High-fat And High-sugar Research Articles

Abstract 4147602: The Paradox Role of Sirtuin 6 In Coronary Microvascular Function under Metabolic Stress

Coronary microvascular dysfunction (CMD), which is associated with diabetic cardiomyopathy, Takotsubo cardiomyopathy, andheart failure with preserved ejection fraction (HFpEF), is understudied. CMD is characterized by impaired endothelial-dependent vasodilation, but detailed mechanisms have yet to be elucidated. Nuclear Sirtuin 6 (SIRT6) plays essential roles in gene transcriptional, stress tolerance, DNA repair, inflammation, and aging. SIRT6 is strongly associated with cardiovascular pathologies, but how SIRT6 regulates endothelial metabolisms and homeostasis under metabolic stress and the underlying mechanism remains poorly understood. It might be because global Sirt6 knockout mice are perinatally lethal caused by hypoglycemia, suggesting the essential role of SIRT6 in glucose metabolism. In our preliminary studies, we generated inducible global Sirt6 knockout mice by crossing with Sirt6 f/f mice with CAG-cre (Sirt6 f/f, CAG ), and mice were viable with normal glucose levels. However, they showed impaired endothelial-dependent dilation (EDD) and impaired coronary flow reserve (CFR), an index clinically used to diagnose CMD. It suggests that deletion of Sirt6 might cause EC dysfunction because Sirt6 is reported to protect EC from premature senescence and oxidative stress by sustaining high eNOS levels. Surprisingly, when we studied non-inducible Sirt6 endothelial-specific knockout (Sirt6 f/f, tie-2 cre ) and inducible Sirt6 endothelial-specific knockout (Sirt6 f/f, Cdh5-cre/ERT2 ) and wild-type (WT) mice, Sirt6 f/f, Tie-2 and Sirt6 f/f, Cadh5 mice do not phenocopy the inducible global SIRT6 knockout mice, they had normal EDD and CFR. When the mice were fed a high fat and high sugar (HFHS) diet, the Sirt6 f/f, Tie-2 and Sirt6 f/f, Cadh5 had impaired EDD, suggesting Sirt 6 functioned differently in the mice fed with chow diet or HFHS diet. We hypothesize Sirt 6 deficiency causes coronary endothelial dysfunction and contributes to CMD; activating Sirt6 will ameliorate CMD. EDD was assessed using myography (DMT). Myocardial blood flow (MBF) was measured by Doppler. Our preliminary data show that the mediator of coronary vasodilation switched from NO to H 2 O 2 in the Sirt6 knockout mice with impaired EDD. Interestingly, when the mice fed on HFHS were treated with Sirt 6 activator MDL-800, the coronary microvascular function was improved, and the blood glucose level was decreased. The underlying mechanism and the pathways involved will be elucidated.

Effect of whole-grain Tartary buckwheat fermentation with Monascus purpureus on the metabolic syndrome and intestinal flora in mice

This study investigated changes in the composition of fermented whole-grain Tartary buckwheat (FTB) by Monascus purpureus and the therapeutic effects of FTB on metabolic diseases in mice fed high-fat and high-sugar (HFHS) diets. Compared to raw Tartary Buckwheat (RTB), the protein, total phenol, and total flavonoid contents of FTB were significantly increased by 67.88%, 24.97%, and 45.74%, respectively, especially the rutin content reached 2607.31 mg/100g DW (p < 0.05, p < 0.01, p < 0.0001). Meanwhile, it exhibits stronger antioxidant properties of DPPH, ABTS, and FRAP (p < 0.05, p < 0.01). Then, the treatment of low (3 g/kg), medium (6 g/kg), and high (12 g/kg) doses of FTB (FL, FM, FH) could positively regulate weight, blood lipids, pro-inflammatory factors, glucose tolerance, and liver damage in HFHS mice. Among all groups, the levels of weight (35.53 g), fat (0.93 g/100 g), TG (0.77 mmol/L), IL-1β (84.77 ng/L), IL-6 (127.62 pg/L) and insulin (7.06 mIU/L) of serum, IL-1β (74.89 ng/L) and TNF-α (840.32 pg/L) of liver were all the lowest in FH group. Furthermore, the intestinal flora compositions were positively regulated by FTB treatment, including reducing the relative abundance of harmful bacteria (Clostridia_UCG-014, Candidatus_Saccharimonas, and Enterorhabdus) and enhancing the relative abundance of beneficial bacteria (Akkermansia and Eubacterium coprostanoligenes). Particularly, the phyla Firmicutes/Bacteroidetes (F/B) ratio was markedly restored and the abundance of Akkermansia and Eubacterium coprostanoligenes was significantly increased in the FH group (p < 0.0001). In conclusion, FTB can be used as a dietary supplement for improving metabolic syndrome and intestinal flora disorders. This study provides new ideas for the use of whole-grain Tartary buckwheat, new product development, and industry chain enhancement.

