An early, reversible cholesterolgenic etiology of diet-induced insulin resistance.

OBJECTIVE: A buildup of skeletal muscle plasma membrane (PM) cholesterol content in mice occurs within 1 week of a Western-style high-fat diet and causes insulin resistance. The mechanism driving this cholesterol accumulation and insulin resistance is not known. Promising cell data implicate that the hexosamine biosynthesis pathway (HBP) triggers a cholesterolgenic response via increasing the transcriptional activity of Sp1. In this study we aimed to determine whether increased HBP/Sp1 activity represented a preventable cause of insulin resistance. METHODS: C57BL/6NJ mice were fed either a low-fat (LF, 10% kcal) or high-fat (HF, 45% kcal) diet for 1 week. During this 1-week diet the mice were treated daily with either saline or mithramycin-A (MTM), a specific Sp1/DNA-binding inhibitor. A series of metabolic and tissue analyses were then performed on these mice, as well as on mice with targeted skeletal muscle overexpression of the rate-limiting HBP enzyme glutamine-fructose-6-phosphate-amidotransferase (GFAT) that were maintained on a regular chow diet. RESULTS: Saline-treated mice fed this HF diet for 1 week did not have an increase in adiposity, lean mass, or body mass while displaying early insulin resistance. Consistent with an HBP/Sp1 cholesterolgenic response, Sp1 displayed increased O-GlcNAcylation and binding to the HMGCR promoter that increased HMGCR expression in skeletal muscle from saline-treated HF-fed mice. Skeletal muscle from these saline-treated HF-fed mice also showed a resultant elevation of PM cholesterol with an accompanying loss of cortical filamentous actin (F-actin) that is essential for insulin-stimulated glucose transport. Treating these mice daily with MTM during the 1-week HF diet fully prevented the diet-induced Sp1 cholesterolgenic response, loss of cortical F-actin, and development of insulin resistance. Similarly, increases in HMGCR expression and cholesterol were measured in muscle from GFAT transgenic mice compared to age- and weight-match wildtype littermate control mice. In the GFAT Tg mice we found that these increases were alleviated by MTM. CONCLUSIONS: These data identify increased HBP/Sp1 activity as an early mechanism of diet-induced insulin resistance. Therapies targeting this mechanism may decelerate T2D development.

The Therapeutic Effects of Ketamine in Mental Health Disorders: A Narrative Review.

Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is commonly used as an anesthetic and analgesic but has recently shown promising research in treating certain psychiatric conditions such as depression, post-traumatic stress disorder (PTSD), suicidal ideation, and substance use disorder. Due to its euphoric, dissociative, and hallucinogenic properties, ketamine has been abused as a recreational drug, which has led to rigid regulation of medication. The COVID-19 pandemic has been an unprecedented challenge for the American population which was reflected in increased reports of problems regarding their mental health. Mood disorders have dramatically increased in the past two years. Approximately one in ten people stated that they had started or increased substance use because of the COVID-19 pandemic. Furthermore, rates of suicidal ideation have significantly increased when compared to pre-pandemic levels, with more than twice the number of adults surveyed in 2018 indicating suicidal thoughts "within the last 30 days" at the time they were surveyed. Moreover, many responders indicated they had symptoms of PTSD. The PubMed database was searched using the keyword "ketamine," in conjunction with "depression," "suicidal ideation," "substance use disorder," and "post-traumatic stress disorder." The inclusion criteria encompassed articles from 2017 to 2022 published in the English language that addressed the relationship between ketamine and mental health disorders. With this sharp increase in the prevalence of psychiatric disorders and an increased public interest in mental health combined with the promise of the therapeutic value of ketamine for certain mental health conditions, including suicidal ideation, this narrative review sought to identify recently published studies that describe the therapeutic uses of ketamine for mental health. Results of this review indicate that ketamine's therapeutic effects offer a potential alternative treatment for depression, suicidal ideation, substance use disorders, and PTSD.

Brain networks shaping religious belief.

We previously demonstrated with functional magnetic resonance imaging (fMRI) that religious belief depends upon three cognitive dimensions, which can be mapped to specific brain regions. In the present study, we considered these co-activated regions as nodes of three networks each one corresponding to a particular dimension, corresponding to each dimension and examined the causal flow within and between these networks to address two important hypotheses that remained untested in our previous work. First, we hypothesized that regions involved in theory of mind (ToM) are located upstream the causal flow and drive non-ToM regions, in line with theories attributing religion to the evolution of ToM. Second, we hypothesized that differences in directional connectivity are associated with differences in religiosity. To test these hypotheses, we performed a multivariate Granger causality-based directional connectivity analysis of fMRI data to demonstrate the causal flow within religious belief-related networks. Our results supported both hypotheses. Religious subjects preferentially activated a pathway from inferolateral to dorsomedial frontal cortex to monitor the intent and involvement of supernatural agents (SAs; intent-related ToM). Perception of SAs engaged pathways involved in fear regulation and affective ToM. Religious beliefs are founded both on propositional statements for doctrine, but also on episodic memory and imagery. Beliefs based on doctrine engaged a pathway from Broca's to Wernicke's language areas. Beliefs related to everyday life experiences engaged pathways involved in imagery. Beliefs implying less involved SAs and evoking imagery activated a pathway from right lateral temporal to occipital regions. This pathway was more active in non-religious compared to religious subjects, suggesting greater difficulty and procedural demands for imagining and processing the intent of SAs. Insights gained by Granger connectivity analysis inform us about the causal binding of individual regions activated during religious belief processing.

Oxytocin receptor genetic variation promotes human trust behavior.

Given that human trust behavior is heritable and intranasal administration of oxytocin enhances trust, the oxytocin receptor (OXTR) gene is an excellent candidate to investigate genetic contributions to individual variations in trust behavior. Although a single-nucleotide polymorphism involving an adenine (A)/guanine (G) transition (rs53576) has been associated with socio-emotional phenotypes, its link to trust behavior is unclear. We combined genotyping of healthy male students (n = 108) with the administration of a trust game experiment. Our results show that a common occurring genetic variation (rs53576) in the OXTR gene is reliably associated with trust behavior rather than a general increase in trustworthy or risk behaviors. Individuals homozygous for the G allele (GG) showed higher trust behavior than individuals with A allele carriers (AA/AG). Although the molecular functionality of this polymorphism is still unknown, future research should clarify how the OXTR gene interacts with other genes and the environment in promoting socio-emotional behaviors.