High Fat High Sugar Diet Reduces Small Intestinal Secretion by Sex-Dependent Mechanisms.

BACKGROUND/AIMS: The goal of this study was to determine the influence of high-fat high-sugar diet (Western diet) on intestinal function and subsequently to determine if there were any beneficial effects of exercise, genistein (a naturally occurring phytoestrogen) or both, on the intestine. METHODS: We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from male and female C57Bl/6J mice randomly assigned to one of the following groups for the 12-week study duration: high-fat high-sugar diet (HFS), HFS with genistein (Gen), HFS with exercise (Ex), or HFS with both genistein and exercise (Gen+Ex) and compared them to lean controls. Genistein concentration was 600 mg genistein/kg diet. Exercise comprised of moderate intensity treadmill running (150 min per week). At the completion of the study, segments of jejunum were frozen for western blot determination of key proteins involved in secretory and absorptive functions, as well as senescence. Intestinal morphology was assessed. Serum cytokine assays were performed. RESULTS: Basal Isc was significantly decreased (by 70%, P<0.05) in HFS females and males versus leans. This decrease was partially mitigated by exercise in both sexes. In females, the HFS-induced decrease in Isc was attributed to a significant loss of CLC2, NKCC1 and CFTR expression whereas in males this was due to a significant loss of Na/K-ATPase, KCa and NKCC1 expression (indicating sex-dependent mechanisms). Exercise mitigated most of the loss of Isc in both sexes. Our data suggested that A2BR levels were dysregulated in HFS fed mice and that concomitant treatment with Gen or Gen+Ex prevented this disruption in females only. Inflammatory state was associated with body weight changes. CONCLUSION: Our data suggests that the reduced basal jejunal Isc in HFS mice is attributed to sex-dependent mechanisms and while exercise partially mitigated this, it's mechanism of action was unclear. Improved understanding of Western diet induced intestinal dysfunctions may allow for the development of novel drug targets to treat gastrointestinal disturbances in diabetic obesity.

Genistein Suppresses IL-6 and MMP-13 to Attenuate Osteoarthritis in Obese Diabetic Mice.

Type 2 diabetes mellitus and osteoarthritis (OA) often present as comorbidities. We examined the role of plasma IL-6, chondrocyte MMP-13, and col10a expression in the development of OA in obese diabetic mice. We further investigated dietary genistein and exercise training as potential mitigators of OA. One hundred adult mice (50 females, 50 males) aged 6 weeks were randomized into 5 groups, including lean controls, obese diabetic controls, and obese diabetic mice treated with genistein, exercise training, and genistein plus exercise training. The obese diabetic state was induced by feeding the mice a high-fat, high-sugar diet. Genistein was incorporated into the diet at a concentration of 600 mg genistein/kg. Exercise training was performed on a treadmill and consisted of daily 30 min sessions at 12 m/min, 5 days/week for a 12-week period. After treatment, plasma was collected, and proximal tibias were removed for analysis. Plasma IL-6 and MMP-13 were elevated while col10a was reduced in obese diabetic mice in comparison to lean controls. Dietary genistein treatment reduced IL-6 and MMP-13 expression and increased col10a expression. Histological examination of articular cartilage showed reduced thickness of the uncalcified zones and proteoglycan content in the cartilage of diabetic mice in comparison to mice fed genistein. Exercise training had no significant effect. In conclusion, genistein (and not exercise training) attenuates OA by reducing IL-6 and MMP-13 expression in diabetic mice.

Effects of face masks on oxygen saturation at graded exercise intensities.