Maternal obesogenic diet operates at the tumor cell of origin to increase incidence and decrease latency of Neurofibromatosis Type 1 optic pathway glioma.

Pediatric low-grade glioma incidence has been rising in the U.S., mirroring the rising rates of pediatric and maternal obesity. Recently, children of obese mothers were demonstrated to develop brain tumors at higher rates. Importantly, obesity in the U.S. is largely driven by diet, given the prevalence of high fat and high sugar (HFHS) food choices. Since high-fat diet exposure can increase embryonic neuroglial progenitor cell (NPC) proliferation, the potential cells of origin for low-grade glioma, we hypothesized that in utero exposure to an obesogenic diet would modify pediatric brain penetrance and latency by affecting the tumor cell of origin. We employed several murine models of the Neurofibromatosis type 1 (NF1) pediatric brain tumor predisposition syndrome, in which optic pathway gliomas (Nf1-OPGs) arise from NPCs in the embryonic third ventricular zone (TVZ). We exposed dams and offspring to an obesogenic HFHS diet or control chow and analysed fetal neurodevelopment at E19.5 and tumor formation at 6w-3mo. Progeny from HFHS diet-exposed dams demonstrated increased TVZ NPC proliferation and glial differentiation. Dietary switch cohorts confirmed that these effects were dependent upon maternal diet, rather than maternal weight. Obesogenic diet (Ob) similarly accelerated glioma formation in a high-penetrance Nf1-OPG strain and increased glioma penetrance in two low-penetrance Nf1-OPG strains. In contrast, Ob exposure in the postnatal period alone did not recapitulate these effects. These findings establish maternal obesogenic diet as a risk factor for murine Nf1-OPG formation, acting in part through in utero effects on the tumor cell of origin.

The Regulatory Role of microRNA-21 in Coronary Microcirculation in Metabolic Syndrome

Coronary vasculature is essential to supply oxygen and nutrients to the heart and maintain normal cardiac function. Obstruction of large vessels of coronaries (atherosclerosis) is well studied, but coronary microvascular dysfunction (CMD), which is associated with diabetic cardiomyopathy, Takotsubo cardiomyopathy, Ischemia with the non-obstructive coronary artery (INOCA), and HFpEF, is understudied. CMD is characterized by impaired endothelial-dependent vasodilation, but detailed mechanisms have yet to be elucidated. The anti-fibrotic role of microRNA-21 (miR-21) is reported in the HFrEF induced by ischemia/reperfusion or pressure overload, but how miR-21 regulates CMD is not entirely understood. Our recent study shows miR-21 ablation ameliorated impaired vasodilation in isolated coronaries of mice fed on high fat and high sugar (HFHS) diet. In this study, we examined the coronary flow reserve (CFR), the relationship between myocardial blood flow (MBF) and cardiac work (doppler) under hyperemia, cardiac function (echocardiography and exercise exertion test), fibrosis and gene expression of miR-21 knockout and wild-type (WT) mice fed on chow or HFHS diet. Our preliminary data show that MBF and CFR were decreased, cardiac index, stroke volume, and running distance were reduced, and the E/E’ ratio was increased in WT mice fed on the HFHS diet compared to the WT mice fed on the chow diet. The perivascular fibrosis was increased in the WT mice fed on the HFHS diet compared to WT mice on the chow diet. The ablation of miR-21 reversed all these changes in the mice treated with HFHS, suggesting miR-21 deficiency ameliorated CMD in metabolic syndrome. Moreover, we used endothelial-specific miR-21 knockout to study the endothelial miR-21 function. Interestingly, the endothelial mi-R21 KO phenocopied the global knockouts, suggesting the benefit of miR-21 deficiency to coronary microvascular function in metabolic syndrome is from endothelial cells. The study provides the potential therapeutic strategy to target vascular endothelial cells with miR-21 antagomir for CMD in metabolic syndromes. AHA 970663,1R56HL165207,1 R01 HL165207-01A1 to LY and 1 F31 HL156726-01A1 to CJ. This is the full abstract presented at the American Physiology Summit 2024 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.

