Metabolic Effects Research Articles

Out-of-phase treatment with the synthetic glucocorticoid betamethasone disturbs glucose metabolism in mice

ObjectiveEndogenous glucocorticoid levels display a strong circadian rhythm, which is often not considered when synthetic glucocorticoids are prescribed as anti-inflammatory drugs. In this study we evaluated the effect timing of glucocorticoid administration, i.e. in-phase (administered when endogenous glucocorticoid levels are high) versus out-of-phase (administered when endogenous glucocorticoid levels are low). We investigated the synthetic glucocorticoid betamethasone – which is extensively used in the clinic - and monitored the development of common metabolic side effects in mice upon prolonged treatment, with a particular focus on glucose metabolism. MethodsMale and female C57BL/6J mice were treated with the synthetic glucocorticoid betamethasone in-phase and out-of-phase, and the development of metabolic side effects was monitored. ResultsWe observed that, compared with in-phase treatment, out-of-phase treatment with betamethasone results in hyperinsulinemia in both male and female C57BL/6J mice. We additionally found that out-of-phase betamethasone treatment strongly reduced insulin sensitivity as compared to in-phase administration during morning measurements. Our study shows that the adverse effects of betamethasone are dependent on the time of treatment with generally less side effects on glucose metabolism with in-phase treatment. ConclusionsThis study highlights differences in glucocorticoid outcome based on the time of measurement, advocating that potential circadian variation should be taken into account when studying glucocorticoid biology.

The future backbone of nutritional science: integrating public health priorities with system-oriented precision nutrition.

Adopting policies that promote health for the entire biosphere (One Health) requires human societies to transition towards a more sustainable food supply as well as to deepen the understanding of the metabolic and health effects of evolving food habits. At the same time, life sciences are experiencing rapid and groundbreaking technological developments, in particular in laboratory analytics and biocomputing, placing nutrition research in an unprecedented position to produce knowledge that can be translated into practice in line with One Health policies. In this dynamic context, nutrition research needs to be strategically organised to respond to these societal expectations. One key element of this strategy is to integrate precision nutrition into epidemiological research. This position article therefore reviews the recent developments in nutrition research and proposes how they could be integrated into cohort studies, with a focus on the Swiss research landscape specifically.

Comment on, "Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1α/GLUTs signaling pathway in rat".

Wu et al. (2021) investigated the neuroprotective effects of hypoxia preconditioning (HPC) in a rat model of traumatic brain injury (TBI). The study demonstrated that HPC enhances brain resilience to TBI by upregulating glucose transporters GLUT1 and GLUT3 through the HIF-1α signaling pathway. Comprehensive molecular and histological analyses confirmed increased expression of these transporters, correlating with reduced neuronal apoptosis and cerebral edema. The robust methodology, including rigorous statistical validation and time-course assessments, underscores HPC's potential therapeutic role in mitigating neuronal loss and improving glucose transport post-injury. However, the study could be strengthened by incorporating additional preconditioning controls, comparative analyses with other neuroprotective strategies, and exploring downstream metabolic effects in greater detail. Furthermore, expanding the research to include diverse animal models and examining sex-dependent responses would enhance the generalizability and translational relevance of the findings. Future studies should also integrate metabolic flux analysis and advanced imaging techniques to further elucidate HPC's mechanisms of action.

Safety and tolerability of a low glycemic load dietary intervention in adults with cystic fibrosis: a pilot study.

To achieve and maintain adequate weight, people with cystic fibrosis (CF) May often consume energy-dense, nutrient-poor foods high in added sugars and refined carbohydrates; however, little is known about the glycemic and metabolic effects of dietary composition in this patient population. The objective of this pilot study was to investigate the safety and tolerability of a low glycemic load (LGL) diet in adults with CF and abnormal glucose tolerance (AGT). Ten adults with CF and AGT completed this prospective, open-label pilot study. Mean age was 27.0 ± 2.1 years, 64% were female, and all had pancreatic insufficiency. Each participant followed his/her typical diet for 2 weeks, then transitioned to a LGL diet via meal delivery service for 8 weeks. The primary outcome was change in weight from baseline to study completion, with safety established if no significant decline was noted. Other key safety outcomes included change in hypoglycemia measured by patient report and continuous glucose monitoring (CGM). Exploratory outcomes included changes in other CGM measures, body composition by dual energy X-ray absorptiometry (DXA), and patient reported outcomes. There were no significant changes in weight or in subjectively-reported or objectively-measured hypoglycemia. Favorable non-significant changes were noted in CGM measures of hyperglycemia and glycemic variability, DXA measures of fat mass, and gastrointestinal symptom surveys. A LGL dietary intervention was safe and well tolerated in adults with CF and AGT. These results lay the groundwork for future trials investigating the impact of low-glycemic dietary interventions on metabolic outcomes in the CF population.