CONTEXT: Mask wearing to mitigate the spread of COVID-19 and other viral infections may raise concerns on the effects of face masks on breathing and cardiopulmonary health. Non-evidence-based apprehensions may limit the use of masks in public. OBJECTIVES: We will assess the parameters related to heart and lung physiology between healthy male and female adults exposed to wearing face masks (or not) under conditions of rest and graded exercise. METHODS: We performed a cross-sectional study including 20 male and 20 female adults who met our inclusion criteria. Adults with underlying respiratory and cardiac conditions were excluded. Physiologic parameters were measured while the participants underwent three activity levels (10 min each) in a randomly assigned order: rest, walking, and stair climbing. Each activity level was conducted under three mask conditions: no mask, surgical mask, and N95 respirator. Heart rate (HR) and blood oxygen saturation (SpO2) were recorded via pulse oximeter after each activity. Perceived exertion was recorded utilizing a Borg 15-point scale. A mixed-effects analysis of variance (ANOVA) was utilized to interpret the results. RESULTS: A significant increase in perceived exertion was reported for N95 users (p<0.0001). There was also a significant increase in mean HR for N95 users in comparison to no-mask users (p=0.0031). The mean SpO2 in females was higher than males under rest and walking conditions (p=0.0055). There was no change in SpO2 between mask type overall, nor between mask type vs. exercise intensity, nor between mask type and sex. CONCLUSIONS: Our findings provide evidence that surgical masks and N95 respirators do not influence SpO2 at rest or during exercise.

The assessment of point-of-care-ultrasound (POCUS) in acute care settings is benefitted by early medical school integration and fellowship training.

CONTEXT: Point-of-care ultrasound (POCUS) has widespread utilization in multiple clinical settings. It has been shown to positively influence clinician confidence in diagnosis and can help appropriately manage patients in acute care settings. There has been a growing trend of increased emphasis on incorporating POCUS training in the first 2 years of the medical school curriculum. OBJECTIVES: This article aims to analyze the clinical use of POCUS in acute settings and how training early in medical school may strengthen clinician confidence and utilization. METHODS: An anonymous 10-question survey on POCUS use was conducted via a secure online platform and distributed to board-certified practicing physicians (MDs and DOs) with educational agreements with Midwestern University (MWU) across acute care specialties. This included preceptors within the MWU graduate medical education clinical consortium. Survey questions were aimed at assessing frequency of use, machine type, reasons for utilizing POCUS, initial ultrasound training, confidence in performing/interpreting POCUS, and perceived impact on patient outcomes. Surveys less than 50% complete were excluded. All surveys returned were more than 50% complete and thus included in the study. Statistical analyses were conducted utilizing the statistical software R version 4.0. RESULTS: Surveys were sent out to 187 participants with 68 responses (36.4% response rate). The survey results demonstrated a relationship between learning POCUS earlier in one's medical career (medical school, residency, or fellowship) to increased use in acute settings when compared to learning POCUS during clinical practice. Of the 68 respondents, 65 (95.6%) indicated that they agree or strongly agree that POCUS use improves patient care, and 64 (94.1%) indicated that they agree or strongly agree that the use of POCUS can improve patient outcomes. CONCLUSIONS: Our survey of acute care physicians indicated that most respondents utilize POCUS daily or weekly (90.8%), and this was related to fewer years of practice (under 10 years from medical school graduation, 94.6%). Moreover, POCUS was utilized primarily in acute care settings for procedures (25%, n=17/68 respondents). These survey results indicate that early integration of POCUS education in osteopathic medical school curricula and throughout fellowship training could likely enhance POCUS utilization in acute care settings.

Exercise Training Prevents the Loss of Wall Thickness and Lowers Expression of Alzheimer's Related Proteins in 3xTg Mouse Jejunum.

Growing evidence has demonstrated the benefits of regular exercise on cardiovascular, neural, and cognitive function in humans with Alzheimer's disease (AD). However, the consequences of AD on gastrointestinal morphology and the effects of regular exercise, which plays an important role against the development of certain gastrointestinal-related diseases, are still poorly understood. Therefore, to assess the changes in intestinal structure in a mouse model of AD and the impact of exercise, 2-month-old 3xTg-AD male mice were subjected to treadmill running 5 days per week for a period of 5 months. Jejunum from 3xTg-AD mice analyzed by histochemical methods revealed significant alterations in morphology. Compared to age-matched wild-type (WT) mice, villi length and crypt depth were increased, and collagen content of jejunum was elevated in 3xTg-AD mice. Jejunum wall dimensions, expressed as total wall thickness, outer longitudinal thickness, and inner circular thickness were decreased in 3xTg-AD compared to WT. Smooth muscle actin expression in jejunal wall was decreased in 3xTg-AD. Most of these aberrations were improved with exercise. Western blot expression of cyclin dependent kinase 5 (CDK5, involved in neural cell death and hyperphosphorylation of tau), was elevated in 3xTg-AD jejunum. This was associated with a 4-fold increase in tau5 expression. Exercise prevented the increase in expression of CDK5 and tau5. Expression of caspase 3 (an apoptotic marker) was elevated in 3xTg-AD jejunum and exercise prevented this. The results of our study indicate that the abnormalities in jejunum of the 3xTg mouse model of AD were prevented with exercise training.

