Dietary Sugar Research Articles

Abstract 3720: Cysteine palmitoylation of astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) regulates its biological and immunological activity

Abstract Non-alcoholic steatohepatitis (NASH) is a major risk factor for hepatocellular carcinoma (HCC). Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) augments steatosis, inflammation, and tumorigenesis, thereby promoting the whole spectrum of this disease process. Targeting AEG-1 is a potential interventional strategy for NASH and HCC. Thus, proper understanding of the regulation of this molecule is essential. We found that AEG-1 is palmitoylated at residue Cysteine75 (Cys75). Mutation of Cys75 to Serine (Ser) completely abolished AEG-1 palmitoylation.Systematic knockdown studies identified zinc finger DHHC-type palmitoyltransferase 6 (ZDHHC6) as the palmitoyltransferase catalyzing the process. To obtain insight into how palmitoylation regulates AEG-1 function, we generated a knock-in mouse by CRISPR/Cas9 in which Cys75 of AEG-1 was mutated to Ser (AEG-1-C75S). No developmental or anatomical abnormality was observed between AEG-1-wild type (AEG-1-WT) and AEG-1-C75S littermates. However, global gene expression analysis by RNA-sequencing unraveled that signaling pathways and upstream regulators, which contribute to cell proliferation, motility, inflammation,angiogenesis, and lipid accumulation, are activated in AEG-1-C75S hepatocytes compared toAEG-1-WT. Feeding these mice with high fat/high sugar diet for 20 weeks showed accumulation of T-regulatory cells and exhausted CD8 T-cells in the livers of AEG-1-C75S mice vs AEG-1-WT, and only in females, suggesting that inhibition of AEG-1 palmitoylation creates an immunosuppressive milieu favoring tumorigenesis. Collectively, these findings suggest that AEG-1-C75S functions as dominant positive, and palmitoylation restricts oncogenic and NASH-promoting functions of AEG-1. Studies are ongoing to unravel the mechanism by which palmitoylation restricts AEG-1 function, and to understand the sex-specific immune-modulatory role of AEG-1 palmitoylation in hepatocarcinogenesis. Citation Format: Maria Del Carmen Camarena, Garrison Komaniecki, Debashri Manna, Rachel Mendoza, Mark A. Subler, Jolene J. Windle, Mikhail G. Dozmorov, Hening Lin, Devanand Sarkar. Cysteine palmitoylation of astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) regulates its biological and immunological activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3720.

Study protocol for a randomized, controlled trial using a novel, family-centered diet treatment to prevent nonalcoholic fatty liver disease in Hispanic children

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the leading liver disorder among U.S. children and is most prevalent among Hispanic children with obesity. Previous research has shown that reducing the consumption of free sugars (added sugars + naturally occurring sugars in fruit juice) can reverse liver steatosis in adolescents with NAFLD. This study aims to determine if a low-free sugar diet (LFSD) can prevent liver fat accumulation and NAFLD in high-risk children. MethodsIn this randomized controlled trial, we will enroll 140 Hispanic children aged 6 to 9 years who are ≥50th percentile BMI and without a previous diagnosis of NAFLD. Participants will be randomly assigned to either an experimental (LFSD) or a control (usual diet + educational materials) group. The one-year intervention includes removal of foods high in free sugars from the home at baseline, provision of LFSD household groceries for the entire family (weeks 1–4, 12, 24, and 36), dietitian-guided family grocery shopping sessions (weeks 12, 24, and 36), and ongoing education and motivational interviewing to promote LFSD. Both groups complete assessment measures at baseline, 6, 12, 18, and 24 months. Primary study outcomes are percent hepatic fat at 12 months and incidence of clinically significant hepatic steatosis (>5%) + elevated liver enzymes at 24 months. Secondary outcomes include metabolic markers potentially mediating or moderating NAFLD pathogenesis. DiscussionThis protocol describes the rationale, eligibility criteria, recruitment strategies, analysis plan as well as a novel dietary intervention design. Study results will inform future dietary guidelines for pediatric NAFLD prevention. Trial registrationClinicalTrials.gov, NCT05292352.

