Association between polychlorinated biphenyl (PCB) and dioxin with metabolic syndrome (METS): a systematic review and meta-analysis.

Polychlorinated biphenyls (PCBs) and dioxin are persistent endocrine disrupting chemicals (EDCs) and have been associated with an increased risk of metabolic syndrome (MetS). The aim of this systematic review and meta-analysis was to assess the associations of PCBs and dioxin with MetS and its risk factors, including obesity, hypertriglyceridaemia (HTG), hypertension (HTN) and diabetes mellitus (DM). We searched three electronic databases for epidemiological studies concerning PCBs and dioxin with MetS published up to the end of 2023. Meta-analysis was performed for MetS itself and each of the MetS risks based on a random-effects meta-analysis model, and odds ratios (ORs) with 95% confidence intervals (CIs) were obtained. Publication bias was assessed based on Egger's test. Eleven studies were included from three databases up to 2023. There were 40,528 participants aged 18-89, where 18-100% of them were males, included in our meta-analysis. The meta-analysis results showed a strong association between PCB exposure and DM (OR = 3.593, 95% CI 2.566, 5.031), while most of the risk factors for MetS, including obesity (OR = 1.875, 95% CI 0.883, 3.979), HTN (OR = 1.335, 95% CI 0.902, 1.976) and HTG (OR = 1.611, 95% CI 0.981, 2.643), were weakly associated with PCB. Furthermore, both PCBs (OR = 1.162, 95% CI 0.994, 1.357) and dioxin (OR = 2.742, 95% CI 1.936, 3.883) were found to be weakly and strongly associated with MetS, respectively. Meta-regression analysis showed that DM in the Asian population is associated with PCB exposure, while HTG in the Northern American population is associated with PCB exposure. Our meta-analysis has demonstrated a strong relationship between DM and PCBs, while the relationship between PCBs with MetS and other risk factors is less pronounced. Additionally, MetS is weakly associated with dioxin exposure. To improve primary care outcomes, healthcare providers should consider incorporating the assessment of patients' risk of exposure to PCBs and dioxins into their evaluation procedures for more targeted medical interventions.

Addressing chemically-induced obesogenic metabolic disruption: selection of chemicals for in vitro human PPARα, PPARγ transactivation, and adipogenesis test methods.

Whilst western diet and sedentary lifestyles heavily contribute to the global obesity epidemic, it is likely that chemical exposure may also contribute. A substantial body of literature implicates a variety of suspected environmental chemicals in metabolic disruption and obesogenic mechanisms. Chemically induced obesogenic metabolic disruption is not yet considered in regulatory testing paradigms or regulations, but this is an internationally recognised human health regulatory development need. An early step in the development of relevant regulatory test methods is to derive appropriate minimum chemical selection lists for the target endpoint and its key mechanisms, such that the test method can be suitably optimised and validated. Independently collated and reviewed reference and proficiency chemicals relevant for the regulatory chemical universe that they are intended to serve, assist regulatory test method development and validation, particularly in relation to the OECD Test Guidelines Programme. To address obesogenic mechanisms and modes of action for chemical hazard assessment, key initiating mechanisms include molecular-level Peroxisome Proliferator-Activated Receptor (PPAR) α and γ agonism and the tissue/organ-level key event of perturbation of the adipogenesis process that may lead to excess white adipose tissue. Here we present a critical literature review, analysis and evaluation of chemicals suitable for the development, optimisation and validation of human PPARα and PPARγ agonism and human white adipose tissue adipogenesis test methods. The chemical lists have been derived with consideration of essential criteria needed for understanding the strengths and limitations of the test methods. With a weight of evidence approach, this has been combined with practical and applied aspects required for the integration and combination of relevant candidate test methods into test batteries, as part of an Integrated Approach to Testing and Assessment for metabolic disruption. The proposed proficiency and reference chemical list includes a long list of negatives and positives (20 chemicals for PPARα, 21 for PPARγ, and 11 for adipogenesis) from which a (pre-)validation proficiency chemicals list has been derived.

Pre-pubertal obesity compromises ovarian oxidative stress, DNA repair and chemical biotransformation.

