High-sugar Diet Research Articles

Lomatogonium rotatum extract alleviates diabetes mellitus induced by a high-fat, high-sugar diet and streptozotocin in rats

<i>Lomatogonium rotatum</i> extract alleviates diabetes mellitus induced by a high-fat, high-sugar diet and streptozotocin in rats

Network pharmacology-based study on the mechanism of ShenKang injection in diabetic kidney disease through Keap1/Nrf2/Ho-1 signaling pathway

ObjectiveTo study the effect of ShenKang Injection (SKI) on the kidneys of DKD rats and its effect on oxidative stress mediated by the Keap1/Nrf2/Ho-1 signaling pathway through network pharmacology and in vivo and in vitro experiments. MethodsSKI drug targets were screened by TCMSP, DKD targets were screened by GenGards, OMIM, Drugbank, TTD, and Disgenet databases, and the two intersected for PPI network analysis and target prediction was performed by GO and KEGG. A total of 40 SD rats were randomly divided into 10 in the control group and 30 in the model group. After the model group was fed 8 W with high-sugar and high-fat diets, a DKD model was constructed by one-time intraperitoneal injection of streptozotocin (35 mg/kg). According to the weight, the model animals were randomly divided into three groups: 8 for model validation group, 8 for Irbesartan (25 mg/kg daily) group, and 8 for SKI group (5 ml/kg). Gavaged deionized water was given to the control group and the model validation group equally. The general conditions of the rats were observed, their body weights measured and their urine volumes recorded for 24 h. After the intervention of 16 W, serum was collected to detect Urea, Scr, blood lipids, and oxidative stress and lipid peroxidation indicators; Transmission electron microscopy, HE and Mallory staining were used to observe the pathological morphology of renal tissue. Immunohistochemistry and RT-PCR were used to detect the expression of Keap1, Nrf2, Ho-1, Gpx4 proteins and mRNA in rat kidney tissues. HK-2 cells were cultured in vitro and divided into: the control group, AGEs (200 μg/ml) group and AGEs + SKI group. The cell activity of the groups was detected using CCK-8 after 48 h of cell culture, and ROS were detected using fluorescent probes. Gpx4 expression was detected by immunofluorescence, while Keap1, Nrf2, Ho-1, and Gpx4 were detected by Western Blot. ResultsNetwork pharmacological analysis predicted that SKI may delay DKD kidney injury by affecting redox-related signaling pathways and mitigating AGEs-induced oxidative stress. In the animal experiment, compared with the model validation group, the general state of rats in the SKI group was improved, and 24-hour urine protein levels were significantly reduced, and the Scr in the serum was reduced. A decreasing trend was seen in Urea, and TC, TG, and LDL levels significantly decreased and the levels of ROS, LPO and MDA were significantly lowered. Pathological staining showed that renal interstitial fibrosis was significantly improved, and electron microscopy showed that foot process effacement was alleviated. Immunohistochemistry and RT-PCR showed decreased expression of Keap1 protein and mRNA in kidney tissues of the SKI group. Additionally, Nrf2, Ho-1, and Gpx4 proteins and mRNA were expressed significantly. In the cell experiment, after 48 h treatment with AGEs, ROS in HK-2 cells increased significantly and cell activity decreased significantly, while cell activity in AGEs + SKI group increased significantly and ROS decreased. The expression of Keap1 protein in HK-2 cells in the AGEs + SKI group decreased, while the expression of Nrf2, Ho-1 and Gpx4 proteins increased significantly. ConclusionSKI can protect kidney function in DKD rats, delay DKD progression, inhibit AGEs-induced oxidative stress damage in HK-2 cells, and the mechanism of SKI to improve DKD may be achieved by activating the Keap1/Nrf2/Ho-1 signal transduction pathway.

The water extract of Potentilla discolor Bunge (PDW) ameliorates high-sugar diet-induced type II diabetes model in Drosophila melanogaster via JAK/STAT signaling