Exercise and/or Genistein Do Not Revert 24-Week High-Fat, High-Sugar Diet-Induced Gut Microbiota Diversity Changes in Male C57BL/6J Adult Mice.

The gut microbiota (GM) has been hypothesized to be a potential mediator in the health benefits of exercise and diet. The current literature is focused on the prevention effects of exercise and diet and could benefit from exploring whether these treatments alone or combined can treat obesity via the gut microbiome. This study aimed to explore the effects of genistein, exercise, and their synergistic effect to revert diet-induced obesity and gut microbiota changes. A total of 57 male adult C57BL/6 mice were randomized to 24 weeks of unpurified diet (chow) or a high-fat, high-sugar diet (HFD; 60% fat total energy). After the first 12 weeks, animals on the HFD were randomized into: HFD + chow, HFD, HFD + exercise (HFD + Exe), HFD + genistein (HFD + Gen), and HFD + Exe + Gen. We compared the body weight change between groups after 24 weeks. GM (α-diversity and ß-diversity) was profiled after sequencing the 16S rRNA gene by Illumina MiSeq. HFD + Exe + Gen significantly (p < 0.05) decreased weight gain relative to the HFD with only HFD + chow reverting the body weight change to that of chow. All diets including HFD reduced the GM richness (observed amplicon sequence variants) relative to chow with the HFD + Gen and HFD + Exe resulting in significantly lower phylogenetic diversity compared to the HFD. Data did not support an additive benefit to the GM for HFD + Gen + Exe. HFD + Exe + Gen showed a greater capacity to revert diet-induced obesity in adult male mice, but it was not as effective as switching from HFD to chow. Lifestyle treatment of HFD-induced obesity including exercise and genistein resulted in a reduction in weight gain and GM richness, but switching from HFD to chow had the greatest potential to revert these characteristics toward that of lean controls.

Evaluation of Candida spp. and Other Fungi in Feces from Dogs with Naturally Occurring Diabetes Mellitus.

Diabetes mellitus is a common endocrinopathy in dogs and in most cases is analogous to type 1 diabetes mellitus (T1DM) in humans. Candida spp. is a common commensal fungi with higher prevalence and magnitude of growth in humans with T1DM. There is currently no published information about the fungal microbiome in diabetic dogs. Therefore, the objectives of this study were to (i) determine whether diabetic dogs were more likely to have Candida spp. or other types of fungi from feces compared to non-diabetic controls, and (ii) identify variables associated with fungi colonization. Fourteen diabetic dogs and 14 age, sex, and breed matched non-diabetic healthy control dogs were included in this prospective case-control study. Matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was used for fungal identification. Diabetic dogs had greater quantitative fungal growth compared to controls (p = 0.004). Moreover, female dogs were more likely to have fungi colonization than males (p = 0.02). All instances of Candida spp. and Aspergillus spp. colonization were exclusively identified in diabetic dogs. Serum fructosamine concentration was higher in diabetic dogs with fecal colonization of Candida spp. compared to diabetic dogs without growth (p = 0.03). Our results indicate that the fungal microbiome in feces is altered in diabetic dogs, which seem to favor an increased prevalence of Candida spp. and higher quantitative fungal growth. Moreover, female sex and glycemic control could affect the intestinal mycobiome.