MODL-17. OBESOGENIC DIET INCREASES NF1-OPTIC PATHWAY GLIOMA FORMATION THROUGH EFFECTS ON THE TUMOR CELL OF ORIGIN

Abstract Rates of both pediatric low-grade glioma and obesity have been rising in the U.S., and children of obese mothers have increased rates of several tumor types, including brain tumors. Importantly, obesity in the U.S. is largely dietary-driven, given the prevalence of high fat and high sugar (HFHS) diets. High-fat diet exposure can promote proliferation of embryonic neuroglial progenitor cells (NPCs), which animal modeling suggests are potential cells of origin for low-grade glioma. Together, these data suggested that in utero exposure to an obesogenic diet might affect the formation of pediatric brain tumors. Using preclinical models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, in which optic pathway gliomas (Nf1-OPGs) arise from NPCs in the developing third ventricular zone (TVZ), we sought to determine whether maternal obesogenic exposure would increase glioma formation through intrinsic effects on the tumor cell of origin. We demonstrated that progeny from obese dams exposed to HFHS diet during and preceding gestation had increased proliferation and glial differentiation of WT and Nf1-mutant TVZ NPCs. Progeny of non-obese dams exposed to this diet during gestation demonstrate a similar phenotype, suggesting these effects are related to maternal diet rather than weight. Obesogenic diet exposure (Ob) also increased glioma penetrance in two low-penetrance murine models of Nf1-OPG. Moreover, we demonstrated that Ob mice developed earlier tumor onset with elevated Erk activity in a high-penetrance Nf1-OPG model. In contrast, when obesogenic diet was introduced postnatally, only 11% of mice showed accelerated tumor formation. Ob-exposed nerves also displayed elevated levels of activated Stat3, consistent with upregulation of the IL6/Jak/Stat3 pathway with HFHS diet exposure. These findings establish maternal obesogenic diet as a risk for pediatric glioma formation, in part through in utero effects on the tumor cell of origin, and identify the MAPK and IL6/Jak/Stat3 pathways as targets for further investigation.

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.

Antiobesity effect of L-arabinose via ameliorating insulin resistance and modulating gut microbiota in obese mice

ObjectivesThe global prevalence of obesity, a chronically trophic metabolic disease, has garnered significant attention. The aim of this study was to investigate L-arabinose, a unique functional sugar that improves insulin resistance and intestinal environment while promoting probiotic proliferation, for its potential in preventing obesity induced by a high-fat and high-sugar (HFHS) diet in mice. MethodsThe L-arabinose group was intragastrically administered with 0.4 mL 60 mg/(kg body weight) L-arabinose for 8 wk. The metformin group was intragastrically administered at 0.4 mL 300 mg/(kg body weight), as a positive control group. ResultsTreatment with L-arabinose resulted in a reduction of various obesity symptoms, such as prevented weight gain, increased liver-to-body ratio, decreased insulin, homeostasis model assessment for insulin resistance (HOMA-IR) index, and lipopolysaccharide (LPS) levels, as well as improved insulin resistance, reduced fat volume, inhibited hepatic steatosis, and repaired the pancreas. The L-arabinose treatment also improved lipid metabolism and inflammatory response, decreased the Firmicutes-to-Bacteroidetes ratio at the phylum level, and increased the relative abundance of Parabacteroides gordonii and Akkermansia muciniphila at the species level. ConclusionBased on these results, L-arabinose could be a promising candidate for combating obesity and obesity-related diseases by regulating insulin resistance and gut microbiota.

Effect of Rosuvastatin and Glibenclamide in Alone or in Combination on Glucose Homeostasis in Diabetic Male Albino Wistar Rats: An Observer-blinded Experimental Interventional Study