Effects of dietary wild bitter melon (Momordica charantia var. abbreviate Ser.) extract on glucose and lipid metabolism in HFD/STZ-induced type 2 diabetic rats.

Plant-based extracts to interfere with the onset of diabetes may be a promising approach towards type 2 diabetes mellitus (T2DM). Bitter gourd (Momordica charantia L.) is popularly consumed as an edible and medicinal resource with hypoglycemic effect in China. Wild bitter gourd (Momordica Charantia var. abbreviata Ser.) is a variant of bitter gourd, but there are relatively few studies on it. The purpose of the experiment is to first screen out the most effective extraction part of Momordica charantia L. and Momordica Charantia var. abbreviata Ser. through the hypoglycemic activity experiment in vitro, and by using a high-fat and high-sugar diet with STZ-induced diabetic rat model in vivo to explore the possible mechanism of action against diabetes. This study first performed α-glucosidase, PTP1B and lipase activities inhibition experiments on the alcohol and water extracts of Momordica charantia L. and Momordica Charantia var. abbreviata Ser. Sprague Dawley rats were either given normal feed or a high sugar and fat diet for four weeks, followed STZ (25 mg/kg, via i. p.) was given. Rats with fasting blood glucose ≥11.1 mmol/l after one week were deemed to be diabetic, treatments were administered for four weeks, and then blood samples were used to evaluate hematological and biochemical indicators, and liver was removed for post-analysis. The expression levels of p-AMPK, AMPK, p-PI3K, PI3K, p-AKT, AKT, p-GSK3β, GSK3β, p-IRS-1, IRS-1, GLUT2 were determined by Western blot. At the same time, the chemical components was identified by liquid-mass spectrometry. Data showed that the ethanol extract of wild bitter gourd (WBGE) had the best ability to regulate glucose and lipid metabolism in vitro. Therefore, we further investigated the antidiabetic effects of oral consumption of WBGE on high-fat diet (HFD) and streptozotocin (STZ)-induced T2DM in SD rats. WBGE effectively reduced blood glucose and lipid levels, alleviated glucose intolerance and insulin resistant. Moreover, WBGE consumption could also inhibited oxidant responses and inflammatory damage. Mechanism studies have shown that WBGE may act by regulating AMPK/PI3K signaling pathway. On the other hand, the content of total phenol, total flavonoids, total saponins and total polysaccharide were measured by UV, 27 compounds were identified by LC-MS. These studies explored the role and mechanism of WBGE in regulating glucose and lipid metabolism, and may support the utilization and further investigation of wild bitter gourd as a dietary intervention strategy to prevent diabetes and related metabolic abnormalities.

EXCESS DIETARY SUGAR ALTERS COLONOCYTE METABOLISM AND IMPAIRS THE EARLY PROLIFERATIVE RESPONSE TO DAMAGE

The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. An important regulator of ISC and TA cell function is dietary metabolites which can affect their proliferative capacity. Over the last 150 years, the diet of high-income countries contains increasing amounts of simple sugars, such as sucrose, but whether excess sugar affects the function of ISCs and TA cells directly is unknown. We used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (DSS colitis) to demonstrate the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. We demonstrate that high sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative and key stem cell gene signatures. Further, high-glucose conditions led to the accumulation of glycolytic metabolite pyruvate in colonoids, with a concomitant decrease in ATP, suggesting impaired glycolytic fuel metabolism. Treatment of colonoids with DCA, which forces pyruvate into the TCA cycle, restored their growth, ATP levels, and the expression of proliferation and stem cell gene signatures. Similarly, DSS treatment of mice fed a high sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Metabolic analyses of crypt cells from high-sucrose-fed mice revealed increased glycolytic potential without a commensurate increase in aerobic respiration. Rather, epithelium from high-sucrose-fed mice has increased mitochondrial content, without increased levels of ATP, further demonstrating impaired oxidative phosphorylation and fuel metabolism. Finally, we demonstrated impaired proliferative potential of ISCs and reduced number of TA direct daughter cells in high-sucrose-fed mice with DSS damage. Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury, as is seen in patients with an acute flare of Ulcerative Colitis.

