD symptomatology.

Obesity is a worldwide epidemic disease marked by changes in the function of various tissue and organs, driven by excessive fat accumulation. In recent years obesity was characterized not just by the increase of fat, but also an imbalance of energy homeostasis mechanisms. In parallel with global rise in obesity, the incidence of obesity during pregnancy and lactation had also been steadily increasing. Maternal obesity is a public health issue that affects the child and the mother, in acute and chronic term, being a risk factor for the development of metabolic, hormonal, neurodevelopmental, and psychiatric disorders in offspring. Obesity during the gestation can reprogram the fetal immune, metabolic, endocrine, and neurological systems, influencing offspring's metabolism and mental health. This is supported by the Developmental Origins of Health and Disease (DOHaD) theory, which proposes that environmental factors during critical periods of early development (as the fetal period) can influence the risk of developing diseases later in life. In this review, we focused on how maternal obesity can affect the brain offspring neurodevelopment, neural circuits, synapses, glial cells, and neuroinflammation, which all can influence offspring behavioral disorders. image

Background/Objectives: Caffeine consumption has been reported to have beneficial effects in metabolic disorders; however, its effects on food intake are not fully elucidated. This study evaluated the impact of chronic caffeine consumption on weight gain, food intake, and metabolic parameters in C57BL/6 male mice. Methods: Eight-week-old male mice (28 animals) were divided into four groups: control (chow diet), caffeine (chow diet + 1 g/L caffeine in drinking water), high-fat diet (HFD), and HFD + caffeine (HFD + 1 g/L caffeine in drinking water). Diets and caffeine were provided ad libitum for 8 weeks. Food and water intake were recorded weekly, and blood glucose was measured every 4 weeks. After 8 weeks of diet and caffeine exposure, metabolic tests were conducted, and tissues were collected for biochemical analysis. Results: HFD consumption for 8 weeks induced an increase in body weight and adiposity compared to the chow diet, without changes in food intake. Caffeine consumption prevented body weight gain and adiposity, although it increased food intake. Caffeine also improved glucose tolerance in the HFD mouse model, without changes in random blood glucose, triglyceride, or cholesterol levels. Analysis of hypothalamic neuropeptide (Agrp, NPY, Pomc, Cart), involved in the control of food intake, showed no differences in expression. There were also no changes observed in locomotion nor in anxiety-like behavior. Conclusions: In conclusion, chronic high-fat diet (HFD) exposure induced obesity characterized by increased body weight and adiposity without altering food intake. Chronic caffeine consumption counteracted HFD-induced weight gain and fat accumulation and improved glucose tolerance, despite increasing food intake. Importantly, caffeine consumption in the HFD group did not affect locomotor activity or anxiety-like behavior, suggesting that its metabolic effects are not driven by changes in general activity or emotional state. Overall, these findings indicate that chronic caffeine consumption improves metabolic homeostasis in HFD-fed mice.