Obesity in adult females impairs fertility by altering oxidative stress, DNA repair and chemical biotransformation. Whether prepubertal obesity results in similar ovarian impacts is under-explored. The objective of this study was to induce obesity in prepubertal female mice and assess puberty onset, follicle number, and abundance of oxidative stress, DNA repair and chemical biotransformation proteins basally and in response to 7,12-dimethylbenz(a)anthracene (DMBA) exposure. DMBA is a polycyclic aromatic hydrocarbon that has been shown to be ovotoxic. Lactating dams (C57BL6J) were fed either a normal rodent containing 3.5% kCal from fat (lean), or a high fat diet comprised of 60% kCal from fat, and 9% kCal from sucrose. The offspring were weaned onto the diet of their dam and exposed at postnatal day 35 to either corn oil or DMBA (1 mg/kg) for 7 d via intraperitoneal injection. Mice on the HFD had reduced (P < 0.05) age at puberty onset as measured by vaginal opening but DMBA did not impact puberty onset. Heart, spleen, kidney, uterus and ovary weight were increased (P < 0.05) by obesity and liver weight was increased (P < 0.05) by DMBA exposure in obese mice. Follicle number was largely unaffected by obesity or DMBA exposure, with the exception of primary follicle number, which were higher (P < 0.05) in lean DMBA exposed and obese control relative to lean control mice. There were also greater numbers (P < 0.05) of corpora lutea in obese relative to lean mice. In lean mice, DMBA exposure reduced (P < 0.05) the level of CYP2E1, EPHX1, GSTP1, BRCA1, and CAT but this DMBA-induced reduction was absent in obese mice. Basally, obesity reduced (P < 0.05) the abundance of CYP2E1, EPHX1, GSTP1, BRCA1, SOD1 and CAT. There was greater (P < 0.05) fibrotic staining in obese DMBA-exposed ovaries and PPP2CA was decreased (P < 0.05) in growing follicles by both obesity and DMBA exposure. Thus, prepubertal obesity alters the capacity of the ovary to respond to DNA damage, ovotoxicant exposure and oxidative stress.

Metformin exposure during pregnancy and lactation affects offspring's long-term body weight and adipose tissue mass independent of the maternal metabolic state.

The increasing prevalence of obesity, type 2 diabetes mellitus (T2DM), and gestational diabetes (GDM) among pregnant women has risen dramatically worldwide. The antihyperglycemic drug metformin is the most common drug for T2DM treatment in non-pregnant individuals; nevertheless, it is increasingly being used for diabetes-complicated pregnancies. Studies on the long-term metabolic effects of this drug in offspring remain scarce. This work aimed to determine the effect of metformin exposure during pregnancy and lactation on the offspring of a model of diet-induced maternal hyperglycemia. Cohorts of pregnant mice were fed a 46% fat diet (HFD) or a control standard diet (SD). A group of dams were exposed to metformin during pregnancy and lactation. After weaning, the offspring were fed SD for 8 weeks and then challenged with a 46% HFD after puberty for 12 weeks. Irrespective of the maternal diet, offspring of metformin-exposed mothers had a lower body weight and reduced inguinal white adipose tissue (iWAT) mass after HFD challenge. This was associated with increased expression of Pparg, Fabp4, Glut4, Srebp1, and Fasn in the iWAT during adulthood in the metabolically impaired dams exposed to metformin, suggesting increased adipogenesis and de novo lipogenesis. Increased expression of Fasn associated with decreased methylation levels at its promoter and proximal coding region in the iWAT was found. These results suggest that metformin modulates gene expression levels by epigenetic mechanisms in maternal metabolic-impaired conditions.

Experimental Model Exposed to Bisphenol and Submitted to a High-Fat Diet and Related Morphologic Testicular Parameters Alterations Analysis.