Introduction: Metabolic Syndrome (MetS) is a complex of metabolic disorders which include obesity, insulin resistance, hyperglycaemia, hypertension along with dyslipidemia. It is not clear whether rosuvastatin is having role in new onset diabetes. Aim: To assess the effect of rosuvastatin in comparison to glibenclamide on blood sugar levels and insulin resistance in diabetic rats. Materials and Methods: This experimental study was carried out at Sri Manakula Vinayagar Medical College and Hospital, Kalitheerthalkuppam, Puducherry on 42 adult male Wistar rats, for 8 weeks. Diabetes was created by feeding rats with High Fat and High Sugar (HFHS) diet over a period of 8 weeks. In total, 42 rats were allocated to in 7 groups, consisting of 6 animals per group. Group I -vehicle treated animals (control), group II - HFHS diet animals (Diabetic Control- DC), group III- glibenclimide (G) (5 mg/kg) + HFHS, group IV-rosuvastatin (R) (5 mg/kg) + HFHS, group V-R (10 mg/kg) + HFHS, group VI-G (5 mg/kg) + R (5 mg/kg) + HFHS diet, group VII-G (5 mg/kg) + R (10 mg/kg) + HFHS diet continued for 4 weeks. Rosuvastatin and glibenclamide were dissolved in distilled water and 95% ethanol respectively, and were given orally daily for 4 weeks after induction of diabetes. Data were subjected to one-way ANOVA using Statistical Package for the Social Sciences (SPSS) version 24.0 followed by non parametric test with significance level set for p-value&lt;0.05. Results: By end of 8th week, on comparison of control group with HFHS diet and glibenclamide treated group, there was significant rise in body weight, serum Low Density Lipoprotein (LDL), in addition to Very Low Density Lipoprotein (VLDL) and Triglycerides (TG) levels. Glibenclamide treated (group III) animals on comparison with groups IV, V, VI, VII revealed reduction in body weight, serum LDL, VLDL and TG levels (p &lt;0.001). Glibenclamide treated (group III) on comparing with groups IV, V, VI, VII, there was significant high serum HDL level (p&lt;0.001). By 8th week, significant decrease in serum insulin and HOMA-IR level was observed when glibenclamide group III was compared with groups IV to VII treated animals (p &lt;0.001). Conclusion: The study results indicate that the combination therapy of rosuvastatin and glibenclamide demonstrate beneficial effects on weight reduction, lipid profile and insulin resistant.

Bifidobacterium longum 070103 Fermented Milk Improve Glucose and Lipid Metabolism Disorders by Regulating Gut Microbiota in Mice.

Background: Fermented milk is beneficial for metabolic disorders, while the underlying mechanisms of action remain unclear. This study explored the benefits and underlying mechanisms of Bifidobacterium longum 070103 fermented milk (BLFM) in thirteen-week high-fat and high-sugar (HFHS) fed mice using omics techniques. Methods and results: BLFM with activated glucokinase (GK) was screened by a double-enzyme coupling method. After supplementing BLFM with 10 mL/kg BW per day, fasting blood glucose, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and leptin were significantly reduced compared with the HFHS group. Among them, the final body weight (BW), epididymal fat, perirenal fat, and brown fat in BLFM group had better change trends than Lacticaseibacillus rhamnosus GG fermented milk (LGGFM) group. The amplicon and metabolomic data analysis identified Bifibacterium as a key gut microbiota at regulating glycolipid metabolism. BLFM reverses HFHS-induced reduction in bifidobacteria abundance. Further studies showed that BLFM significantly reduces the content of 3-indoxyl sulofphate associated with intestinal barrier damage. In addition, mice treated with BLFM improved BW, glucose tolerance, insulin resistance, and hepatic steatosis. Conclusion: BLFM consumption attenuates obesity and related symptoms in HFHS-fed mice probably via the modulation of gut microbes and metabolites.

Construction of the experimental rat model of gestational diabetes.