Toxicogenomics of persistent organic pollutants: Potential impacts on biodiversity and infectious diseases

Pollution is recognized as one of the main causes of biodiversity loss. Growing evidence also points to pollution as an important risk factor for the emergence or reemergence of infectious diseases that affect humans and other animals. However, the mechanisms and pathways that explain how pollution erodes biodiversity and favors infectious diseases are poorly explored. Using the Dirty Dozen (aldrin, chlordane, dichlorodiphenyl trichloroethane - DDT, dieldrin, dioxins, endrin, furans, heptachlor, hexachlorobenzene, mirex, polychlorinated biphenyls - PCBs, and toxaphene) persistent organic pollutants (POPs) as a study model, in this article we demonstrate through toxicogenomic approaches that these POPs affect thousands of genes involved in the immune system and metabolic processes, among other biological pathways (n=19,086 genes from multiple organisms). One of the major findings indicate that POPs interact with hormone receptor genes prominently (i.e., Esr1, Nr1i2 and Ar genes). This finding highlights the activity of these pollutants as hormonal disruptors, with potentially deleterious consequences for the metabolism and reproduction of a wide range of species. These pollutants also have an important genotoxic activity, contributing to genomic instability and other related consequences. In summary, disturbances in the immune system can favor infection and the spread of pathogens, and changes in metabolism and genotoxic effects triggered by pollutants in multiple body systems can reduce fitness, harming the species’ survival in natural environments. The results of this exploratory toxicogenomic analysis represent a new piece in the puzzle that increasingly points to pollution as a major risk factor for both biodiversity loss and emerging infectious diseases.

Virtual screening study for biological activity assessment and metabolism pathway of a fuel dye in airborne exposure scenario.

The utilization of synthetic dyes increases the risk to human health. Despite the progress of information on azo dyes, very little attention has been reported on toxicity assessment of anthraquinone dyes. Solvent Blue 35 (SB35) is one of the anthraquinone dyes likely to be encountered because of its increasing use in various industries. Whereas the design of laboratory tests is very expensive, in silico screening was used to predict the metabolic profile and toxicity effect of SB35. MetaTox software was used to predict the metabolites of phase I and II in two layers. Since airborne exposure has been considered, the pathways of inhalation and dermal absorption of SB35 were investigated through the SwissADME model based on the modified Lipinski's rule of five. To predict the biological effect and toxicity of SB35 and each of the metabolites, PASS online software was used. Chemical activity was considered according to the probability of activation values (Pa) higher than the probability of inactivation values (Pi). N- dealkylation of SB35 was predicted in the first layer, while seven active compounds were obtained in the second layer from phases I and II reactions. Investigating the physicochemical properties of SB35 confirmed inhalation absorption for occupational exposure scenarios. All metabolites are absorbed from intestinal routes based on the RO5 rules. SB35 and their metabolites have an effective substrate role for the sub-type of CYP 450 enzymes. The toxicity effect of carcinogenicity for SB35 and mutagenicity for metabolites are predicted while confirmed with some biological effects. However, reproductive disorders are pointed with SB35 by probability higher than 70%. Virtual screening methods are efficient tools for creating cost-effective predictions in the hazard's evaluation of SB35. However, a perspective view is suggested before decision-making for laboratory designing tests.