Mitigation of MAFLD in High Fat-High Sucrose-Fructose Fed Mice by a Combination of Genistein Consumption and Exercise Training.

Purpose: Metabolic dysfunction-associated fatty liver disease (MAFLD) is fueled by escalations in both sedentary behavior and caloric intake and is noted in obese type 2 diabetic (T2DM) patients. This study aimed to examine the effects of exercise and the phytoestrogen genistein in mice fed a high fat (60% fat) high sugar (55% fructose with 45% sucrose), HFHS diet. Methods: Male C57BL/6J mice were assigned to five groups: HFHS, HFHS with genistein (600 mg/kg diet, HFHS+Gen), HFHS with moderate exercise (HFHS+Ex), and HFHS with combined genistein and moderate exercise (HFHS-Gen+Ex). Control lean mice were fed standard chow and water. Exercise consisted of 30-minute sessions of treadmill running five days/week for the 12-week study duration. Body weight was assessed weekly. Liver, kidney, fecal pellets and serum were extracted at the end of the study and maintained at -80°C. Results: After 12 weeks of treatment, mice in the HFHS group had the highest hepatic lipid content. Plasma levels of glucose, insulin, leptin, cholesterol, amylin, and total fat content were significantly elevated in HFHS mice compared to control mice. HFHS feeding increased protein expression of carnitine palmitoyltransferase 1b (CPT-1b isoform) in gastrocnemius, CPT1a, glucose transporter protein 2 (GLUT2), glucocorticoid receptor (GR), and fructose 1,6-bisphosphate 1 (FBP1) expression in liver. Exercise alone had minor effects on these metabolic abnormalities. Genistein alone resulted in improvements in body weight, fat content, amylin, insulin sensitivity, and liver histopathology, GR, FBP1, and acetyl-CoA carboxylase 1 (ACC1). Combination treatment resulted in additional metabolic improvements, including reductions in hepatic lipid content and lipid area, alanine transferase activity, CPT1b, and CPT1a. Conclusion: Our results indicate that a HFHS diet is obesogenic, inducing metabolic perturbations consistent with T2DM and MAFLD. Genistein alone and genistein combined with moderate intensity exercise were effective in reducing MAFLD and the aberrations induced by chronic HFHS feeding.

Systematic review of the impact of genistein on diabetes-related outcomes.

Diabetes is the eighth leading cause of death in the world and the prevalence is rising in low-income countries. Cardiovascular diseases are the leading cause of death worldwide, especially for individuals with diabetes. Although medications exist to treat symptoms of diabetes, lack of availability and high costs may deter their use by individuals with low incomes as well as those in low-income nations. Therefore, this systematic review was performed to determine whether genistein, a phytoestrogen found in soy products, could provide therapeutic benefits for individuals with diabetes. We searched PubMed and SCOPUS using the terms "genistein," "diabetes," and "glucose" and identified 33 peer-reviewed articles that met our inclusion criteria. In general, preclinical studies demonstrated that genistein decreases body weight and circulating glucose and triglycerides concentrations, whereas increasing insulin levels and insulin sensitivity. Genistein also delayed the onset of type 1 and type 2 diabetes. In contrast, clinical studies utilizing genistein generally reported no significant relationship between genistein and body mass, circulating glucose, glycated hemoglobin (A1C) concentrations, or onset of type 1 diabetes. However, genistein was found to improve insulin sensitivity and serum triglyceride concentrations and delayed the onset of type 2 diabetes. In summary, preclinical and clinical studies suggest that genistein may help delay the onset of type 2 diabetes and improve several symptoms associated with the disease. Although additional research is required to confirm these findings, the results highlighted in this review provide some evidence that genistein may offer a natural approach to mitigating some of the complications associated with diabetes.

Effects of Genistein and Exercise Training on Brain Damage Induced by a High-Fat High-Sucrose Diet in Female C57BL/6 Mice.