PURPOSE: To evaluate the morphological and stereological parameters of the testicles in mice exposed to bisphenol S and/or high-fat diet-induced obesity. MATERIAL AND METHODS: Forty adult male C57BL/6 mice were fed a standard diet (SC) or high-fat diet (HF) for a total of 12 weeks. The sample was randomly divided into 4 experimental groups with 10 mices as follows: a) SC - animals fed a standard diet; b) SC-B - animals fed a standard diet and administration of BPS (25 µg/kg of body mass/day) in drinking water; c) HF: animals fed a high-fat diet; d) HF-B - animals fed a high-fat diet and administration of BPS (25 µg/Kg of body mass/day) in drinking water. BPS administration lasted 12 weeks, following exposure to the SC and HF diets. BPS was diluted in absolute ethanol (0.1%) and added to drinking water (concentration of 25 µg/kg body weight/day). The animals were euthanized, and the testes were processed and stained with hematoxylin and eosin (H&E) for morphometric and stereological parameters, including density of seminiferous tubules per area, length density and total length of seminiferous tubules, height of the tunica albuginea and the diameter of the seminiferous tubules. The images were captured with an Olympus BX51 microscope and Olympus DP70 camera. The stereological analysis was done with the Image Pro and Image J programs. Means were statistically compared using ANOVA and the Holm-Sidak post-test (p<0.05). RESULTS: The seminiferous tubule density per area reduced in all groups when compared with SC samples (p<0.001): HF (40%), SC-B 3(2%), and HF-B (36%). Length density was reduced significantly (p<0.001) in all groups when compared with SC group: HF (40%), SC-B (32%), and HF-B (36%). The seminiferous tubule total length was reduced (p<0.001) when compared to f HF (28%) and SC-B (26%) groups. The tubule diameter increased significantly (p<0.001) only when we compared the SC group with SC (54%) an SC-B (25%) groups and the tunica thickness increased significantly only in HF group (117%) when compared with SC-B (20%) and HF-B 31%. CONCLUSION: Animals exposed to bisphenol S and/or high-fat diet-induced obesity presented important structural alterations in testicular morphology.

Consumption of interesterified palm oil leads inflammation of white adipose tissue and triggers metabolic disturbances in mice on a high-fat diet.

Growing obesity is linked to shifts in dietary patterns, particularly the increased intake of ultra-processed high-fat foods. This study aimed to evaluate the effects of interesterified palm oil consumption on glucose homeostasis, adipose tissue remodeling, and hepatic lipogenesis in C57BL/6 mice fed a high-fat diet. Sixty C57BL/6 mice were divided into four groups (n = 15): the control group (C) fed a standard diet (4% soybean oil), the high-fat group (HF) (23.8% lard), the high palm oil fat group (HFP) (23.8% palm oil), and the high interesterified palm fat group (HFI) (23.8% interesterified palm oil) for 8 weeks (all groups received 50% energy from lipids). The HFI group exhibited higher body mass than the HF group (+ 11%, P < 0.05), which was attributed to an increased percentage of fat mass. Plasma concentrations of IL-6, insulin, and HOMA-IR were also elevated in the HFI group. Both the HFP and HFI groups showed hypertrophied adipocytes and pancreatic islets, increased alpha and beta cell masses, hepatic steatosis, low expression of genes related to beta-oxidation, and upregulated lipogenesis. In conclusion, the consumption of interesterified palm oil alters inflammatory and glucose profiles.

Effects of Excessive High-fructose Corn Syrup Drink Intake in Middle-aged Mice.

BACKGROUND/AIM: The global prevalence of type 2 diabetes (T2D) continues to increase, necessitating the need for understanding the causes of its development. The widespread use of high-fructose corn syrup (HFCS) in drinks and diets is suspected to play a role in metabolic disorders. Although many studies have reported on the effects of excessive HFCS and excessive energy intakes in middle-aged individuals, few have focused on energy restriction. This study aimed to investigate the effects of excessive HFCS drink intake under energy restriction on developing T2D in early middle-aged mice. MATERIALS AND METHODS: Early middle-aged mice were divided in HFCS and control groups; they were provided either 10% HFCS water or deionized water ad libitum for 12 weeks, respectively. Total energy intake was controlled using a standard rodent diet. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), tissue weight measurements, serum parameter analyses, and mRNA expression assessments were performed. RESULTS: No increase in body and adipose tissue weight was observed with excessive HFCS intake under energy restriction. Moreover, serum lipid parameters did not differ from those of controls. However, in the OGTT and ITT, the HFCS group showed higher blood glucose levels than the control group. Moreover, the pancreatic weight and insulin II mRNA expression were reduced. CONCLUSION: The excessive HFCS drink intake under energy restriction did not induce obesity; however, it induced impaired glucose tolerance, indicating its negative effects on the pancreas in early middle-aged mice. When translated in human physiology, our results show that even if one does not become obese, excessive HFCS may affect the overall metabolic mechanism; these effects may vary depending on age.

Long-term Bisphenol S exposure induced gut microbiota dysbiosis, obesity, hepatic lipid accumulation, intestinal lesions and dyslipidemia in mice.