Animal model for high consumption and preference of ethanol and its interplay with high sugar and butter diet, behavior, and neuroimmune system.

Mechanisms that dictate the preference for ethanol and its addiction are not only restricted to the central nervous system (CNS). An increasing body of evidence has suggested that abusive ethanol consumption directly affects the immune system, which in turn interacts with the CNS, triggering neuronal responses and changes, resulting in dependence on the drug. It is known that neuroinflammation and greater immune system reactivity are observed in behavioral disorders and that these can regulate gene transcription. However, there is little information about these findings of the transcriptional profile of reward system genes in high consumption and alcohol preference. In this regard, there is a belief that, in the striatum, an integrating region of the brain reward system, the interaction of the immune response and the transcriptional profile of the Lrrk2 gene that is associated with loss of control and addiction to ethanol may influence the alcohol consumption and preference. Given this information, this study aimed to assess whether problematic alcohol consumption affects the transcriptional profile of the Lrrk2 gene, neuroinflammation, and behavior and whether these changes are interconnected. An animal model developed by our research group has been used in which male C57BL/6 mice and knockouts for the Il6 and Nfat genes were subjected to a protocol of high fat and sugar diet intake and free choice of ethanol in the following stages: Stage 1 (T1)-Dietary treatment, for 8 weeks, in which the animals receive high-calorie diet, High Sugar and Butter (HSB group), or standard diet, American Institute of Nutrition 93-Growth (AIN93G group); and Stage 2 (T2)-Ethanol consumption, in which the animals are submitted, for 4 weeks, to alcohol within the free choice paradigm, being each of them divided into 10 groups, four groups continued with the same diet and in the other six the HSB diet is substituted by the AIN93G diet. Five groups had access to only water, while the five others had a free choice between water and a 10% ethanol solution. The weight of the animals was evaluated weekly and the consumption of water and ethanol daily. At the end of the 12-week experiment, anxiety-like behavior was evaluated by the light/dark box test; compulsive-like behavior by Marble burying, transcriptional regulation of genes Lrrk2, Tlr4, Nfat, Drd1, Drd2, Il6, Il1β, Il10, and iNOS by RT-qPCR; and inflammatory markers by flow cytometry. Animals that the diet was replaced had an ethanol high preference and consumption. We observed that high consumption and preference for ethanol resulted in (1) elevation of inflammatory cells in the brain, (2) upregulation of genes associated with cytokines (Il6 and Il1β) and pro-inflammatory signals (iNOS and Nfat), downregulation of anti-inflammatory cytokine (Il10), dopamine receptor (Drd2), and the Lrrk2 gene in the striatum, and (3) behavioral changes such as decreased anxiety-like behavior, and increased compulsive-like behavior. Our findings suggest that interactions between the immune system, behavior, and transcriptional profile of the Lrrk2 gene influence the ethanol preferential and abusive consumption.

A Low Daily Intake of Simple Sugars in the Diet Is Associated with Improved Liver Function in Cirrhotic Liver Transplant Candidates.