Ethnopharmacological relevancePotentilla discolor Bunge (PD) is a member of the Rosaceae family. It has been traditionally used in folk medicine for the treatment of diabetes. Additionally, people in folk also eat fresh and tender PD stems as vegetables or brew them as tea. Aim of the studyThe aim of this study was to explore the antidiabetic effects and underlying mechanisms of the water extract of Potentilla discolor (PDW) in a fruit fly model of high-sugar diet-induced type 2 diabetes. Materials and methodsThe antidiabetic efficacy of PDW was evaluated in a fruit fly model of diabetes induced by a high-sugar diet (HSD). Various physiological parameters were tested to evaluate the anti-diabetic effect of PDW. Gene expression levels related to insulin signaling pathways, glucose metabolism, lipid metabolism, and JAK/STAT signaling pathways were primarily analyzed using RT-qPCR to investigate the therapeutic mechanisms. ResultsIn this study, we found that the water extract of Potentilla discolor (PDW) can ameliorate type II diabetes phenotypes induced by the HSD in fruit flies. These phenotypes include growth rate, body size, hyperglycemia, glycogen metabolism, fat storage, and intestinal microflora homeostasis. PDW also improved the body size of s6k and rheb knockdown flies, suggesting its potential to activate the downstream insulin pathway and alleviate insulin resistance. Furthermore, we demonstrated that PDW reduced the expression of two target genes of the JAK/STAT signaling pathway, namely the insulin antagonist Impl2 and insulin receptor inhibitor Socs36E, which act as regulators inhibiting the activation of the insulin signaling pathway. ConclusionsThis study provides evidence for the anti-diabetic activity of PDW and suggests that its underlying mechanism may involve the improvement of insulin resistance by inhibiting the JAK/STAT signaling pathway.

Low glycemic index potato biscuits alleviate physio-histological damage and gut dysbiosis in rats with type-2 diabetes mellitus induced by high-sugar and high-fat diet and streptozotocin

Type 2 diabetes mellitus (T2DM) is the most common type of diabetes globally and poses a major concern for human health. This study aimed to investigate the effects on T2DM of low-glycemic index (GI) potato biscuits with oat bran and inulin as functional additives. T2DM was induced in rats by streptozotocin (STZ) and a high-sugar and high-fat diet. The alleviation of T2DM by low-GI potato biscuits at different doses was evaluated based on the analysis of glycolipid levels, histological observations, inflammatory markers, and gut microbiota structure. Compared to wheat biscuits, low-GI potato biscuits resulted in lower postprandial blood glucose levels. After 8 weeks of intervention, fasting blood sugar levels were 16.9% lower in T2DM rats fed high-dose low-GI potato biscuits than in untreated T2DM rats. Moreover, the intervention with low-GI potato biscuits significantly alleviated T2DM-induced pathological damage, glucose and lipid metabolic disorders, and inflammation by reversing the levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, transforming growth factor-β, interleukin-1β, interleukin-6 and tumor necrosis factor-α. Moreover, the levels of short-chain fatty acids and gut microbiota structure in T2DM rats were significantly reversed. The abundance of beneficial bacteria (e.g., Bifidobacterium, Lachnoclostridium, Roseburia) in the gut of T2DM rats was significantly increased whereas the abundance of Escherichia-Shigella and Desulfovibrio decreased. The present study revealed that low-GI potato biscuits alleviated damages caused by high-sugar and high-fat diet- and STZ-induced T2DM in rats, as well as reversed disturbances in the gut microbiota. Thus, low-GI potato biscuits are potentially beneficial to T2DM patients.

Rapid determination of triglyceride and glucose levels in Drosophila melanogaster induced by high-sugar or high-fat diets based on near-infrared spectroscopy

Triglyceride and glucose levels are important indicators for determining metabolic syndrome, one of the leading public-health burdens worldwide. Drosophila melanogaster is an ideal model for investigating metabolic diseases because it has 70% homology to human genes and its regulatory mechanism of energy metabolism homeostasis is highly similar to that of mammals. However, traditional analytical methods of triglyceride and glucose are time-consuming, laborious, and costly. In this study, a simple, practical, and reliable near-infrared (NIR) spectroscopic analysis method was developed for the rapid determination of glucose and triglyceride levels in an in vivo model of metabolic disorders using Drosophila induced by high-sugar or high-fat diets. The partial least squares (PLS) model was constructed and optimized using different spectral regions and spectral pretreatment methods. The overall results had satisfactory prediction performance. For Drosophila induced by high-sugar diets, the correlation coefficient (RP) and root mean square error of prediction (RMSEP) were 0.919 and 0.228 mmoL gprot−1 for triglyceride and 0.913 and 0.143 mmoL gprot−1 for glucose respectively; for Drosophila induced by high-fat diets, the RP and RMSEP were 0.871 and 0.097 mmoL gprot−1 for triglyceride and 0.853 and 0.154 mmoL gprot−1 for glucose, respectively. This study demonstrated the potential of using NIR spectroscopy combined with PLS in the determination of triglyceride and glucose levels in Drosophila, providing a rapid and effective method for monitoring metabolite levels during disease development and a possibility for evaluating metabolic diseases in humans in clinical practice.