Numerous methods for modeling gestational diabetes mellitus (GDM) in rats exist. However, their repeatability and stability are unclear. This study aimed to compare the effects of high-fat and high-sugar (HFHS) diet, HFHS diet combined with streptozotocin (STZ) administration, and HFHS diet combined with movement restriction (MR) modeling methods on rat models to confirm the best method for constructing a rat model of GDM. Forty female Sprague-Dawley rats were randomly divided into four groups (n = 10): the normal control (NC), HFHS, HFHS+STZ, and HFHS+MR groups. The rats in the NC group were fed with a standard diet, and those in the remaining groups were fed with a HFHS diet. The rats in the HFHS+STZ group received 25 mg/kg STZ on their first day of pregnancy, and those in the HFHS+MR group were subjected to MR during pregnancy. Bodyweight, food intake, water intake, fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of insulin sensitivity (HOMA-IS), homeostasis model assessment of β-cell function, pancreatic and placental morphology, and the expression levels of glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3) in placentas were then quantified. Moreover, iTRAQ was used to identify placental proteomics. During pregnancy, the rats in the HFHS+STZ group showed FBG levels that were kept stable in a state of moderate hyperglycemia; the typical GDM symptoms of polydipsia, polyphagia, polyuria, and increased body weight; and the modeling rate of 87.5%. On the first and 19th days of pregnancy, the rats in the HFHS group showed higher FBG than that of the NC group, increasing body weight and food intake and the modeling rate of 50%. On the 19th day of pregnancy, the FBG of the rats in the HFHS+MR group was higher than that of the rats in the NC group, and the modeling rate of 42.9%. Comparison with the NC group revealed that the three modeling groups exhibited increased FINS and HOMA-IR, decreased HOMA-IS, and different degrees of pathological changes in pancreases and placentas. Among the groups, the HFHS+STZ group displayed the greatest changes with significant reductions in the numbers of pancreatic and placental cells and appeared cavitation. The expression levels of GLUT1 and GLUT3 in the placentas of the HFHS+STZ and HFHS+MR groups were higher than those in the placentas of the NC and HFHS groups. The above results indicated that the rats in the HFHS+STZ group showed the best performance in terms of modeling indicators. After the changes in placental proteomics in the HFHS+STZ group were compared with those in the NC group, we found that in the HFHS+STZ group, five proteins were up-regulated and 18 were down-regulated; these proteins were enriched in estrogen signaling pathways. HFHS combined with the intraperitoneal injection of 25 mg/kg STZ was the best modeling method for the nonspontaneous model of experimentally induced GDM, and its modeling rate was high. The pathological characteristics of the constructed GDM rat model were similar to those of human patients with GDM. Moreover, the model was stable and reliable. The modeling method can provide a basis for constructing a GDM rat model for subsequent research on the prevention and treatment of GDM.

Early Dietary Exposures Epigenetically Program Mammary Cancer Susceptibility through Igf1-Mediated Expansion of the Mammary Stem Cell Compartment.

Diet is a critical environmental factor affecting breast cancer risk, and recent evidence shows that dietary exposures during early development can affect lifetime mammary cancer susceptibility. To elucidate the underlying mechanisms, we used our established crossover feeding mouse model, where exposure to a high-fat and high-sugar (HFHS) diet during defined developmental windows determines mammary tumor incidence and latency in carcinogen-treated mice. Mammary tumor incidence is significantly increased in mice receiving a HFHS post-weaning diet (high-tumor mice, HT) compared to those receiving a HFHS diet during gestation (low-tumor mice, LT). The current study revealed that the mammary stem cell (MaSC) population was significantly increased in mammary glands from HT compared to LT mice. Igf1 expression was increased in mammary stromal cells from HT mice, where it promoted MaSC self-renewal. The increased Igf1 expression was induced by DNA hypomethylation of the Igf1 Pr1 promoter, mediated by a decrease in Dnmt3b levels. Mammary tissues from HT mice also had reduced levels of Igfbp5, leading to increased bioavailability of tissue Igf1. This study provides novel insights into how early dietary exposures program mammary cancer risk, demonstrating that effective dietary intervention can reduce mammary cancer incidence.

Obesogenic diet in mice compromises maternal metabolic physiology and lactation ability leading to reductions in neonatal viability.

Diets containing high-fat and high sugar (HFHS) lead to overweight/obesity. Overweight/obesity increases the risk of infertility, and of the pregnant mother and her child for developing metabolic conditions. Overweight/obesity has been recreated in mice, but most studies focus on the effects of chronic, long-term HFHS diet exposure. Here, we exposed mice to HFHS from 3 weeks prior to pregnancy with the aim of determining impacts on fertility, and gestational and neonatal outcomes. Time-domain NMR scanning was used to assess adiposity, glucose, and insulin tolerance tests were employed to examine metabolic physiology, and morphological and proteomic analyses conducted to assess structure and nutrient levels of maternal organs and placenta. Fertility measures of HFHS dams were largely the same as controls. HFHS dams had increased adiposity pre-pregnancy, however, exhibited exacerbated lipolysis/hyper-mobilization of adipose stores in late pregnancy. While there were no differences in glucose or insulin tolerance, HFHS dams were hyperglycemic and hyperinsulinemic in pregnancy. HFHS dams had fatty livers and altered pancreatic islet morphology. Although fetuses were hyperglycemic and hyperinsulinemic, there was no change in fetal growth in HFHS dams. There were also reductions in placenta formation. Moreover, there was increased offspring loss during lactation, which was related to aberrant mammary gland development and milk protein composition in HFHS dams. These findings are relevant given current dietary habits and the development of maternal and offspring alterations in the absence of an increase in maternal weight and adiposity during pregnancy, which are the current clinical markers to determine risk across gestation.