(1) Background: We investigated, for the first time, whether dietary simple sugar intake affects MELD score changes over time in a cohort of cirrhotic liver transplant candidates. (2) Methods: the MELD score, dietary habits using a 3-day food diary, and visceral adipose tissue index (VATI) measured with CT scan were assessed in 80 consecutive outpatient cirrhotic patients at baseline, after counseling to follow current nutritional guidelines. The MELD score was reassessed after six months and the DELTA-MELD was calculated as the MELD at the second assessment minus the MELD at baseline. (3) Results: Compared with the baseline, the MELD score of cirrhotic patients at the end of the study was decreased, stable, or increased in 36%, 8% and 56% of patients, respectively. In separate multiple linear regression models, DELTA-MELD was positively and independently correlated with the daily intake of simple sugars expressed in g/kg body weight (p = 0.01) or as a percentage of total caloric intake (p = 0.0004) and with the number of daily portions of fruit, added sugar, jam, and honey (p = 0.003). These associations were present almost exclusively in patients with VATI above the median value. (4) Conclusions: In cirrhotic patients with high amounts of visceral adipose tissue the consumption of simple sugars and fructose should be limited to improve their clinical outcome.

SUGAR SWEETENED BEVERAGE TAX AND ITS IMPLICATIONS FOR PUBLIC HEALTH

Introduction: Sugar Sweetened Beverages (SSBs) consumption has increased to higher levels across all corners of the world. High sugar diets in the form of SSBs lead to increased calorie intake with almost no nutritive value when compared to solid food and contributes to the increased energy intake resulting in an unhealthy weight gain, often associated with health issues such as obesity, diabetes, cardio-vascular diseases, early tooth decay and formation of cavities. It is also observed that consumption of SSBs is linked to unhealthy habits like smoking, decreased physical activity, increased intake of fast food and increased screen time. Method: The required information on SSB tax implementation at the global level was retrieved from the literature reviews. Result: Taking such detrimental effects of SSBs into consideration, many countries are putting efforts to tackle the problem of higher consumption of SSBs by adopting measures such as taxations on SSBs. However, it is also extremely important to understand how these taxes help in generating higher revenues to the government which, in turn, can be used for various community needs in the respective countries. Conclusion: The same revenue can also be utilised for implementation of comprehensive healthcare programmes especially in Low and Middle-Income Countries (LMIC), by providing preventive, promotive, curative, rehabilitative and palliative services as a way to progress towards Universal Health Coverage (UHC).

Dietary Trehalose as a Bioactive Nutrient

Trehalose is a naturally occurring, non-reducing disaccharide comprising two covalently-linked glucose molecules. It possesses unique physiochemical properties, which account for multiple biological roles in a variety of prokaryotic and eukaryotic organisms. In the past few decades, intensive research on trehalose has uncovered its functions, and extended its uses as a sweetener and stabilizer in the food, medical, pharmaceutical, and cosmetic industries. Further, increased dietary trehalose consumption has sparked research on how trehalose affects the gut microbiome. In addition to its role as a dietary sugar, trehalose has gained attention for its ability to modulate glucose homeostasis, and potentially as a therapeutic agent for diabetes. This review discusses the bioactive effects of dietary trehalose, highlighting its promise in future industrial and scientific contributions.

Rare sugar l-sorbose exerts antitumor activity by impairing glucose metabolism

Rare sugars are monosaccharides with low natural abundance. They are structural isomers of dietary sugars, but hardly be metabolized. Here, we report that rare sugar l-sorbose induces apoptosis in various cancer cells. As a C-3 epimer of d-fructose, l-sorbose is internalized via the transporter GLUT5 and phosphorylated by ketohexokinase (KHK) to produce l-sorbose-1-phosphate (S-1-P). Cellular S-1-P inactivates the glycolytic enzyme hexokinase resulting in attenuated glycolysis. Consequently, mitochondrial function is impaired and reactive oxygen species are produced. Moreover, l-sorbose downregulates the transcription of KHK-A, a splicing variant of KHK. Since KHK-A is a positive inducer of antioxidation genes, the antioxidant defense mechanism in cancer cells can be attenuated by l-sorbose-treatment. Thus, l-sorbose performs multiple anticancer activities to induce cell apoptosis. In mouse xenograft models, l-sorbose enhances the effect of tumor chemotherapy in combination with other anticancer drugs. These results demonstrate l-sorbose as an attractive therapeutic reagent for cancer treatment.

Metabolome × Microbiome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys.