Effects of high-sugar, high-cholesterol, and high-fat diet on phospholipid profile of mouse tissues with a focus on the mechanism of plasmalogen synthesis

High-sugar diet (HSD), high-cholesterol diet (HCD), and high-fat diet (HFD) all modulate the levels of lipids. However, there is a lack of comparative data on the effects of different diets on phospholipids (PLs). Given their important role in physiology and disease, there has been an increasing focus on altered PLs in liver and brain disorders. This study aims to determine the effects of HSD, HCD, and HFD for 14-week feeding on the PL profile of the mouse liver and hippocampus. Quantitative analysis of 116 and 113 PL molecular species in liver and hippocampus tissues revealed that the HSD, HCD, and HFD significantly affected the PLs in liver and hippocampus, especially decreased the levels of plasmenylethanolamine (pPE) and phosphatidylethanolamine (PE). Overall, the impact of HFD on liver PLs was more significant, consistent with the morphological changes in the liver. Compared to HSD and HCD, HFD induced a significant decrease in PC (P-16:0/18:1) and an increase in LPE (18:0) and LPE (18:1) in liver. In the liver of mice fed with different diets, the expression of the key enzymes Gnpat, Agps in the pPE biosynthesis pathway and peroxisome-associated membrane proteins pex14p were decreased. In addition, all diets significantly reduced the expression of Gnpat, pex7p, and pex16p in hippocampus tissue. In conclusion, HSD, HCD, and HFD enhanced lipid accumulation in the liver, led to liver injury, significantly affected the liver and hippocampus PLs, and decreased the expression of genes related to plasmalogen synthesis in mouse liver and hippocampus, which caused severe plasmalogen reduction.

The Effect of Overnutrition on Mediated Collagen in Drosophila Melanogaster Physiology

Obesity affects approximately 13% of the adult population, resulting in excessive fat cell deposition and metabolic dysfunction. Collagen, a protein that supports skin regeneration, muscle building, and pain relief, is studied in Drosophila melanogaster under different diet conditions. This experiment aims to test whether overnutrition affects physiology and collagen due to any anatomical changes in Drosophila Melanogaster, more commonly known as fruit flies. The research conducted over several weeks utilizes two diets: an obesity-inducing diet containing excessive glucose and coconut oil and a traditional diet of blue food medium, yeast, and water. The study groups include a wild-type, collagen-mutated, and obesity-mutated group, with multiple assays measuring how the obesity-inducing diet affects each population and their collagen levels. The results reveal that the obese group experienced higher food consumption levels but had lower locomotive ability than the other test groups. Hydroxyproline, the building amino acid for collagen, and collagen levels were higher in the obesity mutant than in the wild-type and collagen mutated group. The study shows that anatomical changes in organisms are influenced by both diet and movement. The obesity group, on an obesity-inducing diet, experienced decreased movement related to increased food intake and decreased neural activity. The high-fat and high-sugar diet suppressed neuronal autophagy, created inaccurate hunger and satiety perceptions, and increased collagen deposition. Anatomical changes were observed in collagen-heavy tissue areas, whereas decreased neural activity and increased feeding rates were behavioral changes. The study emphasized the importance of a healthy diet and exercise in promoting overall health.

