GPR119 agonists for type 2 diabetes: past failures and future hopes for preclinical and early phase candidates.

INTRODUCTION: Type 2 diabetes (T2D) is metabolic disorder associated with a decrease in insulin activity and/or secretion from the ß-cells of the pancreas, leading to elevated circulating glucose. Current management practices for T2D are complex with varying long-term effectiveness. Agonism of the G protein-coupled receptor GPR119 has received a lot of recent interest as a potential T2D therapeutic. AREAS COVERED: This article reviews studies focused on GPR119 agonism in animal models of T2D and in patients with T2D. EXPERT OPINION: GPR119 agonists in vitro and in vivo can potentially regulate incretin hormone release from the gut, then pancreatic insulin release which regulates blood glucose concentrations. However, the success in controlling glucose homeostasis in rodent models of T2D and obesity, failed to translate to early-stage clinical trials in patients with T2D. However, in more recent studies, acute and chronic dosing with the GPR119 agonist DS-8500a had increased efficacy, although this compound was discontinued for further development. New trials on GPR119 agonists are needed, however it may be that the future of GPR119 agonists lie in the development of combination therapy with other T2D therapeutics.

Maternal Diet High in Linoleic Acid Alters Offspring Lipids and Hepatic Regulators of Lipid Metabolism in an Adolescent Rat Model.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. A maternal high LA (HLA) diet alters cardiovascular development in adolescent rats and hepatic function in adult rats in a sex-specific manner. We investigated the effects of an HLA diet on adolescent offspring hepatic lipids and hepatic lipid metabolism gene expression, and the ability of the postnatal diet to alter these effects. Female Wistar Kyoto rats were fed low LA (LLA; 1.44% energy from LA) or high LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring, weaned at postnatal day (PN) 25, were fed LLA or HLA and euthanised at PN40 (n = 6-8). Maternal HLA increased circulating uric acid, decreased hepatic cholesterol and increased hepatic Pparg in males, whereas only hepatic Srebf1 and Hmgcr increased in females. Postnatal (post-weaning) HLA decreased liver weight (% body weight) and increased hepatic Hmgcr in males, and decreased hepatic triglycerides in females. Maternal and postnatal HLA had an interaction effect on Lpl, Cpt1a and Pparg in females. These findings suggest that an HLA diet both during and after pregnancy should be avoided to improve offspring disease risk.

Gynostemma Pentaphyllum Increases Exercise Performance and Alters Mitochondrial Respiration and AMPK in Healthy Males.

This research aimed to determine the effects of Gynostemma pentaphyllum (G. pentaphyllum) on exercise performance, AMP-activated protein kinase (AMPK), and mitochondrial signaling in human muscle. This randomized double-blind placebo control crossover study provided placebo or 450 mg of G. pentaphyllum dried leaf extract equivalent to 2.25 g of dry leaf per day for four weeks to 16 healthy untrained young males, separated by four weeks wash-out. Following 4-week supplementation with G. pentaphyllum, participants had significantly lower leptin and blood glucose levels and improved time trial performance over 20 km, which corresponded with a higher muscle oxygen flux compared to placebo. Muscle AMPK Thr172 phosphorylation significantly increased after 60 min exercise following G. pentaphyllum supplementation. AMPK Thr172 phosphorylation levels relative to total AMPK increased earlier following exercise with G. pentaphyllum compared to placebo. Total ACC-α was lower following G. pentaphyllum supplementation compared to placebo. While further research is warranted, G. pentaphyllum supplementation improved exercise performance in healthy untrained males, which corresponded with improved mitochondrial respiration, altered AMPK and ACC, and decreased plasma leptin and glucose levels.

Intake of polyphenols from cereal foods and colorectal cancer risk in the Melbourne Collaborative Cohort Study.

BACKGROUND: Cereal-derived polyphenols have demonstrated protective mechanisms in colorectal cancer (CRC) models; however, confirmation in human studies is lacking. Therefore, this study examined the association between cereal polyphenol intakes and CRC risk in the Melbourne Collaborative Cohort Study (MCCS), a prospective cohort study in Melbourne, Australia that recruited participants between 1990 and 1994 to investigate diet-disease relationships. METHODS: Using food frequency questionnaire diet data matched to polyphenol data, dietary intakes of alkylresorcinols, phenolic acids, lignans, and total polyphenols from cereals were estimated. Hazard ratios (HRs) and 95% confidence intervals for CRC risk were estimated for quintiles of intake with the lowest quintile as the comparison category, using multivariable adjusted Cox proportional hazards models with age as the time axis adjusted for sex, socio-economic status, alcohol consumption, fibre intake, country of birth, total energy intake, physical activity and smoking status. RESULTS: From 35,245 eligible adults, mean (SD) age 54.7 (8.6) years, mostly female (61%) and Australian-born (69%), there were 1394 incident cases of CRC (946 colon cancers and 448 rectal cancers). Results for total cereal polyphenol intake showed reduced HRs in Q2 (HR: 0.80; 95% CI, 0.68-0.95) and Q4 (HR: 0.75; 95% CI, 0.62-0.90), and similar for phenolic acids. Alkylresorcinol intake showed reduced HR in Q3 (HR: 0.80; 95% CI, 0.67-0.95) and Q4 (HR: 0.79; 95% CI, 0.66-0.95). CONCLUSIONS: Overall, the present study showed little evidence of association between intakes of cereal polyphenols and CRC risk. Future investigations may be useful to understand associations between cereal-derived polyphenols and additional cancers in different populations.