Bisphenol S (BPS) is a commonly detected chemical raw material in water, which poses significant threats to both the ecological environment and human health. Despite being recognized as a typical endocrine disruptor and a substitute for Bisphenol A, the toxicological effects of BPS remain nonnegligible. In order to comprehensively understand the health impacts of BPS, a long-term (154 days) exposure experiment was conducted on mice, during which the physiological indicators of the liver, intestine, and blood were observed. The findings revealed that exposure to BPS resulted in dysbiosis of the gut microbiota, obesity, hepatic lipid accumulation, intestinal lesions, and dyslipidemia. Furthermore, there exists a significant correlation between gut microbiota and indicators of host health. Consequently, the identification of specific gut microbiota can be considered as potential biomarkers for the evaluation of risk associated with BPS. This study will effectively address the deficiency in toxicological data pertaining to BPS. The novel BPS data obtained from this research can serve as a valuable reference for professionals in the field.

Relationship between functional connectivity and weight-gain risk of antipsychotics in schizophrenia.

BACKGROUND: The mechanisms by which antipsychotic medications (APs) contribute to obesity in schizophrenia are not well understood. Because AP effects on functional brain connectivity may contribute to weight effects, the current study investigated how AP-associated weight-gain risk relates to functional connectivity in schizophrenia. METHODS: Fifty-five individuals with schizophrenia (final N = 54) were divided into groups based on previously reported AP weight-gain risk (no APs/low risk [N = 19]; moderate risk [N = 17]; high risk [N = 18]). Resting-state functional magnetic resonance imaging (fMRI) was completed after an overnight fast ("fasted") and post-meal ("fed"). Correlations between AP weight-gain risk and functional connectivity were assessed at the whole-brain level and in reward- and eating-related brain regions (anterior insula, caudate, nucleus accumbens). RESULTS: When fasted, greater AP weight-gain risk was associated with increased connectivity between thalamus and sensorimotor cortex (pFDR = 0.021). When fed, greater AP weight-gain risk was associated with increased connectivity between left caudate and left precentral/postcentral gyri (pFDR = 0.048) and between right caudate and multiple regions, including the left precentral/postcentral gyri (pFDR = 0.001), intracalcarine/precuneal/cuneal cortices (pFDR < 0.001), and fusiform gyrus (pFDR = 0.008). When fed, greater AP weight-gain risk was also associated with decreased connectivity between right anterior insula and ventromedial prefrontal cortex (pFDR = 0.002). CONCLUSIONS: APs with higher weight-gain risk were associated with greater connectivity between reward-related regions and sensorimotor regions when fasted, perhaps relating to motor anticipation for consumption. Higher weight-gain risk APs were also associated with increased connectivity between reward, salience, and visual regions when fed, potentially reflecting greater desire for consumption following satiety.

The impact of metformin on weight and metabolic parameters in patients with obesity: A systematic review and meta-analysis of randomized controlled trials.

There are conflicting data on the weight-reducing potential of metformin (MTF) in nondiabetic patients with obesity. The purpose of this systematic review and meta-analysis was to evaluate the effect of MTF on weight and cardiometabolic parameters in adults with overweight/obesity with or without nonalcoholic fatty liver disease (NAFLD) (CRD42018085512). We included randomized controlled trials (RCTs) in adults without diabetes mellitus, with mean body mass index (BMI) ≥ 25 kg/m2, with or without NAFLD, comparing MTF to placebo/control, lifestyle modification (LSM) or a US Food and Drug Administration-approved anti-obesity drug, reporting on weight or metabolic parameters, and extending over at least 3 months. We conducted a systematic search in MEDLINE, EMBASE, PubMed and the Cochrane Library without time limitation (until March 2022). We screened and selected eligible articles, abstracted relevant data, and assessed the risk of bias. All steps were in duplicate and independently. We conducted a random-effects model meta-analysis using Review Manager version 5.3, with prespecified subgroup analyses in case of heterogeneity. We identified 2650 citations and included 49 trials (55 publications). Compared to placebo, MTF was associated with a significant reduction in BMI (mean difference [MD] -0.56 [-0.74, -0.37] kg/m2; p < 0.0001), at doses ranging from 500 to 2550 mg/day, and with a significant percentage change in BMI of -2.53% (-2.90, -2.17) at the dose 1700 mg/day. There was no interaction by baseline BMI, MTF dose or duration, nor presence or absence of NAFLD. There was no significant difference between MTF and LSM. Orlistat was more effective than MTF (at doses of 1000-1700 mg/day) in terms of weight loss, with an MD in BMI of -3.17 (-5.88; -0.47) kg/m2, favouring the former. Compared to placebo/control, MTF improved insulin parameters, while no effect was detected when compared to LSM. A few small trials showed heterogenous effects on liver parameters in patients with NAFLD treated with MTF compared to placebo/control. There was a large variability in the expression of outcome measures and RCTs were of low quality. In conclusion, MTF was associated with a modest weight reduction in obese nondiabetic patients. Further high-quality and better powered studies are needed to examine the impact of MTF in patients with insulin resistance and NAFLD.