0085 Peripheral glucose metabolism bidirectionally modulates sleep in a model of Alzheimer's disease

Abstract Introduction Metabolic impairments and sleep disruptions are both recognized as modifiable risk factors in the development of Alzheimer’s disease (AD). A bidirectional relationship exists between sleep and AD where pathology can disrupt sleep, but sleep disturbances can also increase AD-related pathology. This results in a feed-forward cycle of disease progression and further sleep impairments. Sleep fragmentation and poor sleep quality can also cause glucose intolerance and insulin resistance. However, it remains unclear if peripheral metabolic dysfunction alone can impair sleep, particularly in the context of AD-related pathology. Therefore, the goal of this study was to establish mechanisms connecting peripheral metabolic and sleep disruptions and identify potential therapeutic targets for mitigating AD risk. Methods We implanted biosensors measuring interstitial fluid (ISF) levels of glucose and lactate, biomarkers of cerebral metabolism and neuronal activity, respectively, directly into the hippocampus of wildtype and APP/PS1 mice, a model of amyloid-beta (Aβ) overexpression. Biosensors were paired with cortical EEG and EMG recordings for simultaneous sleep/wake analysis. To understand the relationship between metabolic dysfunction and sleep, we altered the peripheral metabolic environment using two paradigms: an acute high-fat, high-sugar diet (HF/HSD) and a pharmacological metabolic rescue. Results We found short-term HF/HSD exposure was sufficient to disrupt ISF glucose and lactate diurnal rhythms, independent of changes to pathology burden. Moreover, we found significant sleep disruptions, particularly decreased delta power, indicating slow wave sleep impairments. These findings were exacerbated in mice with Aβ pathology who have disrupted metabolic and sleep functioning at baseline. Conversely, we found normalizing peripheral glucose tolerance in mice with Aβ pathology was sufficient to rescue impaired ISF glucose and lactate rhythms. We also saw a restoration of normal sleep-wake patterns, specifically within slow wave activity. Conclusion We found modulating peripheral glucose metabolism can bidirectionally alter sleep, particularly slow wave sleep, independent of changes in Aβ burden. This indicates sleep as a mediator in the relationship between metabolic impairments and AD pathophysiology. While impaired sleep increases AD risk, improved sleep slows pathology accumulation. Therefore, this study demonstrates targeting peripheral glucose regulation is a potential avenue for early AD intervention and risk mitigation. Support (if any) F31-AG066302, R01-AG068330, P30-AG072947

A Drosophila model of diabetic neuropathy reveals a role of proteasome activity in the glia

Diabetic peripheral neuropathy (DPN) is the most common chronic, progressive complication of diabetes mellitus. The main symptom is sensory loss; the molecular mechanisms are not fully understood. We found that Drosophila fed a high-sugar diet, which induces diabetes-like phenotypes, exhibit impairment of noxious heat avoidance. The impairment of heat avoidance was associated with shrinkage of the leg neurons expressing the Drosophila transient receptor potential channel Painless. Using a candidate genetic screening approach, we identified proteasome modulator 9 as one of the modulators of impairment of heat avoidance. We further showed that proteasome inhibition in the glia reversed the impairment of noxious heat avoidance, and heat-shock proteins and endolysosomal trafficking in the glia mediated the effect of proteasome inhibition. Our results establish Drosophila as a useful system for exploring molecular mechanisms of diet-induced peripheral neuropathy and propose that the glial proteasome is one of the candidate therapeutic targets for DPN.

Serotonin reuptake transporter deficiency promotes liver steatosis and impairs intestinal barrier function in obese mice fed a Western-style diet.

Intestinal barrier dysfunctions have been associated with liver steatosis and metabolic diseases. Besides nutritional factors, like a Western-style diet (WSD), serotonin has been linked with leaky gut. Therefore, we aimed to evaluate the role of serotonin in the pathogenesis of intestinal barrier dysfunctions and liver steatosis in mice fed high-fat and high-sugar diets. 6-8 weeks old male serotonin reuptake transporter knockout mice (SERT-/- ) and wild-type controls (SERT+/+ ) were fed either a WSD or a control diet (CD) ad libitum with or without fructose 30% (F) added to the drinking water for 12 weeks. Markers of liver steatosis and intestinal barrier function were assessed. SERT-/- mice showed increased weight gain compared with SERT+/+ mice when fed a WSD ± F for 12 weeks (p < 0.05), whereby SERT-/- mice exhibited reduced energy (-21%) intake. Furthermore, SERT knockout resulted in a more pronounced liver steatosis (p < 0.05), enhanced levels of endotoxin in portal vein plasma (p < 0.05), and increased liver expression of Tnf and Myd88 (p < 0.05), when mice were fed a WSD ± F. Finally, SERT-/- mice, when compared with SERT+/+ mice, had a decreased mRNA expression of Muc2 (p < 0.01), Ocln (p < 0.05), Cldn5 (p = 0.054) and 7 (p < 0.01), Defa5 (p < 0.05) and other antimicrobial peptides in the ileum. On the protein level, ZO-1 (p < 0.01) and DEFA5 protein (p < 0.0001) were decreased. Our data demonstrate that SERT knockout causes weight gain, liver steatosis, and leaky gut, especially in mice fed a WSD. Therefore, SERT induction could be a novel therapeutic approach to improve metabolic diseases associated with intestinal barrier dysfunction.

Protective role of cGAS in NASH is related to the maintenance of intestinal homeostasis.