The role of prolactin levels in metabolic syndrome: a systematic review

Introduction and purpose: Prolactin is primarily associated with lactation and gonadal function, but it also has metabolic effects. Recent research shows prolactin's role in food intake, body weight, glucose, and lipid profile. Both low and excessive prolactin levels can lead to metabolic dysfunctions such as metabolic syndrome, type 2 DM, and dyslipidemia. Dopamine agonists, like cabergoline, used to treat hyperprolactinemia, may help balance metabolic homeostasis, likely due to their effect on prolactin. This study aims to synthesize current research on prolactin's metabolic effects, focusing on metabolic syndrome.State of knowledge: Metabolic syndrome is a cluster of dysfunctions like central obesity, atherogenic dyslipidemia, hypertension, and insulin resistance. It increases the risk of diabetes and cardiovascular diseases, affecting a quarter of the European population. Different combinations of metabolic syndrome components require various treatment approaches. New research focuses on prolactin and dopamine agonists in its pathogenesis and treatment.Materials and methods: This literature review is based on PubMed materials using keywords “prolactin,” “hyperprolactinemia,” “hypoprolactinemia,” “metabolic syndrome,” “diabetes mellitus,” “obesity.”Conclusions: This study highlights prolactin's importance in metabolic homeostasis, finding a positive correlation between both low and high prolactin levels and metabolic syndrome. However, gender differences and the pathogenesis of metabolic disorders should be further explored.

Protective role of melatonin against radiation-induced disruptions in behavior rhythm of zebrafish (danio rerio)

Ionizing radiation, as an increasingly serious environmental pollutant, has aroused widespread public concern. Melatonin, as an indole heterocyclic compound, is known to have anti-inflammatory and antioxidant effects. However, few studies have considered the comprehensive impact of melatonin on radiation damage. In this study, we used zebrafish as experimental materials and employed methods such as acridine orange staining, enzyme-linked immunosorbent assay (ELISA), video tracking for automated behavior analysis, microscope imaging, and real-time fluorescence quantitative analysis. Zebrafish embryos at 2 h post-fertilization (hpf) were treated under four different experimental conditions to assess their growth, development, and metabolic consequences. Our findings indicate that 0.10 Gy gamma radiation significantly augments body length, eye area, spine width, and tail fin length in zebrafish, along with a marked increase in oxidative stress (P < 0.05). Moreover, it enhances cumulative swimming distance, time, and average speed, suggesting elevated activity levels. We observed circadian rhythm phase shifts, peak increases, and cycle shortening, accompanied by abnormal expression of genes pivotal to biological rhythms, exercise, melatonin synthesis, apoptosis/anti-apoptosis, and oxidation/antioxidant balance. The inclusion of melatonin (1 × 10-5 mol/L MLT) ameliorated these radiation-induced anomalies, while its independent effect on zebrafish was negligible. Melatonin can regulate oxidative stress responses, hinders apoptosis responses, and reprogramming the expression of rhythm-related genes in zebrafish embryos after reprogramming radiation stimulation. Overall, our research highlights melatonin's critical role in countering the biological damage inflicted by gamma radiation, proposing its potential as a therapeutic agent in radiation protection.

Metabolic and neurodevelopmental effects of the environmental endocrine disruptor di-2-ethylhexyl phthalate: a review

Metabolic and neurodevelopmental effects of the environmental endocrine disruptor di-2-ethylhexyl phthalate: a review

Long-term metabolic effectiveness and safety of growth hormone replacement therapy in patients with adult growth hormone deficiency: a single-institution study in Japan.

To elucidate the long-term efficacy and safety of growth hormone replacement therapy (GHRT) in Japanese patients with adult growth hormone deficiency (AGHD). We conducted a retrospective study. A total of 110 patients with AGHD receiving GHRT were enrolled. Clinical and laboratory data were collected annually from the beginning of the study. Statistical analysis was performed using a linear mixed-effects model. Of all patients, 46.4% were males, 70.9% had adult-onset GHD, and follow-up was up to 196 months, with a median of 68 months. The insulin-like growth factor-1 standard deviation score increased after the start of GHRT and remained constant for more than 11 years. Seventeen patients were followed up for more than 11 years. The body mass index increased. Waist circumference decreased in the short term but increased in the long term. The diastolic blood pressure decreased 1-5 years after the start of GHRT, and the systolic blood pressure increased 11 years after GHRT. Moreover, a long-term decrease in low-density lipoprotein cholesterol, an increase in high-density lipoprotein cholesterol, and a decrease in aspartate aminotransferase and alanine aminotransferase levels were observed. The glycosylated hemoglobin level increased after 3 years. The bone mineral density in the lumbar spine and total hip increased significantly 3 years after the start of GHRT. Finally, the number of adverse events was eight. We demonstrated the metabolic effectiveness and safety of GHRT in Japanese patients with AGHD over a long follow-up period of 16 years.

Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits

ObjectiveIntestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues. MethodsWe genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months. ResultsInduction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism. ConclusionThese findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.

Neuroprotective Activity of GLP-1 Analogues: General Understanding of Implementation Mechanisms

Glucagon-like peptide-1 (GLP-1) is a hormone possessing extensive pharmacologic potential. Additionally, to its multiple metabolic effects, GLP-1 also exhibits cardiac and neuroprotective effects. Native GLP-1 is not used as a medicinal agent, however, now GLP-1 analogues structurally similar to it and having a long-lasting effect have been developed and used in the treatment of type 2 diabetes mellitus (T2DM). The review focuses on the neuroprotective effect of these drugs and discusses possible mechanisms of this effect. Aim: To identify information about experimental and clinical evidence about the role of GLP-1 analogues in brain protection in neurodegenerative dis[1]eases. Materials and Methods: The review was performed in accordance with the PRISMA 2020 statement; publications were searched for in the PubMed, MedLine, Web of Science, Scopus, and Google Scholar databases covering the period from 2014 to 2024. Results: The publications provide strong evidence of the association between T2DM and cognitive impairment, as well as information on the effectiveness of GLP-1 analogues in the management of neurodegenerative diseases. Possible mechanisms are discussed. Conclusion: This review shows that GLP-1 can prevent cognitive and motor disorders. There is sufficient experimental evidence of the neurotropic activity of the drugs, and clinical trials are ongoing.

The hidden impact: the rate of nicotine metabolism and kidney health.

The effects of nicotine metabolism on the kidneys of healthy individuals have not been determined. The nicotine metabolite ratio (NMR) indicates the rate of nicotine metabolism and is linked to smoking behaviors and responses to tobacco treatments. We conducted this study in order to investigated the relationship between nicotine metabolite ratio (NMR) and kidney function. An analysis of cross-sectional data of adults was conducted using a population survey dataset (National Health and Nutrition Examination Survey Data 2013/2018 of the United States). A weighted multivariate regression analysis was conducted to estimate the correlation between NMR and kidney function. Furthermore, we apply fitting smooth curves to make the relationship between NMR and estimated glomerular filtration rate (eGFR) more visualized. The research included a total of 16153 participants. Weighted multivariate regression analyses adjusted for possible variables showed a negative relationship between NMR and estimated glomerular filtration rate (eGFR).The β (95%CI) of the regression equation between NMR and eGFR was -2.24 (-2.92, -1.55), the trend testing showed consistent results. NMR is positively correlated with urinary albumin creatinine ratio (uACR), but it is not statistically significant. A stratified analysis found a negative correlation between NMR and eGFR in all age, gender and diabetes subgroups, the results were not statistically significant among Mexican Americans and other races. Notably, each unit rise in NMR corresponded to a 4.54 ml/min·1.73m² lower eGFR in diabetic participants and a 6.04 ml/min·1.73m² lower eGFR in those aged 60 and above. Our study shows that nicotine metabolite ratio is negatively associated with kidney function among most adults. It will be necessary to conduct more well-designed prospective clinical trials in order to determine the exact causal interactions between NMR and kidney function. Specific mechanisms also need to be further explored in basic experiments.

Urinary bladder carcinogenic potential of 4,4'-methylenebis(2-chloroaniline) in humanized-liver mice.