Dietary sugar reduction is one therapeutic strategy for improving nonalcoholic fatty liver disease (NAFLD), and the underlying mechanisms for this effect warrant further investigation. Here, we employed metabolomics and metagenomics to examine systemic biological adaptations associated with dietary sugar restriction and (subsequent) hepatic fat reductions in youth with NAFLD. Data/samples were from a randomized controlled trial in adolescent boys (11-16 years, mean ± SD: 13.0 ± 1.9 years) with biopsy-proven NAFLD who were either provided a low free-sugar diet (LFSD) (n = 20) or consumed their usual diet (n = 20) for 8 weeks. Plasma metabolomics was performed on samples from all 40 participants by coupling hydrophilic interaction liquid chromatography (HILIC) and C18 chromatography with mass spectrometry. In a sub-sample (n = 8 LFSD group and n = 10 usual diet group), 16S ribosomal RNA (rRNA) sequencing was performed on stool to examine changes in microbial composition/diversity. The diet treatment was associated with differential expression of 419 HILIC and 205 C18 metabolite features (p < 0.05), which were enriched in amino acid pathways, including methionine/cysteine and serine/glycine/alanine metabolism (p < 0.05), and lipid pathways, including omega-3 and linoleate metabolism (p < 0.05). Quantified metabolites that were differentially changed in the LFSD group, compared to usual diet group, and representative of these enriched metabolic pathways included increased serine (p = 0.001), glycine (p = 0.004), 2-aminobutyric acid (p = 0.012), and 3-hydroxybutyric acid (p = 0.005), and decreased linolenic acid (p = 0.006). Microbiome changes included an increase in richness at the phylum level and changes in a few genera within Firmicutes. In conclusion, the LFSD treatment, compared to usual diet, was associated with metabolome and microbiome changes that may reflect biological mechanisms linking dietary sugar restriction to a therapeutic decrease in hepatic fat. Studies are needed to validate our findings and test the utility of these "omics" changes as response biomarkers.

Differential disruption on glucose and insulin metabolism in two rat models of diet-induced obesity, based on carbohydrates or lipids.

Obesity is a relevant health public issue and is the main factor for glucose metabolism dysregulation and diabetes progression; however, the differential role of a high-fat diet or high sugar diet consumption on glucose metabolism and insulin processing is not well understood and has been scarcely described. Our research aimed to analyze the effects of chronic consumption of both high sucrose and high-fat diets on glucose and insulin metabolism regulation. Wistar rats were fed with high-sugar or high-fat diets for 12months; after that, fasting glucose and insulin levels were measured along with a glucose tolerance test (GTT). Proteins related to insulin synthesis and secretion were quantified in pancreas homogenates, whereas islets were isolated to analyze ROS generation and size measurement. Our results show that both diets induce metabolic syndrome, linked with central obesity, hyperglycemia, and insulin resistance. We observed alterations in the expression of proteins related with insulin synthesis and secretion, along with diminution of Langerhans islets size. Interestingly, the severity and number of alterations were more evident in the high-sugar diet than in the high-fat diet group. In conclusion, obesity and glucose metabolism dysregulation induced by carbohydrate consumption, led to worst outcomes than high-fat diet.

Sugar content and erosive potential of commonly prescribed Orodispersible tablets- An in vitro study.