Allyl isothiocyanate, a TRPA1 agonist, protects against olanzapine-induced hypothalamic and hepatic metabolic aberrations in female mice.

Olanzapine, a widely prescribed atypical antipsychotic, poses a great risk to the patient's health by fabricating a plethora of severe metabolic and cardiovascular adverse effects eventually reducing life expectancy and patient compliance. Its heterogenous receptor binding profile has made it difficult to point out a specific cause or treatment for the related side effects. Growing body of evidence suggest that transient receptor potential (TRP) channel subfamily Ankyrin 1 (TRPA1) has pivotal role in pathogenesis of type 2 diabetes and obesity. With this background, we aimed to investigate the role of pharmacological manipulations of TRPA1 channels in antipsychotic (olanzapine)-induced metabolic alterations in female mice using allyl isothiocyanate (AITC) and HC-030031 (TRPA1 agonist and antagonist, respectively). It was found that after 6 weeks of treatment, AITC prevented olanzapine-induced alterations in body weight and adiposity; serum, and liver inflammatory markers; glucose and lipid metabolism; and hypothalamic appetite regulation, nutrient sensing, inflammatory and TRPA1 channel signaling regulating genes. Furthermore, several of these effects were absent in the presence of HC-030031 (TRPA1 antagonist) indicating protective role of TRPA1 agonism in attenuating olanzapine-induced metabolic alterations. Supplementary in-depth studies are required to study TRPA1 channel effect on other aspects of olanzapine-induced metabolic alterations.

Highly crystalline cellulose microparticles from dealginated seaweed waste ameliorate high fat-sugar diet-induced hyperlipidemia in mice by modulating gut microbiota.

The effects of seaweed cellulose (SC) on high fat-sugar diet (HFSD)-induced glucolipid metabolism disorders in mice and potential mechanisms were investigated. SC was isolated from dealginated residues of giant kelp (Macrocystis pyrifera), with a crystallinity index of 85.51 % and an average particle size of 678.2 nm. Administering SC to C57BL/6 mice at 250 or 500 mg/kg BW/day via intragastric gavage for six weeks apparently inhibited the development of HFSD-induced obesity, dyslipidemia, insulin resistance, oxidative stress and liver damage. Notably, SC intervention partially restored the structure and composition of the gut microbiota altered by the HFSD, substantially lowering the Firmicutes to Bacteroidetes ratio, and greatly increasing the relative abundance of Lactobacillus, Bifidobacterium, Oscillospira, Bacteroides and Akkermansia, which contributed to improved short-chain fatty acid (SCFA) production. Supplementing with a higher dose of SC led to more significant increases in total SCFA (67.57 %), acetate (64.56 %), propionate (73.52 %) and butyrate (66.23 %) concentrations in the rectal contents of HFSD-fed mice. The results indicated that highly crystalline SC microparticles could modulate gut microbiota dysbiosis and ameliorate HFSD-induced obesity and related metabolic syndrome in mice. Furthermore, particle size might have crucial impact on the prebiotic effects of cellulose as insoluble dietary fiber.

Pubertal glyphosate-based herbicide exposure aggravates high-fat diet-induced obesity in female mice.