Occupational exposure to 4,4'-methylenebis(2-chloroaniline) (MOCA) has been linked to an increased risk of bladder cancer among employees in Japanese plants, indicating its significance as a risk factor for urinary bladder cancer. To investigate the role of MOCA metabolism in bladder carcinogenesis, we administered MOCA to non-humanized (F1-TKm30 mice) and humanized-liver mice for 4 and 28 weeks. We compared MOCA-induced changes in metabolic enzyme expression, metabolite formation, and effects on the urinary bladder epithelium in the two models. At week 4, MOCA exposure induced simple hyperplasia, cell proliferation, and DNA damage in the urothelium of the humanized-liver mice, while in the non-humanized mice these effects were not observed. Notably, the concentration of 4-amino-4'-hydroxylamino-3,3'-dichlorodiphenylmethane (N-OH-MOCA) in the urine of humanized-liver mice was more than 10 times higher than that in non-humanized mice at the 4-week mark. Additionally, we observed distinct differences in the expression of cytochrome P450 isoforms between the two models. Although no bladder tumors were detected after 28 weeks of treatment in either group, these findings suggest that N-OH-MOCA significantly contributes to the carcinogenic potential of MOCA in humans.

Lifestyle interventions in cardiometabolic HFpEF: dietary and exercise modalities.

Heart failure with preserved ejection fraction (HFpEF) is rapidly growing as the most common form of heart failure. Among HFpEF phenotypes, the cardiometabolic/obese HFpEF - HFpEF driven by cardiometabolic alterations - emerges as one of the most prevalent forms of this syndrome and the one on which recent therapeutic success have been made. Indeed, pharmacological approaches with sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have proved to be effective due to metabolic protective effects. Similarly, lifestyle changes, including diet and exercise are crucial in HFpEF management. Increasing evidence supports the important role of diet and physicalactivity in the pathogenesis, prognosis, and potential reversal of HFpEF. Metabolic derangements and systemic inflammation are key features of HFpEF and represent the main targets of lifestyle interventions. However, the underlying mechanisms of the beneficial effects of these interventions in HFpEF are incompletely understood. Hence,there is an unmet need of tailored lifestyle intervention modalities for patients with HFpEF. Here we present the current available evidence on lifestyle interventions in HFpEF management and therapeutics, discussing their modalities and potential mechanisms.

Randomized dose-response trial of n-3 fatty acids in hormone receptor negative breast cancer survivors- impact on breast adipose oxylipin and DNA methylation patterns.

Increasing evidence suggests the unique susceptibility of estrogen receptor and progesterone receptor negative (ERPR-) breast cancer to dietary fat amount and type. Dietary n-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may modulate breast adipose fatty acid profiles and downstream bioactive metabolites to counteract pro-inflammatory, pro-carcinogenic signaling in the mammary microenvironment. To determine effects of ~1 to 5 g/d EPA+DHA over 12 months on breast adipose fatty acid and oxylipin profiles in women with ERPR(-) breast cancer, a high-risk molecular subtype. We conducted a 12-month randomized controlled, double-blind clinical trial of ~5g/d vs ~1g/d DHA+EPA supplementation in women within 5 years of completing standard therapy for ERPR(-) breast cancer Stages 0-III. Blood and breast adipose tissue specimens were collected every 3 months for biomarker analyses including fatty acids by gas chromatography, oxylipins by LC-MS/MS, and DNA methylation by reduced-representation bisulfite sequencing (RRBS). A total of 51 participants completed the 12-month intervention. Study treatments were generally well-tolerated. While both doses increased n-3 PUFAs from baseline in breast adipose, erythrocytes, and plasma, the 5g/d supplement was more potent (n =51, p <0.001). The 5g/d dose also reduced plasma triglycerides from baseline (p =0.008). Breast adipose oxylipins at 0, 6, and 12 months showed dose-dependent increases in unesterified and esterified DHA and EPA metabolites (n =28). Distinct DNA methylation patterns in adipose tissue after 12 months were identified, with effects unique to the 5g/d dose group (n =17). Over the course of 1 year, EPA+DHA dose-dependently increased concentrations of these fatty acids and their derivative oxylipin metabolites, producing differential DNA methylation profiles of gene promoters involved in metabolism-related pathways critical to ERPR(-) breast cancer development and progression. These data provide evidence of both metabolic and epigenetic effects of n-3 PUFAs in breast adipose tissue, elucidating novel mechanisms of action for high-dose EPA+DHA-mediated prevention of ERPR(-) breast cancer.