QSHY Granules Promote White Adipose Tissue Browning and Correct BCAAs Metabolic Disorder in NAFLD Mice.

PurposeWhite adipose tissue (WAT) has positive effects on peripheral metabolism parameters and liver energy metabolism. This study aimed to explain the pharmacological mechanism of Qushi Huayu (QSHY) granules in the treatment of nonalcoholic fatty liver disease (NALFD) mice based on branched-chain amino acid (BCAA) catabolism and WAT browning.Patients and MethodsThirty C57BL/6J mice were randomly divided into a (Ctrl) control group, fed with a control diet, a NAFLD model group, fed with a high-fat and high-sugar (HFHS) diet, and a QSHY granules treatment (HFHS+QSHY) group, administered with QSHY granules. After 14 weeks of feeding, HFHS+QSHY group mice were administered QSHY granules through oral gavage for 6 weeks. The metabolic parameters were assessed, the circular and fecal BCAA content was observed, and liver and epididymal WAT (eWAT) were collected for pathological, quantitative real-time polymerase chain reaction, and Western blotting analyses.ResultsCompared with the HFHS group, mice in the HFHS+QSHY group demonstrated restored liver histological changes, ameliorated hepatocyte steatosis, and alleviated inflammatory cell infiltration. Consistent with the pathological changes, QSHY granules significantly reduced the elevated levels of liver triglycerides, and serum alanine aminotransferase, and it relieved hypercholesterolemia and insulin resistance in mice with HFHS-induced NAFLD. Furthermore, it corrected BCAA metabolic disorders in serum and feces and promoted the expression of BCAA catabolic genes in the eWAT of HFHS mice. QSHY granules also increased the expression of phosphorylated AMP-activated protein kinase (AMPK) protein, up-regulating the protein expression of the AMPK/SIRT1/UCP-1 pathway in the eWAT.ConclusionQSHY granules improved hepatic steatosis and corrected the BCAA disorder in NAFLD mice, and the related mechanisms regulated the AMPK/SIRT1/UCP-1 pathway and promoted WAT browning.

Impaired brown adipose tissue is differentially modulated in insulin-resistant obese wistar and type 2 diabetic Goto-Kakizaki rats

Brown adipose tissue (BAT) is a potential target to treat obesity and diabetes, dissipating energy as heat. Type 2 diabetes (T2D) has been associated with obesogenic diets; however, T2D was also reported in lean individuals to be associated with genetic factors. We aimed to investigate the differences between obese and lean models of insulin resistance (IR) and elucidate the mechanism associated with BAT metabolism and dysfunction in different IR animal models: a genetic model (lean GK rats) and obese models (diet-induced obese Wistar rats) at 8 weeks of age fed a high-carbohydrate (HC), high-fat (HF) diet, or high-fat and high-sugar (HFHS) diet for 8 weeks. At 15 weeks of age, BAT glucose uptake was evaluated by 18F-FDG PET under basal (saline administration) or stimulated condition (CL316,243, a selective β3-AR agonist). After CL316, 243 administrations, GK animals showed decreased glucose uptake compared to HC animals. At 16 weeks of age, the animals were euthanized, and the interscapular BAT was dissected for analysis. Histological analyses showed lower cell density in GK rats and higher adipocyte area compared to all groups, followed by HFHS and HF compared to HC. HFHS showed a decreased batokine FGF21 protein level compared to all groups. However, GK animals showed increased expression of genes involved in fatty acid oxidation (CPT1 and CPT2), BAT metabolism (Sirt1 and Pgc1-α), and obesogenic genes (leptin and PAI-1) but decreased gene expression of glucose transporter 1 (GLUT-1) compared to other groups. Our data suggest impaired BAT function in obese Wistar and GK rats, with evidence of a whitening process in these animals

Thymopentin alleviates premature ovarian failure in mice by activating YY2/Lin28A and inhibiting the expression of let-7 family microRNAs.