In recent decades, a shift in the nutritional landscape to the Western-style diet has led to an unprecedented rise in the prevalence of obesity and neurodegenerative diseases. Consumption of a healthy diet and engaging in regular physical activity represents safe and affordable approaches known to mitigate the adverse consequences of the Western diet. We examined whether genistein treatment, exercise training, and a combination treatment (genistein and exercise training) mitigated the effects of a Western diet-induced by high-fat, high-sugar (HFHS) in brain of female mice. HFHS increased the amyloid-beta (Aß) load and phosphorylation of tau, apoptosis, and decreased brain-derived neurotrophic factor (BDNF) levels. Exercise training and genistein each afforded modest protection on Aß accumulation and apoptosis, and both increased BDNF. The greatest neuroprotective effect occurred with combination treatment. BDNF and all markers of Aß accumulation, phosphorylation of tau, and apoptosis were improved with combined treatment. In a separate series of experiments, PC12 cells were exposed to high glucose (HG) and palmitate (PA) to determine cell viability with genistein as well as in the presence of tamoxifen, an estrogen receptor antagonist, to assess a mechanism of action of genistein on cell apoptosis. Genistein prevented the neurotoxic effects of HG and PA in PC12 cells and tamoxifen blocked the beneficial effects of genistein on apoptosis. Our results indicate the beneficial effects of genistein and exercise training on HFHS-induced brain damage. The benefits of genistein may occur via estrogen receptor-mediated pathways.

Genistein: A focus on several neurodegenerative diseases.

Neurodegenerative diseases are caused by the progressive loss of function or structure of nerve cells in the central nervous system. The most common neurodegenerative diseases include Alzheimer's disease, Huntington's disease, motor neuron disease, and Parkinson's disease. Although the physical or mental symptoms of neurodegenerative disease may be relieved by various treatment combinations, there are currently no strategies to directly slow or prevent neurodegeneration. Given the demographic evidence of a rapidly growing aging population and the associated prevalence of these common neurodegenerative diseases, it is paramount to develop safe and effective ways to protect against neurodegenerative diseases. Most neurodegenerative diseases share some common etiologies such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. Genistein is an isoflavone found in soy products that have been shown to exhibit antioxidant, anti-inflammation, and estrogenic properties. Increasing evidence indicates the protective potential of genistein in neurodegenerative disorders. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disease. PRACTICAL APPLICATIONS: Genistein is a naturally occurring isoflavone found mainly in soybean, but also green peas, legumes, and peanuts. Genistein is found to pass through the blood-brain barrier and possess a neuroprotective effect. In this review, we discuss studies in support of these actions and the underlying biological mechanisms. Together, these data indicate that genistein may hold neuroprotective effects in either delaying the onset or relieving the symptoms of neurodegenerative disease.

Voluntary Wheel Running Reduces Vesicle Development in an Endometriosis Animal Model Through Modulation of Immune Parameters.

Endometriosis is a chronic gynecological disorder characterized by the growth of endometrial glands and stroma outside the endometrial cavity producing inflammation and pain. Previously we demonstrated that modulation of the hypothalamic pituitary adrenal (HPA) axis exacerbates the development and severity of this condition. A physically active lifestyle has been shown to confer health benefits in many chronic conditions by potentially acting as a stress buffer, thus we hypothesized that voluntary physical exercise can 'realign/reset' the HPA axis resulting in reduced endometriosis symptoms in an animal model. Methods: Endometriosis was induced in female Sprague Dawley rats by implanting uterine tissue next to the intestinal mesentery on day 0. Sham controls received sutures only. One group of endometriosis animals had access to a running wheel for 2 weeks prior to endometriosis induction until time of sacrifice at day 60. Sham and endometriosis controls received no exercise. All animals were examined for developed vesicles which were collected and measured. Uterine tissue was analyzed for cellular infiltration. Brain, liver, spleen, adrenal glands, leg muscles and fat were collected, along with peritoneal fluid and blood. Results: Endometriosis animals developed vesicles in 86.96% of the implants with significantly increased mesenteric fat compared to sham (p<0.05). Exposure to exercise significantly decreased the size (p<0.01) and number (p<0.05) of vesicles that developed, as well as the mesenteric fat (p<0.01). Exercised animals had higher levels of lactoferrin in peritoneal fluid, and decreased serum fractalkine and leptin. Exercise significantly increased estrogen alpha receptor expression levels (p<0.01), while significantly decreasing estrogen receptor beta expression (p<0.01) and macrophage infiltration (p<0.05) in vesicles compared to non- exercised animals. Conclusions: Our results suggest that voluntary physical activity might protect against endometriosis and alleviate the associated inflammation via immune modulation of the HPA axis. This offers the potential for further exploration of exercise as a complementary therapy in endometriosis patients.