Glyphosate-based herbicides (GBH) are the most widely used pesticides globally. Studies have indicated that they may increase the risk of various organic dysfunctions. Herein, we verified whether exposure to GBH during puberty increases the susceptibility of male and female mice to obesity when they are fed a high-fat diet (HFD) in adulthood. From the 4th-7th weeks of age, male and female C57Bl/6 mice received water (CTL group) or 50 mg GBH /kg body weight (BW; GBH group). From the 8th-21st weeks of age, the mice were fed a standard diet or a HFD. It was found that pubertal GBH exposure exacerbated BW gains and hyperphagia induced by HFD, but only in female GBH-HFD mice. These female mice also exhibited high accumulation of perigonadal and subcutaneous fat, as well as reduced lean body mass. Both male and female GBH-HFD displayed hypertrophic white adipocytes. However, only in females, pubertal GBH exposure aggravated HFD-induced fat accumulation in brown adipocytes. Furthermore, GBH increased plasma cortisol levels by 80% in GBH-HFD males, and 180% in GBH-HFD females. In conclusion, pubertal GBH exposure aggravated HFD-induced obesity, particularly in adult female mice. This study provides novel evidence that GBH misprograms lipid metabolism, accelerating the development of obesity when individuals are challenged by a second metabolic stressor, such as an obesogenic diet.

Epidemiology studies on effects of lithium salts in pregnancy are confounded by the inability to control for other potentially teratogenic factors.

INTRODUCTION: In bipolar women who took lithium during pregnancy, several epidemiology studies have reported small increases in a rare fetal cardiac defect termed Ebstein's anomaly. METHODS: Behavioral, environmental, and lifestyle-associated risk factors associated with bipolar disorder and health insurance status were determined from an Internet search. The search was conducted from October 1, 2023, through October 14, 2023. The search terms employed included the following: bipolar, bipolar disorder, mood disorders, pregnancy, congenital heart defects, Ebstein's anomaly, diabetes, hypertension, Medicaid, Medicaid patients, alcohol use, cigarette smoking, marijuana, cocaine, methamphetamine, narcotics, nutrition, diet, obesity, body mass index, environment, environmental exposures, poverty, socioeconomic status, divorce, unemployment, and income. No quotes, special fields, truncations, etc., were used in the searches. No filters of any kind were used in the searches. RESULTS: Women who remain on lithium in the United States throughout their pregnancy are likely to be experiencing mania symptoms and/or suicidal ideation refractory to other drugs. Pregnant women administered the highest doses of lithium salts would be expected to have been insufficiently responsive to lower doses. Any small increases in the retrospectively determined risk of fetal cardiac anomalies in bipolar women taking lithium salts cannot be disentangled from potential developmental effects resulting from very high rates of cigarette smoking, poor diet, alcohol abuse, ingestion of illegal drugs like cocaine or opioids, marijuana smoking, obesity, and poverty. CONCLUSIONS: The small risks in fetal cardiac abnormalities reported in the epidemiology literature do not establish a causal association for lithium salts and Ebstein's anomaly.

The "crosstalk" between microbiota and metabolomic profile in high-fat-diet-induced obese mice supplemented with Bletilla striata polysaccharides and composite polysaccharides.

The potential prebiotic feature of Bletilla striata polysaccharides (BSP) has been widely accepted, while the beneficial effect of BSP on high-fat-diet-induced obesity is unclear. Moreover, the "crosstalk" between microbiota and metabolomic profile in high-fat-diet-induced obese mice supplemented with BSP still need to be further explored. The present study attempted to illustrate the effect of BSP and/or composite polysaccharides on high-fat-diet-induced obese mice by combining multi-matrix (feces, urine, liver) metabolomics and gut microbiome. The results showed that BSP and/or composite polysaccharides were able to reduce the abnormal weight gain induced by high-fat diet. A total of 175 molecules were characterized by proton nuclear magnetic resonance (1H NMR) in feces, urine and liver, suggesting that multi-matrix metabolomics could provide a comprehensive view of metabolic regulatory mechanism of BSP in high-fat-diet-induced obese mice. Several pathways were altered in response to BSP supplementation, mainly pertaining to amino acid, purine, pyrimidine, ascorbate and aldarate metabolisms. In addition, BSP ameliorated high-fat-diet-induced imbalanced gut microbiome, by lowering the ratio of Firmicutes/Bacteroidetes. Significant correlations were illustrated between particular microbiota's features and specific metabolites. Overall, the anti-obesity effect of BSP could be attributed to the amelioration of the disorders of gut microbiota and to the regulation of the "gut-liver axis" metabolism.

Psychotropic Drug-Related Weight Gain and Its Treatment.