ObjectiveThymopentin (5TP) significantly improved typical murine premature ovarian failure (POF) symptoms induced by a high‐fat and high‐sugar (HFHS) diet. However, its effect and mechanism remain unclear.Materials and methodsRNA‐Seq was used to detect the differentially expressed genes among each group. HFHS‐induced POF mouse model was generated and injected with siRNA using Poly (lactic‐co‐glycolic acid) (PLGA) as a carrier.ResultsRNA‐Seq suggested that 5TP promoted the expression of Yin Yang 2 (YY2) in mouse ovarian granulosa cell (mOGC) of HFHS‐POF mice. Luciferase reporter assay indicated that 5TP promoted the binding of YY2 to the specific sequence C(C/T)AT(G/C)(G/T) on the Lin28A promoter and promoted Lin28A transcription and expression. We continuously injected PLGA‐cross‐linked siRNA nanoparticles targeting YY2 into HFHS‐POF mice (siYY2@PLGA), which significantly reduced the therapeutic effect of 5TP. siYY2@PLGA injection also significantly attenuated the upregulation of Lin28a expression in mOGCs induced by 5TP and enhanced the expression of let‐7 family microRNAs, thereby inhibiting the proliferation and division of mOGCs. qPCR results showed that there was a significant difference in the expression levels of exosome‐derived Yy2 mRNAs between POF patients and normal women, and that there was a specific correlation between the expression level of exosome‐derived Yy2 and the peripheral concentrations of the blood hormones pregnenolone, progesterone and oestradiol.ConclusionsThymopentin promotes the transcriptional activation of Lin28A via stimulating transcription factor YY2 expression, inhibits the activity of let‐7 family microRNAs and alleviates the ageing of ovarian granulosa cells, ultimately achieving a therapeutic effect on POF in mice.

Age-dependent and region-specific alteration of parvalbumin neurons, perineuronal nets and microglia in the mouse prefrontal cortex and hippocampus following obesogenic diet consumption

Emergent evidence demonstrates that excessive consumption of high fat and high sugar (HFHS) diets has negative consequences on hippocampal and prefrontal cortex (PFC) function. Moreover, the delayed maturation of the PFC including the late development of parvalbumin-expressing (PV) interneurons and perineuronal nets (PNNs) may promote vulnerability to HFHS diet-induced nutritional stress. However, the young brain may have some resistance to diet-induced neuroinflammation. Thus, we examined the impact of a HFHS diet commencing either in adolescence or adulthood in male mice. PV interneurons, PNNs and microglia were assessed using immunohistochemistry. We observed greater numbers of PV neurons and PNNs in the hippocampus and the prelimbic and infralimbic PFC in adult mice in comparison to our younger cohort. Mice that consumed HFHS diet as adults had reduced numbers of hippocampal PV neurons and PNNs, which correlated with adiposity. However, we saw no effects of diet on PV and PNNs in the PFC. HFHS diet increased microgliosis in the adult cohort, and morphological changes to microglia were observed in the PFC and hippocampus of the adolescent cohort, with a shift to activated microglia phenotypes. Taken together, these findings demonstrate different regional and age-specific effects of obesogenic diets on PV neurons, PNNs and microglia.

Thymopentin treatment of murine premature ovarian failure via attenuation of immune cell activity and promotion of the BMP4/Smad9 signalling pathway.

Premature ovarian failure (POF) is a typical form of pathological aging with complex pathogenesis and no effective treatment. Meanwhile, recent studies have reported that a high-fat and high-sugar (HFHS) diet adversely affects ovarian function and ovum quality. Here, we investigated the therapeutic effect of thymopentin (TP-5) as a treatment for murine POF derived from HFHS and its target. Pathological examination and hormone assays confirmed that TP-5 significantly improved murine POF symptoms. And, TP-5 could reduce oxidative stress injury and blood lipids in the murine POF derived from HFHS. Flow cytometry and qPCR results suggested that TP-5 attenuated activation of CD3+ T cells and type I macrophages. RNA-Seq results indicated somedifferences in gene transcription between the TP-5 intervention group and the control group. KEGG analysis indicated that the expression of genes involved in the mTOR signaling pathway was the most significantly different between the two groups. Additionally, compared with the control groups, the expression levels of interleukin, NFκB, and TNF families of genes were significantly downregulated in the POF+TP-5 group, whereas expression of the TGFβ/Smad9 genes was significantly upregulated. Finally, immunofluorescence staining and qPCR confirmed that TP-5 promoted the polarization of Mø2 cells in the ovary by activating the expression of the BMP4/Smad9 signalling pathway. Thus, our study confirmed that TP-5 has a significant therapeutic effect on POF by upregulating BMP4/Smad9 signalling pathway so as to promote the balance and polarization of immune cell and reducing the release of inflammatory factors and reduce lipid oxidative stress injury.