Background:Dental caries is a major non-communicable disease of public health concern caused due to freely available dietary sugars. We aimed to compare the sugar content and erosive potential with duration of use and drug classes of orodispersible tablets (ODTs). Methods:We conducted an in vitroevaluation of the total sugar content (TSC), Potential of Hydrogen (pH), solubility, and Titratable Acidity (TA) of commonly prescribed 62 ODTs. TA was measured by titrating the samples with known amount of. 0.1N sodium hydroxide (NaOH) with phenolphthalein indicator and pH was determined by digital pH meter. TSC was evaluated by phenol sulphuric acid. Solubility was assessed by filtration. Results:Out of the 62 ODTs, majority were Antimicrobials (n=30). One-quarter of the ODTs (26%) had a mean pH below ≤5.5. No significant difference was seen in the mean pH with respect to different drug classes (p=0.082) and duration of use of ODTs. A significant difference was seen in the mean percentage solubility with respect to drug classes (p<0.001). Antimicrobials had the least percentage of solubility as compared to other drug classes. Antiemetics and proton pump inhibitors (24.33 ± 17.34) had significantly higher mean percentage sugar content than Antimicrobials (23.25 ± 17.16). No significant difference was seen in the mean TSC with respect to various drug classes (p=0.718) and between the duration of use of drugs (P=0.568) respectively.No significant difference was seen in the mean percentage TA with respect to drug class (p=0.123) and duration of use of drugs (p=0.424). Conclusion:Overall, we can conclude that one in four ODT formulations had a pH below 5.5 (critical pH). Only one ODT formulation did not have a sugar content. No difference was seen in the mean pH, sugar content, and TA with respect to duration of use of drugs and drug classes.

The Effect of Mobile Health (mHealth) Interventions on Clinical Outcomes and Self-Management Behaviours in Individuals with Metabolic Syndrome: A Narrative Review of Evidence

Introduction: There has been an exponential growth in mobile health (mHealth) technology for self-management of chronic conditions including metabolic syndrome (MetS). This narrative review aims to summarise the evidence on the effect of mHealth interventions on clinical outcomes and/or self-management behaviours among individuals with MetS or its components. Methods: Literature search for original research articles on mHealth for self-management of MetS or any of its components (type 2 diabetes mellitus, hypertension, dyslipidaemia, and obesity) from 2010-2021 was conducted using Web of Science, Scopus, PubMed, Cochrane Central Register of Controlled Trials, Google Scholar, SAGE and ScienceDirect. Keywords such as mHealth, effectiveness, self-management, MetS, hypertension, type 2 diabetes mellitus, dyslipidaemia and obesity were used. Articles in languages other than English, without access to full-text, outcomes unrelated to the effectiveness, and involved individuals aged &lt;18 or &gt;80 years old were excluded. All study designs were included except for study protocols. Results: A total of 184 potential papers were retrieved. Of these, 137 were excluded as they did not meet the inclusion/exclusion criteria. Consequently, 47 papers were included. Of these, 38 studies demonstrated effect of mHealth interventions in improving clinical outcomes (blood pressure, glycated haemoglobin, lipid profile, weight) and/or improvement in self-management behaviours (home blood pressure or blood sugar monitoring, exercise, diet or medication adherence) among individuals with MetS or its components. Only 12 studies were conducted in primary care. Apart from mHealth technologies, multifaceted elements such as doctor-patient interaction and wearable devices were also shown to be effective. Conclusion: This narrative review suggests that mHealth interventions may have positive effect on clinical outcomes and/or self-management behaviours among individuals with MetS and its components. This evidence should support development and evaluation of mHealth interventions to suit the needs of the Malaysian population, especially in primary care.

Sugary solutions

Sugary solutions

Circulating fructose regulates a germline stem cell increase via gustatory receptor-mediated gut hormone secretion in mated Drosophila.

Oogenesis is influenced by multiple environmental factors. In the fruit fly, Drosophila melanogaster, nutrition and mating have large impacts on an increase in female germline stem cells (GSCs). However, it is unclear whether these two factors affect this GSC increase interdependently. Here, we report that dietary sugars are crucial for the GSC increase after mating. Dietary glucose is required for mating-induced release of neuropeptide F (NPF) from enteroendocrine cells (EECs), followed by NPF-mediated enhancement of GSC niche signaling. Unexpectedly, dietary glucose does not directly act on NPF-positive EECs. Rather, it contributes to elevation of hemolymph fructose generated through the polyol pathway. Elevated fructose stimulates the fructose-specific gustatory receptor, Gr43a, in NPF-positive EECs, leading to NPF secretion. This study demonstrates that circulating fructose, derived from dietary sugars, is a prerequisite for the GSC increase that leads to enhancement of egg production after mating.