Exercise and/or Genistein Treatment Impact Gut Microbiota and Inflammation after 12 Weeks on a High-Fat, High-Sugar Diet in C57BL/6 Mice.

Genistein (Gen) and exercise (Exe) have been postulated as potential strategies to ameliorate obesity, inflammation, and gut microbiota (GM) with promising results. However, the impact of the combination of both Exe and Gen is yet to be investigated. We aimed to analyze the impacts of Exe, Gen, and their combined effects on GM and inflammation in mice after a 12-week high-fat, high-sugar diet (HFD). Eighty-three C57BL/6 mice were randomized to control, HFD, HFD + Exe, HFD + Gen, or HFD + Exe + Gen. The V4 region of the 16S rRNA gene was analyzed with Illumina MiSeq. Serum samples were used to analyze interleukin (Il)-6 and Tumor Necrosis Factor alpha (TNF-alpha). The HFD + Exe and HFD + Exe + Gen treatments resulted in significantly greater microbial richness compared to HFD. All the treatments had a significantly different impact on the GM community structure. Ruminococcus was significantly more abundant after the HFD + Exe + Gen treatment when compared to all the other HFD groups. Exe + Gen resulted in serum Il-6 concentrations similar to that of controls. TNF-alpha concentrations did not differ by treatment. Overall, Exe had a positive impact on microbial richness, and Ruminococcus might be the driving bacteria for the GM structure differences. Exe + Gen may be an effective treatment for preventing HFD-induced inflammation.

Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer's Disease.

To date, there is no cure or effective treatment for Alzheimer's disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aß) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aß and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aß oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aß oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

Beneficial Effect of Genistein on Diabetes-Induced Brain Damage in the ob/ob Mouse Model.

PURPOSE: Diabetes mellitus (DM)-induced brain damage is characterized by cellular, molecular and functional changes. The mechanisms include oxidative stress, neuroinflammation, reduction of neurotrophic factors, insulin resistance, excessive amyloid beta (Aß) deposition and Tau phosphorylation. Both antidiabetic and neuroprotective effects of the phytoestrogen genistein have been reported. However, the beneficial effect of genistein in brain of the ob/ob mouse model of severe obesity and diabetes remains to be determined. METHODS: In this study, female ob/ob mice and lean control mice were fed with either a standard diet or a diet containing genistein (600mg/kg) for a period of 4 weeks. Body weight was monitored weekly. Blood was collected for the measurement of glucose, insulin and common cytokines. Mice brains were isolated for Western immunoblotting analyses. RESULTS: Treatment with genistein reduced weight gain of ob/ob mice and decreased hyperglycemia compared to ob/ob mice fed the standard diet. The main findings show that genistein treatment increased insulin sensitivity and the expression levels of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factors (BDNF). In these mice, genistein also reduced Aß deposition and the level of hyper-phosphorylated Tau protein. CONCLUSION: The results of our study indicate the beneficial effects of genistein in the obese diabetic mouse brain, including improving brain insulin signaling, increasing neurotrophic support, and alleviating Alzheimer's disease-related pathology.

Soy Isoflavones and Gastrointestinal Health.