Various intracellular pathways regulate inflammation in NASH. Cyclic GMP-AMP synthase (cGAS) is a DNA sensor that activates STING and plays a role in inflammatory diseases. Here, we explored the role of cGAS in hepatic damage, steatosis, inflammation, and liver fibrosis in mouse models of NASH. cGAS deficient (cGAS-KO) and STING deficient (STING-KO) mice received high fat-high cholesterol-high sugar diet (HF-HC-HSD) or relevant control diets. Livers were evaluated after 16 or 30 weeks. HF-HC-HSD diet, both at 16 and 30 weeks, resulted in increased cGAS protein expression as well as in increased ALT, IL-1β, TNF-α and MCP-1 in wild-type (WT) mice compared to controls. Surprisingly, liver injury, triglyceride accumulation, and inflammasome activation were greater in HF-HC-HSD cGAS-KO compared to WT mice at 16 and to a lesser extent at 30 weeks. STING, a downstream target of cGAS was significantly increased in WT mice after HF-HC-HSD. In STING-KO mice after HF-HC-HSD feeding, we found increased ALT and attenuated MCP1 and IL-1β expression compared to WT mice. Markers of liver fibrosis were increased in cGAS- and STING-KO mice compared to WT on HF-HC-HSD. We discovered that cGAS-KO mice had a significant increase in circulating endotoxin levels on HF-HC-HSD that correlated with changes in intestinal morphology which was exacerbated by HF-HC-HSD compared to WT mice. Our findings indicate that cGAS or STING deficiency exacerbate liver damage, steatosis, and inflammation in HF-HC-HSD diet-induced NASH, which might be linked to the disruption of the gut barrier.

Rapid Transition from a High-Fat, High-Fructose to a Low-Fat, Low-Fructose Diet Reverses Gains in Bone Mass and Strength.

Obesity is thought to negatively impact bone quality and strength despite improving bone mineral density. We hypothesized that 1) continuous consumption of a high-fat, high-sugar (HFS) diet would impair bone quality and strength, and 2) a change from an HFS diet to a low-fat, low-sugar (LFS) would reverse HFS-induced impairments to bone quality and strength. Six-week-old male C57Bl/6 mice ( n = 10/group) with access to a running wheel were randomized to an LFS diet or an HFS diet with simulated sugar-sweetened beverages (20% fructose in place of regular drinking water) for 13 wk. HFS mice were subsequently randomized to continuing HFS feeding (HFS/HFS) or transition to the LFS diet (HFS/LFS) for four additional weeks. HFS/HFS mice exhibited superior femoral cancellous microarchitecture (i.e., greater BV/TV, Tb.N, Tb.Th, and decreased Tb.Sp) and cortical bone geometry (i.e., lower Ct.CSA and pMOI) compared with all other groups. At the femoral mid-diaphysis, structural, but not material, mechanical properties were greatest in HFS/HFS mice. However, HFS/HFS exhibited greater femoral neck strength only when compared with mice assigned to diet transition (HFS/LFS). Osteoclast surface and the percentage of osteocytes staining positive for interferon-gamma were greater in HFS/LFS mice, consistent with reduced cancellous microarchitecture postdiet transition. HFS feeding enhanced bone anabolism and structural, but not material, mechanical properties in exercising mice. A change from an HFS to LFS diet returned the bone structure to that of continuously LFS-fed mice while compromising strength. Our results indicate rapid weight loss from obese states should be performed with caution to prevent bone fragility. A deeper analysis into the altered bone phenotype in diet-induced obesity from a metabolic standpoint is needed.

DIETS THAT HAVE POTENTIAL TO STIMULATE THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN SPRAGUE DAWLEY RATS

The pituitary gland is the master gland which regulates the body hormones. From the corticotrophs of the anterior pituitary gland, adrenocorticotrophic hormone (ACTH) is secreted and influences corticosterone production in rodents via the hypothalamic–pituitary–adrenal axis (HPA axis). ACTH and corticosterone are frequently used as a hormonal marker of stress level. Disturbance in ACTH and corticosterone were observed in many diseases especially Addison’s disease, Cushing’s syndrome, and metabolic syndrome. Our objective is to observe which diet produces the most and least stress to the Sprague Dawley rat’s physiology. Method: Thirty-five Sprague Dawley rats were grouped into five groups (n=7) and were given five different types of diets (control, high-fat, high-protein, high-sugar, and high-starch) with tap water supplied as drinking water ad libitum. By the end of eight weeks, the rat’s blood was collected, and serum separated. The individual components of ACTH and corticosterone from the blood was extracted, purified, identified, and quantified using the High-Performance Liquid Chromatography (HPLC) with photodiode array (PDA) analysis method. Result: The analytical studies revealed a high -sugar diet registered highest ACTH blood level. It was also revealed that the high-fat and high-sugar diet group presented with the highest peak for corticosterone. Conclusion: Consumption of high-fat and high-sugar diet for eight weeks is suggested to induce physiologic and metabolic stress in Sprague Dawley rats as evidenced by the HPA activation.