The role of intestinal microbiota in physiologic and body compositional changes that accompany CLA-mediated weight loss in obese mice

ObjectiveObesity continues to be a major problem, despite known treatment strategies such as lifestyle modifications, pharmaceuticals, and surgical options, necessitating the development of novel weight loss approaches. The naturally occurring fatty acid, 10,12 conjugated linoleic acid (10,12 CLA), promotes weight loss by increasing fat oxidation and browning of white adipose tissue, leading to increased energy expenditure in obese mice. Coincident with weight loss, 10,12 CLA also alters the murine gut microbiota by enriching for microbes that produce short chain fatty acids (SCFAs), with concurrent elevations in fecal butyrate and plasma acetate. MethodsTo determine if the observed microbiota changes are required for 10,12 CLA-mediated weight loss, adult male mice with diet-induced obesity were given broad-spectrum antibiotics (ABX) to perturb the microbiota prior to and during 10,12 CLA-mediated weight loss. Conversely, to determine whether gut microbes were sufficient to induce weight loss, conventionally-raised and germ-free mice were transplanted with cecal contents from mice that had undergone weight loss by 10,12 CLA supplementation. ResultsWhile body weight was minimally modulated by ABX-mediated perturbation of gut bacterial populations, adult male mice given ABX were more resistant to the increased energy expenditure and fat loss that are induced by 10,12 CLA supplementation. Transplanting cecal contents from donor mice losing weight due to oral 10,12 CLA consumption into conventional or germ-free mice led to improved glucose metabolism with increased butyrate production. ConclusionsThese data suggest a critical role for the microbiota in diet-modulated changes in energy balance and glucose metabolism, and distinguish the metabolic effects of orally delivered 10,12 CLA from cecal transplantation of the resulting microbiota.

Olanzapine-induced Metabolic Syndrome and its Association with -759C&gt;T Polymorphism of the HTR2C Gene in Iraqi Schizophrenic Patients

The hazardous metabolic effects of treating schizophrenia patients with olanzapine comprise serotonin 2C receptor (5-HT2C) antagonists. Metabolic side effects of antipsychotic drugs, including lipid abnormalities, disturbed glucose metabolism, and weight gain, can have a major impact on treating psychiatric patients. The intent of this study was to investigate whether there is an associated link between the genetic polymorphism at -759C&gt;T in the promoter region of the 5-hydroxytryptamine 2C receptor (HTR2C) gene and the metabolic syndrome driven by olanzapine in schizophrenia patients. A cross-sectional study that involved fifty hospitalized patients with schizophrenia. The patients were split into two groups (metabolic and non-metabolic) according to the classification criteria of the metabolic syndrome. The HTR2C promoter region polymorphism was identified through sequencing using the Sanger method after polymerase chain reaction amplification of the extracted deoxyribonucleic acid. Even though none of the genotypes of the -759C&gt;T variant are associated with the propensity to develop metabolic syndrome, there is a significant difference in the -759C&gt;T variant's T allele (p-value = 0.001). The presence of the T allele in the -759 C/T variant was significantly associated with developing metabolic syndrome. Keywords: Schizophrenic patients, Olanzapine, Genetic polymorphism, 5-hydroxytryptamine 2C receptor (HTR2C) gene, -759C&gt;T.