Dietary Sugar Shifts Mitochondrial Metabolism and Small RNA Biogenesis in Sperm.

Aims: Increasing concentrations of dietary sugar results in a linear accumulation of triglycerides in male Drosophila, while inducing a U-shaped obesity response in their offspring. Here, using a combination of proteomics and small RNA (sRNA) sequencing, we aimed at understanding the molecular underpinning in sperm for such plasticity. Results: Proteomic analysis of seminal vesicles revealed that increasing concentrations of dietary sugar resulted in a bell-shaped induction of proteins involved in metabolic/redox regulation. Using stains and in vivo redox reporter flies, this pattern could be explained by changes in sperm production of reactive oxygen species (ROS), more exactly mitochondria-derived H2O2. By quenching ROS with the antioxidant N-acetyl cysteine and performing sRNA-seq on sperm, we found that sperm miRNA is increased in response to ROS. Moreover, we found sperm mitosRNA to be increased in high-sugar diet conditions (independent of ROS). Reanalyzing our previously published data revealed a similar global upregulation of human sperm mitosRNA in response to a high-sugar diet, suggesting evolutionary conserved mechanisms. Innovation: This work highlights a fast response to dietary sugar in mitochondria-produced H2O2 in Drosophila sperm and identifies redox-sensitive miRNA downstream of this event. Conclusions: Our data support a model where changes in the sperm mitochondria in response to dietary sugar are the primary event, and changes in redox homoeostasis are secondary to mitochondrial ROS production. These data provide multiple candidates for paternal intergenerational metabolic responses as well as potential biomarkers for human male fertility. Antioxid. Redox Signal. 38, 1167-1183.

Ketohexokinase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation

The consumption of sugar and a high-fat diet (HFD) promotes the development of obesity and metabolic dysfunction. Despite their well-known synergy, the mechanisms by which sugar worsens the outcomes associated with a HFD are largely elusive. Six-week-old, male, C57Bl/6J mice were fed either chow or a HFD and were provided with regular, fructose- or glucose-sweetened water. Moreover, cultured AML12 hepatocytes were engineered to overexpress ketohexokinase-C (KHK-C) using a lentivirus vector, while CRISPR-Cas9 was used to knockdown CPT1α. The cell culture experiments were complemented with invivo studies using mice with hepatic overexpression of KHK-C and in mice with liver-specific CPT1α knockout. We used comprehensive metabolomics, electron microscopy, mitochondrial substrate phenotyping, proteomics and acetylome analysis to investigate underlying mechanisms. Fructose supplementation in mice fed normal chow and fructose or glucose supplementation in mice fed a HFD increase KHK-C, an enzyme that catalyzes the first step of fructolysis. Elevated KHK-C is associated with an increase in lipogenic proteins, such as ACLY, without affecting their mRNA expression. An increase in KHK-C also correlates with acetylation of CPT1α at K508, and lower CPT1α protein invivo. Invitro, KHK-C overexpression lowers CPT1α and increases triglyceride accumulation. The effects of KHK-C are, in part, replicated by a knockdown of CPT1α. An increase in KHK-C correlates negatively with CPT1α protein levels in mice fed sugar and a HFD, but also in genetically obese db/db and lipodystrophic FIRKO mice. Mechanistically, overexpression of KHK-C invitro increases global protein acetylation and decreases levels of the major cytoplasmic deacetylase, SIRT2. KHK-C-induced acetylation is a novel mechanism by which dietary fructose augments lipogenesis and decreases fatty acid oxidation to promote the development of metabolic complications. Fructose is a highly lipogenic nutrient whose negative consequences have been largely attributed to increased de novo lipogenesis. Herein, we show that fructose upregulates ketohexokinase, which in turn modifies global protein acetylation, including acetylation of CPT1a, to decrease fatty acid oxidation. Our findings broaden the impact of dietary sugar beyond its lipogenic role and have implications on drug development aimed at reducing the harmful effects attributed to sugar metabolism.