TDAG51 Attenuates Impaired Lipid Metabolism and Insulin Resistance in Gestational Diabetes Mellitus Through SREBP-1/ANGPTL8 Pathway.

T-cell death-associated gene 51 (TDAG51) belongs to the transcription factor family and is involved in the energy homeostasis of the liver through the regulation of lipogenesis. To evaluate the role of T-cell death-associated gene 51 in gestational diabetes mellitus. Experimental study. A total of 30 patients with GDM were enrolled in the study. TDAG51 expression in patients with gestational diabetes mellitus was assessed by Western blotting and quantitative reverse-transcription polymerase chain reaction. A high-fat and high-sugar diet was used to establish a Gestational diabetes mellitus model. gestational diabetes mellitus mice were injected with lentivirus-mediated overexpression of TDAG51. Blood glucose was measured using a glucometer, and glucose and insulin tolerance tests were performed to detect insulin resistance. Liver and adipose tissues were subjected to hematoxylineosin staining. Cell apoptosis was detected by TUNEL staining. Human villous trophoblast cells (HTR-8/SVneo) were treated with a high-glucose medium to induce gestational diabetes mellitus. TDAG51 was downregulated in gestational diabetes mellitus and high glucose-induced HTR-8/SVneo. TDAG51 overexpression reduced the level of blood glucose, enhanced serum insulin, and attenuated glucose and insulin tolerance in gestational diabetes mellitus mice. TDAG51 overexpression also ameliorated impaired lipid metabolism and alleviated adipocyte hypertrophy and hepatic lipid droplets in gestational diabetes mellitus mice. The expressions of SREBP-1 and ANGPTL8 were upregulated in gestational diabetes mellitus and showed a negative correlation with TDAG51 in patients with gestational diabetes mellitus. TDAG51 increased the expressions of SREBP-1 and ANGPTL8 in gestational diabetes mellitus mice. TDAG51 overexpression reduced cell apoptosis and enhanced cell viability of high glucose-induced HTR-8/SVneo. Ectopic expression of ANGPTL8 attenuated the TDAG51-induced increase in cell viability and decrease in apoptosis in high glucose-induced HTR-8/SVneo. TDAG51 alleviated impaired lipid metabolism and insulin resistance in gestational diabetes mellitus via downregulation of SREBP 1/ANGPTL8 pathway.

Maternal monosaccharide diets evoke cognitive, locomotor, and emotional disturbances in adolescent and young adult offspring rats.

Anxiety and depression are the most common mental disorders affecting people worldwide. Recent studies have highlighted that a maternal high-sugar diet (HSD) could be a risk factor for neurobehavioural dysregulations, including mood disorders. Increased consumption of added sugar in food such as refined fructose/glucose can increase the risk of metabolic disorders and impact susceptibility to mental disorders. Furthermore, a few papers have reported disabilities in learning and memory among offspring after maternal HSD, thus suggesting a relationship between maternal nutrition and offspring neurogenesis. In this study, we evaluated the impact of maternal monosaccharide consumption based on a glucose (GLU) or fructose (FRU) diet during pregnancy and lactation in adolescent and young adult offspring rats of both sexes on cognitive, locomotor, and emotional disturbances. Locomotor activity, short-term memory, anxiety-like and depressive-like behavior were evaluated in the offspring. We report for the first time that the maternal GLU or FRU diet is sufficient to evoke anxiety-like behavior among adolescent and young adult offspring. Moreover, we found that maternal monosaccharide diets lead to hyperactivity and depressive-like behavior in male adolescent rats. We also noticed that a maternal FRU diet significantly enhanced novelty-seeking behavior only in young adult male rats. Our novel findings indicated that the maternal monosaccharide diet, especially a diet enriched in FRU, resulted in strong behavioral alterations in offspring rats at early life stages. This study also revealed that male rats were more susceptible to hyperactivity and anxiety- and depressive-like phenotypes than female rats. These results suggest that maternal monosaccharide consumption during pregnancy and lactation is an important factor affecting the emotional status of offspring.