Psychotropic drug-related weight gain (PDWG) is a common occurrence and is highly associated with non-initiation, discontinuation, and dissatisfaction with psychiatric drugs. Moreover, PDWG intersects with the elevated risk for obesity and associated morbidity that has been amply reported in the psychiatric population. Evidence indicates that differential liability for PDWG exists for antipsychotics, antidepressants, and anticonvulsants. During the past two decades, agents within these classes have become available with significantly lower or no liability for PDWG and as such should be prioritized. Although lithium is associated with weight gain, the overall extent of weight gain is significantly lower than previously estimated. The benefit of lifestyle and behavioral modification for obesity and/or PDWG in psychiatric populations is established, with effectiveness similar to that in the general population. Metformin is the most studied pharmacological treatment in the prevention and treatment of PDWG, and promising data are emerging for glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide, exenatide, semaglutide). Most pharmacologic antidotes for PDWG are supported with low-confidence data (e.g., topiramate, histamine-2 receptor antagonists). Future vistas for pharmacologic treatment for PDWG include large, adequately controlled studies with GLP-1 receptor agonists and possibly GLP-1/glucose-dependent insulinotropic polypeptide co-agonists (e.g., tirzepatide) as well as specific dietary modifications.

Olanzapine attenuates 5-HT2cR and GHSR1a interaction to increase orexigenic hypothalamic NPY: Implications for neuronal molecular mechanism of metabolic side effects of antipsychotics.

The main cause of second-generation antipsychotic (SGA)-induced obesity is considered due to the antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling. It is reported that 5-HT2cR interacted with GHSR1a, however it is unknown whether one of the SGA olanzapine alters the 5-HT2cR/GHSR1a interaction, affecting orexigenic neuropeptide signalling in the hypothalamus. We found that olanzapine treatment increased average energy intake and body weight gain in mice; olanzapine treatment also increased orexigenic neuropeptide (NPY) and GHSR1a signaling molecules, pAMPK, UCP2, FOXO1 and pCREB levels in the hypothalamus. By using confocal fluorescence resonance energy transfer (FRET) technology, we found that 5-HT2cR interacted/dimerised with the GHSR1a in the hypothalamic neurons. As 5-HT2cR antagonist, both olanzapine and S242084 decreased the interaction between 5-HT2cR and GHSR1a and activated GHSR1a signaling. The 5-HT2cR agonist lorcaserin counteracted olanzapine-induced attenuation of interaction between 5-HT2cR and GHSR1a and inhibited activation of GHSR1a signalling and NPY production. These findings suggest that 5-HT2cR antagonistic effect of olanzapine in inhibition of the interaction of 5-HT2cR and GHSR1a, activation GHSR1a downstream signaling and increasing hypothalamic NPY, which may be the important neuronal molecular mechanism underlying olanzapine-induced obesity and target for prevention metabolic side effects of antipsychotic management in psychiatric disorders.

Obesogenic polystyrene microplastic exposures disrupt the gut-liver-adipose axis.

Microplastics (MP) derived from the weathering of polymers, or synthesized in this size range, have become widespread environmental contaminants and have found their way into water supplies and the food chain. Despite this awareness, little is known about the health consequences of MP ingestion. We have previously shown that the consumption of polystyrene (PS) beads was associated with intestinal dysbiosis and diabetes and obesity in mice. To further evaluate the systemic metabolic effects of PS on the gut-liver-adipose tissue axis, we supplied C57BL/6J mice with normal water or that containing 2 sizes of PS beads (0.5 and 5 µm) at a concentration of 1 µg/ml. After 13 weeks, we evaluated indices of metabolism and liver function. As observed previously, mice drinking the PS-containing water had a potentiated weight gain and adipose expansion. Here we found that this was associated with an increased abundance of adipose F4/80+ macrophages. These exposures did not cause nonalcoholic fatty liver disease but were associated with decreased liver:body weight ratios and an enrichment in hepatic farnesoid X receptor and liver X receptor signaling. PS also increased hepatic cholesterol and altered both hepatic and cecal bile acids. Mice consuming PS beads and treated with the berry anthocyanin, delphinidin, demonstrated an attenuated weight gain compared with those mice receiving a control intervention and also exhibited a downregulation of cyclic adenosine monophosphate (cAMP) and peroxisome proliferator-activated receptor (PPAR) signaling pathways. This study highlights the obesogenic role of PS in perturbing the gut-liver-adipose axis and altering nuclear receptor signaling and intermediary metabolism. Dietary interventions may limit the adverse metabolic effects of PS consumption.