Abstract C033: Targeting PIKfyve-driven lipid metabolism in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes including macropinocytosis. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development. In our study, we aimed to characterize PIKfyve, a lipid kinase integral to lysosomal functioning, as a novel and targetable vulnerability in PDAC. We first confirmed that PIKfyve inhibition disrupted autophagic flux and disrupted lysosomal function. Next, to understand the metabolic effects of PIKfyve inhibition in PDAC cells, we employed a metabolism-focused CRISPR screen. Through this, we identified that PIKfyve inhibition increases PDAC cells’ dependency on de novo fatty acid synthesis through genes such as FASN and ACACA. Accordingly, PIKfyve inhibition triggered an increase in SREBP1-driven transcriptional and metabolic signatures favoring de novo fatty acid synthesis through increasing expression of genes such as FASN and ACACA. Further, employing targeted lipidomics, we determined that PIKfyve inhibition triggered an SREBP1-dependent accumulation of long-chain sphingolipids and that knockout of serine palmitoyl transferase subunits SPTLC1 and SPTLC2 sensitized PDAC cells to PIKfyve inhibition. Taken together, PIKfyve inhibition disrupts PDAC lipid homeostasis such that PDAC cells upregulate de novo synthesis of sphingolipids as a compensatory mechanism, suggesting that co-targeting de novo fatty acid synthesis and PIKfyve would result in synergistic effects. Given the importance of KRAS-MAPK signaling in controlling PDAC metabolic homeostasis, we hypothesized that the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels. Utilizing chromatin immunoprecipitation sequencing, we determined that KRAS or MEK inhibition reduces MYC binding to FASN and ACACA promoters. In line with this observation, KRAS or MEK perturbation decreased FASN and ACACA transcript and protein levels, suggesting that KRAS or MEK inhibition may sensitize PDAC cells to PIKfyve inhibition. Indeed, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC. Citation Format: Caleb Cheng, Jasmine P Wisniewski, Sydney Peters, Jing Hu, Rahul Mannan, Bailey Jackson, Rüya Pakkan, Pietro Morlacchi, Brian Magnuson, Tongchen He, Rupam Bhattacharyya, Yuanyuan Qiao, Costas A Lyssiotis, Arul M Chinnaiyan. Targeting PIKfyve-driven lipid metabolism in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C033.

Abstract C043: Hyperinsulinemia promotes pancreatic cancer progression by altering tumor metabolism

Abstract Metabolic diseases, such as type 2 diabetes (T2D), insulin resistance, and obesity, often accompany pancreatic ductal adenocarcinoma (PDAC), and they are associated with reduced survival. Hyperinsulinemia is a common hallmark symptom shared by those disorders and is independently associated with reduced survival of PDAC patients. While it has been established that endogenous hyperinsulinemia accelerates PDAC initiation by promoting the formation of KRAS-driven pre-cancerous lesions, its role in the progression of established tumors remains poorly understood. This represents a major knowledge gap in our understanding of whether insulin needs to be monitored and controlled during PDAC treatment, as it is not typically considered in current treatment paradigms. We hypothesized that hyperinsulinemia promotes the progression of PDAC tumors. Using patient-derived PDAC organoids (PDOs) and a mouse model of metabolic disorders, we found that insulin may promote PDOs’ growth by reprogramming tumor metabolism. A High-fat diet (HFD) treatment that induces hyperinsulinemia, but not hyperglycemia in mice accelerated the growth of PDO-derived orthotopic xenografts. Importantly, the fasting insulin level showed a significant positive correlation with the endpoint tumor volume, suggesting that endogenous insulin may positively contribute to PDOs’ growth in vivo. To assess the direct effect of insulin on the growth and molecular profile of PDOs, we treated an early passage PDO line with different concentrations of insulin and glucose at physiologically relevant levels. We observed a ∼1.2-fold increase in cell number after 7 days of culture in high insulin (10 nM) conditions with high (15 mM) or physiological (6 mM) levels of glucose, relative to the low insulin control. Phosphoproteomic analysis demonstrated significantly greater PI3K/AKT/mTOR, but not RAF/MEK/ERK, activity under high insulin with high or physiological levels of glucose compared to the control, directing the investigation toward the metabolic effects of insulin. Consistently, unbiased proteomics profiling revealed that metabolic proteins were significantly enriched in both high insulin conditions, and interestingly insulin enriched different sets of proteins in various metabolic pathways depending on glucose levels. Together, our preliminary results suggest that hyperinsulinemia may enhance the growth and progression of PDAC by altering tumor metabolism to support cell growth. Further experiments are needed to functionally link the insulin-mediated metabolic changes with increased PDO growth, as well as testing the direct effect of endogenous insulin on PDAC cells in vivo. Citation Format: Jeffrey Lin, James D Johnson, David Schaeffer, Vincent Richard, Christoph Borchers, Janel L Kopp. Hyperinsulinemia promotes pancreatic cancer progression by altering tumor metabolism [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C043.