High-fat-sugar diet is associated with impaired hippocampus-dependent memory in humans

Overconsumption of high-fat and high-sugar (HFS) diet may affect the hippocampus, and consequently, memory functions. Yet, converging evidence is needed to demonstrate that the type of memory affected by HFS diet consumption is indeed hippocampus dependent. Moreover, the extent to which HFS diet can also affect executive functioning, and indirectly affect memory requires further examination. In this online study, we asked 349 young adults to report their HFS diet consumption and complete a word memory task, the Everyday Memory Questionnaire, and importantly two memory tasks that have been shown to robustly engage the hippocampus, i.e., the Pattern Separation and Associative Memory Tasks. Participants also completed two executive functioning tasks, the Trail Making Task (TMT) and the Stroop Task. These measures assess attention/cognitive flexibility and the ability to inhibit cognitive interference, respectively. After controlling for confounding variables, we found that participants who reported higher level consumption of a HFS diet performed worse on the Pattern Separation Task and that higher HFS intake was significantly associated with poorer TMT task performance and longer Stroop average reaction time (RT). TMT and Stroop RT scores indicative of reduced executive function also partially mediated the relationship between HFS diet and memory performance on the pattern separation task. Taken together, our results provide converging evidence that HFS diet may impair hippocampus-dependent memory. HFS diet may also affect executive functioning and indirectly impair memory function. The findings are consistent with human subject and animal studies and call for further investigations on the psychological and neural mechanisms underlying the dietary effects on cognitive processes.

High fat-high sugar diet induces sex-dependent effects on the small intestine

Background: Metabolic syndrome includes a plethora of symptoms ultimately leading to obesity and type 2 diabetes. Obesity has been linked to chronic gastrointestinal dysfunction (constipation, or diarrhea) and specifically females with high BMI have been associated with increased prevalence of diarrhea. We aimed to better understand the influence of high fat-high sugar diet (Western diet) on small intestinal function and to assess sex-dependent effects. Methods: We measured transepithelial short circuit current (Isc) a measure of chloride secretory function, across freshly isolated segments of jejunum from male and female C57Bl/6J mice fed a high fat high sugar diet (HFS) for 12 weeks, compared to lean controls. At the completion of the study, segments of jejunum were frozen for western blot determination of key proteins involved in secretory and absorptive functions and senescence. Intestinal morphology was assessed. Serum cytokine assays were performed. Results: Basal Isc was significantly decreased 70% ( P&lt;0.05) in HFS both females and males versus leans. In females, the HFS-induced decrease in Isc was attributed to a significant loss of CLC2, NKCC1 and CFTR expression whereas in males the decrease in Isc was due to a significant loss of Na/K-ATPase, KCa and NKCC1 expression (indicating interesting sex-dependent etiology). A2BR levels were also dysregulated in HFS fed male and female mice. Inflammatory state and shadowed body weight changes with feeding a western diet. Assessment of intestinal morphology and metabolic profile is being further evaluated. Conclusions: Our data suggests that the reduced basal jejunal Isc in HFS mice is attributed to sex-dependent mechanisms. Improved understanding of Western diet-induced intestinal dysfunctions may provide improved drug targets to treat gastrointestinal disturbances in obesity and diabetes. Midwestern Arizona Alzheimer’s Consortium and Diabetes Action Research and Education Foundation This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

High sugar diet-induced insulin resistance in glia impairs axonal clearance after injury by downregulating Draper signaling

Obesity significantly increases the risk for developing neurodegenerative disorders, yet the precise mechanisms underlying this connection remain unclear. Defects in glial phagocytic function is a key feature of neurodegenerative disorders, as delayed clearance of neuronal debris can result in inflammation, cytotoxicity, secondary neuronal death, and poor nervous system recovery. Whether or how diet-induced obesity disrupts glial phagocytosis is unknown. Here, using a Drosophila diet-induced obesity model, we show that subjecting adult flies to a chronic high sugar diet (HSD) treatment delays the clearance of degenerating axons by causing glial insulin resistance. We find that HSD downregulates the basal and injury-induced expression of the glia-associated phagocytic receptor, Draper. Genetically inducing Insulin release from the Insulin producing cells (IPCs) phenocopies the HSD-induced Draper downregulation and insulin resistance, while attenuating insulin release from the IPCs rescues HSD-induced Draper downregulation and insulin resistance. Significantly, we show that genetically stimulating Phosphoinositide 3-kinase (PI3K), a downstream effector of Insulin receptor signaling rescues HSD-induced glial defects. Together, we provide mechanistic insights into how HSD alters glial phagocytic function in the adult brain. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Gut microbiota modulation by high glucose diet invigorates anti-tumor immune response to glioblastoma multiforme