MicroRNA-146b-5p overexpression attenuates premature ovarian failure in mice by inhibiting the Dab2ip/Ask1/p38-Mapk pathway and γH2A.X phosphorylation.

ObjectiveTo examine the role of high‐fat and high‐sugar (HFHS) diet‐induced oxidative stress, which is a risk factor for various diseases, in premature ovarian failure (POF).Materials and methodsOvarian granulosa cells (OGCs) were isolated from mice and cultured in medium supplemented with HFHS and poly (lactic‐co‐glycolic acid) (PLGA)‐cross‐linked miR‐146b‐5p nanoparticles (miR‐146@PLGA). RNA and protein expression levels were examined using quantitative real‐time polymerase chain reaction and Western blotting, respectively. HFHS diet‐induced POF model mice were administered miR‐146@PLGA.ResultsThe ovarian tissue of mice fed a HFHS diet exhibited the typical pathological characteristics of POF. HFHS supplementation induced oxidative stress injury in the mouse OGCs, activation of the Dab2ip/Ask1/p38‐Mapk signalling pathway and phosphorylation of γH2A.X in vitro and in vivo. The results of the luciferase reporter assay revealed that miR‐146 specifically downregulated p38‐Mapk14 expression. Meanwhile, co‐immunoprecipitation and Western blot analyses revealed that HFHS supplementation upregulated nuclear p38‐Mapk14 expression and consequently enhanced γH2A.X (Ser139) phosphorylation. The HFHS diet‐induced POF mouse model treated with miR‐146@PLGA exhibited downregulated p38‐Mapk14 expression in the OGCs, mitigated OGC ageing and alleviated the symptoms of POF.ConclusionsThis study demonstrated that HFHS supplementation activates the Dab2ip/Ask1/p38‐Mapk signalling pathway and promotes γH2A.X phosphorylation by inhibiting the expression of endogenous miR‐146b‐5p, which results in OGC ageing and POF development.

Effects of Exercise Training on Renal Carnitine Biosynthesis and Uptake in the High-Fat and High-Sugar-Fed Mouse.

(1) Background: Diet-induced obesity inhibits hepatic carnitine biosynthesis. Herein, the effects of high-fat (HF) and high-sugar (HFHS) feeding and exercise training (ET) on renal carnitine biosynthesis and uptake were determined. (2) Methods: Male C57BL/6J mice were assigned to the following groups: lean control (standard chow), HFHS diet, and HFHS diet with ET. ET consisted of 150 min of treadmill running per week for 12 weeks. Protein levels of γ-butyrobetaine hydroxylase (γ-BBH) and organic cation transporter-2 (OCTN2) were measured as markers of biosynthesis and uptake, respectively. (3) Results: HFHS feeding induced an obese diabetic state with accompanying hypocarnitinemia, reflected by decreased free carnitine levels in plasma and kidney. This hypocarnitinemia was associated with decreased γ-BBH (~30%) and increased OCTN2 levels (~50%). ET failed to improve the obesity and hyperglycemia, but improved insulin levels and prevented the hypocarnitinemia. ET increased protein levels of γ-BBH, whereas levels of OCTN2 were decreased. Peroxisome proliferator-activated receptor-alpha content was not changed by the HFHS diet or ET. (4) Conclusions: Our results indicate that ET prevents the hypocarnitinemia induced by HFHS feeding by increasing carnitine biosynthesis in kidney. Increased expression of OCTN2 with HFHS feeding suggests that renal uptake was stimulated to prevent carnitine loss.

Diet-Induced Metabolic Dysregulation in Female Mice Causes Osteopenia in Adult Offspring.

Bone mass and quality in humans are controlled by numerous genetic and environmental factors that are not fully understood. Increasing evidence has indicated that maternal metabolic dysregulation impairs multiple physiological processes in the adult offspring, but a similar effect on bone health is yet to be established. Here, we have analyzed the bones of first-generation offspring from murine dams that present metabolic syndrome due to a high-fat and high-sugar (HF/HS) diet. Micro-CT analyses show that the long bones of HF/HS offspring possess lower cortical bone mass and weaker mechanical strength than normal, even though the trabecular bone is not affected. Histomorphometry and serum biochemistry indicate that both bone formation and resorption are diminished in the HF/HS offspring. In vitro, both osteoblast and osteoclast progenitors from the HF/HS offspring are deficient in differentiation, likely due to impairment of mitochondrial respiration. The study, therefore, identifies maternal metabolic health as an important environmental factor influencing bone volume and strength.