Inositol in Disease and Development: Roles of Catabolism via myo-Inositol Oxygenase in Drosophila melanogaster.

Inositol depletion has been associated with diabetes and related complications. Increased inositol catabolism, via myo-inositol oxygenase (MIOX), has been implicated in decreased renal function. This study demonstrates that the fruit fly Drosophila melanogaster catabolizes myo-inositol via MIOX. The levels of mRNA encoding MIOX and MIOX specific activity are increased when fruit flies are grown on a diet with inositol as the sole sugar. Inositol as the sole dietary sugar can support D. melanogaster survival, indicating that there is sufficient catabolism for basic energy requirements, allowing for adaptation to various environments. The elimination of MIOX activity, via a piggyBac WH-element inserted into the MIOX gene, results in developmental defects including pupal lethality and pharate flies without proboscises. In contrast, RNAi strains with reduced levels of mRNA encoding MIOX and reduced MIOX specific activity develop to become phenotypically wild-type-appearing adult flies. myo-Inositol levels in larval tissues are highest in the strain with this most extreme loss of myo-inositol catabolism. Larval tissues from the RNAi strains have inositol levels higher than wild-type larval tissues but lower levels than the piggyBac WH-element insertion strain. myo-Inositol supplementation of the diet further increases the myo-inositol levels in the larval tissues of all the strains, without any noticeable effects on development. Obesity and blood (hemolymph) glucose, two hallmarks of diabetes, were reduced in the RNAi strains and further reduced in the piggyBac WH-element insertion strain. Collectively, these data suggest that moderately increased myo-inositol levels do not cause developmental defects and directly correspond to reduced larval obesity and blood (hemolymph) glucose.

Nutritional resources modulate the responses of three bee species to pesticide exposure.

The response of bee species to various stressors is assumed to depend on the availability of sufficient nutrients in their environment. We compare the response of three bee species (Apis mellifera, Bombus terrestris, Osmia bicornis) under laboratory conditions. Survival, physiology, and sensitivity, after exposure to the fungicide prochloraz, the insecticide chlorantraniliprole, and their mixture with different nutritional resources (sugar only, sugar with amino acids or pollen) were observed. Prochloraz reduced the bee survival of A. mellifera and O. bicornis fed with pollen, but not with other diets. Chlorantraniliprole impaired the survival of A. mellifera fed with sugar or pollen diet, but not with amino acid diet. The mixture impaired survival of A. mellifera and O. bicornis in association with every diet. B. terrestris was only affected by chlorantraniliprole and its mixture with prochloraz fed with sugar diet. The activity of P450 reductase was higher in A. mellifera fed with amino acids in all treatments, whereas no effect emerged in O. bicornis and B. terrestris. Our results indicate that the sensitivity of bee species after exposure to agrochemicals is affected by diet. Thus, balanced and species-dependent nutrition ameliorated the effects. Further field studies are necessary to evaluate the potential effects of such mixtures on bee populations.

The Human Gut Game

The human gut microbiome is an important part of the digestive system and the human body as a whole. The abundance and richness of bacterial species in your digestive tract change based on your diet and lifestyle. A diet full of fresh vegetables, meat, and whole grains will cultivate a variety of bacteria that will help you absorb nutrients, prevent disease, keep your skin hydrated, and even improve cognitive function. A diet of sugar- and fat-rich foods will cultivate less diverse bacteria and species that cause inflammation in your gut and impair memory and focus (Quercia et al., 2014). I designed a simulation that uses inquiry and game play to teach high school (grades 9–12) biology students these concepts. The game involves teamwork, decisions about diet, cause and effect of various life events, and data analysis. Educational approaches such as game play and active learning have been shown to improve student engagement, retention of concepts, and overall success of a lesson (Sengupta and Clark, 2016; Michael, 2006).