Abstract Most studies about the relationship between high sugar diet and tumor progression state that the pro-tumoral effects of high sugar diet are induced by metabolic diseases such as obesity and diabetes caused by long-term, excessive sugar diet. However, there are still many unknowns about the effect of high sugar diet on tumors when it lasts for a relatively short period that does not cause metabolic diseases. In this background, we find that survival rate of glioblastoma (GBM) is increased through supplement of high glucose diet (HGD) for several weeks. We find that gut microbiota modulation by HGD plays a crucial role in enhancement of anti-tumor immune response. Through single cell RNA sequencing analysis, modulation of gut microbiota by HGD results in an increase in T cell-mediated anti-tumor immune response in GBM. In addition, we find the novel cytotoxic CD4+ T cell population in GBM is increased due to synergistic action with anti PD-1 and the change occurs only through the synergistic action of anti PD-1 treatment and HGD. As a result, we identify that HGD can enhance anti-tumor immune response in GBM through changes in gut microbiota and suggest that the role of glucose diet on GBM needs to be elucidated from a different perspective.

Combined effect of high-fat, high-sugar diet and volumetric muscle loss injury on skeletal muscle bioenergetics, pyruvate dehydrogenase activity and post-translational regulation

INTRODUCTION: Volumetric muscle loss (VML) injury due to trauma or surgery cannot fully rejuvenate muscle mass and function, resulting in pathologic comorbidities, including alteration in whole-body metabolism, and long-term disability. Western diets (WD), i.e., high-fat, high-sugar diets, are associated with metabolic stress in the skeletal muscle because of the excessive fuel supplies regardless of energy demand. The objective of this study was to determine the extent to which WD affects metabolic function following a VML injury, and to interrogate enzyme kinetics as potential mechanistic contributors if metabolic dysfunction is present. METHODS: Male C57BL/6 mice (N=35) were randomized into four groups: Normal Chow (NC), WD, VML, and VML+WD. At age 12 weeks, VML groups underwent unilateral VML surgery to the plantar flexors (gastrocnemius, plantaris, soleus). WD groups received a 60% high-fat diet plus 11% high-fructose corn syrup for 8 weeks ad libitum, and diet was started at age 12 weeks also. Mitochondrial function was assessed by oxygen consumption rate and electron conductance (efficiency of electron flow) in permeabilized gastrocnemius muscle fibers using carbohydrate substrate glutamate/malate; enzyme kinetic function included citrate synthase (CS) and pyruvate dehydrogenase (PDH); PDH post-translational regulation included immunoblots for PDH kinase 4 (PDK4), PDH phosphatase (PDP), total PDH, phospho-PDHser293. Two-way ANOVA was used to detect significant interaction effects between diet and injury, or in the absence of a significant interaction, the main effects of diet or injury. RESULTS: Mice on WD had 51% greater body mass compared to mice on NC (p&lt;0.001), independent of injury and worse blood glucose regulation (ipGTT 83% higher in WD groups compared to NC groups, irrespective of injury, p&lt;0.001). There were significant interaction effects between diet and injury for permeabilized muscle fiber maximal JO2 (p=0.014) and conductance (p=0.027). Especially, the VML+WD group had 48% lower maximal JO2, and 47% reduced conductance compared to the VML group. PDH enzyme activity was 20% less in WD groups, independent of injury (p&lt;0.001), and 24% lower in VML-injured groups, independent of diets (p&lt;0.001). CS activity was 23% greater in WD groups compared to NC groups, regardless of injury (p=0.005). WD had 48% greater phospho-to-total PDH at the inhibitor site ser293 compared to NC groups, irrespective of injury (p=0.041). CONCLUSIONS: PDH plays an important role in glucose-dependent NADH-linked mitochondrial function as it converts glycolysis end-product pyruvate into acetyl-CoA for Krebs cycle entry. This study demonstrates WD exacerbates carbohydrate-supported mitochondrial function after VML injury. PDH regulation and enzymatic function may influence this phenomenon and future research is required to further define the cellular mechanisms. W81XWH-20-1-0885 to JAC and SMG, R01-AR078903 to JAC and SMG This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.