PURPOSE OF REVIEW: Soy isoflavones are known to have beneficial effects on several aspects of gastrointestinal physiological functions (contractility or motility, secretion, morphology, and barrier function). In this review, we discuss the effects of soy isoflavones on the overall gut function and inflammation and assess how these effects might be implicated in the treatment of several gut-related diseases. RECENT FINDINGS: Soy isoflavones influence several key aspects of gastrointestinal health: improve basal intestinal secretion, alleviate inflammation, limit intestinal morphological damage, and improve epithelial barrier function in several clinically relevant murine models of gastrointestinal diseases. Dietary supplementation with isoflavones proves to be a key means to improve the overall gut function and health. Future mechanistic studies with isoflavone interventions will help treat clinically related diseases such as cystic fibrosis and inflammatory-related gut problems such as colitis and diabetes.

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.

Genistein diet improves body weight, serum glucose and triglyceride levels in both male and female ob/ob mice.

PURPOSE: Diabetic obesity in the leptin-deficient ob/ob mouse is associated with weight gain, and hyperglycemia, along with hyperinsulinemia. We have previously examined the effects of genistein (a naturally occurring isoflavone found in soy) on metabolic disturbances in the ob/ob mouse and demonstrated beneficial effects of genistein (600 mg genistein/kg diet, for 4-weeks) on T3 production and corticosterone status. The goal of this study was to examine whether dietary genistein could prevent, or at least lessen, the typical phenotype in this murine model of diabetic-obesity, and to assess potential sex-differences. PATIENTS AND METHODS: The ob/ob mice (male and female) aged 4-5 weeks were randomly assigned to one of two diets for a period of 4-weeks: standard rodent diet, or genistein-containing diet (600 mg genistein/kg diet). Comparisons were made to a lean control group. RESULTS: Genistein diet significantly reduced body weight by 12% in females and 9% in males. Genistein significantly lowered serum glucose levels by 18% in females and 43% in males, yet had no effect on serum insulin. Genistein diet significantly lowered serum triglyceride levels in both ob/ob male and female mice returning them to lean levels. In females only, genistein significantly reduced serum pancreatic polypeptide levels by 56% and increased serum GIP levels 2.3-fold. Genistein had sex-dependent effects on hepatic steatosis: in females, genistein further increased the % fat area and the fat droplet diameter 2.6-fold, along with additionally increasing hepatic TBARS. CONCLUSION: The results from this study indicate interesting beneficial effects of genistein diet for both male and female ob/ob mice.

Bone Strength Is Improved with Genistein Treatment in Mice with Diet-Induced Obesity.

BACKGROUND: High caloric intake of saturated fat and refined sugars accelerates the development of obesity and diabetes and increases bone fracture risk. Some evidence suggests that consumption of a diet rich in phytoestrogens like genistein has the potential to strengthen bone biomechanical properties. Its bone-strengthening properties may mitigate fracture risk associated with metabolic conditions like obesity and diabetes, especially when combined with exercise. OBJECTIVE: In this study, we test the effects of genistein, exercise training, and combination treatment on biomechanical properties of cortical bone in mice fed a high-fat, high-sugar (HFHS) diet. METHODS: Eighty C67BL6 mice (40 females, 40 males) aged 6 wk were treated for 12 wk with an HFHS diet containing 60% fat and drinking water with 4.2 g/L sugar (55% sucrose, 45% fructose). Subgroups of the mice were also treated with genistein and/or moderate exercise (treadmill running). Genistein was incorporated into the HFHS diet (600 mg genistein/kg HFHS) and exercise was performed daily for 30 min, 5 d/wk (n = 10 females, 10 males per group). Three-point bending mechanical testing and quantitative fluorescence microscopy were conducted on femurs to measure bone strength and matrix quality. RESULTS: Mechanical testing revealed HFHS-fed mice treated with genistein, either alone or combined with exercise, had femurs that exhibited increased postyield displacement and reduced stiffness during 3-point bending in comparison with mice only treated with the HFHS diet. Femurs of genistein-treated mice also exhibited greater ultimate force required to achieve fracture. Quantitative fluorescence showed genistein reduced advanced glycation end product accumulation in bone matrix. Exercise treatment alone had no effect. CONCLUSIONS: Treatment with genistein, either alone or in combination with exercise, improves fracture resistance in mice fed an HFHS diet by improving bone matrix quality and increasing bone strength.