Estimated dietary intake of polyphenols from cereal foods and associated lifestyle and demographic factors in the Melbourne Collaborative Cohort Study.

Cereal foods are consumed globally and are important sources of polyphenols with potential health benefits, yet dietary intakes are unclear. We aimed to calculate the dietary intakes of polyphenols from cereal foods in the Melbourne Collaborative Cohort Study (MCCS), and describe intakes by demographic and lifestyle factors. We estimated intakes of alkylresorcinols, lignans and phenolic acids in n = 39,892 eligible MCCS participants, using baseline dietary data (1990-1994) from a 121-item FFQ containing 17 cereal foods, matched to a polyphenol database developed from published literature and Phenol-Explorer Database. Intakes were estimated within groups according to lifestyle and demographic factors. The median (25th-75th percentile) intake of total polyphenols from cereal foods was 86.9 mg/day (51.4-155.8). The most consumed compounds were phenolic acids, with a median intake of 67.1 mg (39.5-118.8), followed by alkylresorcinols of 19.7 mg (10.8-34.6). Lignans made the smallest contribution of 0.50 mg (0.13-0.87). Higher polyphenol intakes were associated with higher relative socio-economic advantage and prudent lifestyles, including lower body mass index (BMI), non-smoking and higher physical activity scores. The findings based on polyphenol data specifically matched to the FFQ provide new information on intakes of cereal polyphenols, and how they might vary according to lifestyle and demographic factors.

Changes in Essential Fatty Acids and Ileal Genes Associated with Metabolizing Enzymes and Fatty Acid Transporters in Rodent Models of Cystic Fibrosis.

Cystic fibrosis (CF), the result of mutations in the CF transmembrane conductance regulator (CFTR), causes essential fatty acid deficiency. The aim of this study was to characterize fatty acid handling in two rodent models of CF; one strain which harbors the loss of phenylalanine at position 508 (Phe508del) in CFTR and the other lacks functional CFTR (510X). Fatty acid concentrations were determined using gas chromatography in serum from Phe508del and 510X rats. The relative expression of genes responsible for fatty acid transport and metabolism were quantified using real-time PCR. Ileal tissue morphology was assessed histologically. There was an age-dependent decrease in eicosapentaenoic acid and the linoleic acid:α-linolenic acid ratio, a genotype-dependent decrease in docosapentaenoic acid (n-3) and an increase in the arachidonic acid:docosahexaenoic acid ratio in Phe508del rat serum, which was not observed in 510X rats. In the ileum, Cftr mRNA was increased in Phe508del rats but decreased in 510X rats. Further, Elvol2, Slc27a1, Slc27a2 and Got2 mRNA were increased in Phe508del rats only. As assessed by Sirius Red staining, collagen was increased in Phe508del and 510X ileum. Thus, CF rat models exhibit alterations in the concentration of circulating fatty acids, which may be due to altered transport and metabolism, in addition to fibrosis and microscopic structural changes in the ileum.

Treatment of Diet-Induced Obese Rats with CB2 Agonist AM1241 or CB2 Antagonist AM630 Reduces Leptin and Alters Thermogenic mRNA in Adipose Tissue.

Diet-induced obesity (DIO) is a contributor to co-morbidities, resulting in alterations in hormones, lipids, and low-grade inflammation, with the cannabinoid type 2 receptor (CB2) contributing to the inflammatory response. The effects of modulating CB2 with pharmacological treatments on inflammation and adaptations to the obese state are not known. Therefore, we aimed to investigate the molecular mechanisms in adipose tissue of CB2 agonism and CB2 antagonism treatment in a DIO model. Male Sprague Dawley rats were placed on a high-fat diet (HFD) (21% fat) for 9 weeks, then received daily intraperitoneal injections with a vehicle, AM630 (0.3 mg/kg), or AM1241 (3 mg/kg), for a further 6 weeks. AM630 or AM1241 treatment in DIO rats did not alter their body weight, food intake, or liver weight, and it had no effect on their numerous circulating cytokines or peri-renal fat pad mass. AM1241 decreased heart weight and BAT weight; both treatments (AM630 or AM1241) decreased plasma leptin levels, while AM630 also decreased plasma ghrelin and GLP-1 levels. Both treatments decreased Adrb3 and TNF-α mRNA levels in eWAT and TNF-α levels in pWAT. AM630 treatment also decreased the mRNA levels of Cnr2, leptin, and Slc2a4 in eWAT. In BAT, both treatments decreased leptin, UCP1, and Slc2a4 mRNA levels, with AM1241 also decreasing Adrb3, IL1ß, and PRDM16 mRNA levels, and AM630 increasing IL6 mRNA levels. In DIO, CB2 agonist and CB2 antagonist treatment reduces circulating leptin in the absence of weight loss and modulates the mRNA responsible for thermogenesis.

CB1 Ligand AM251 Induces Weight Loss and Fat Reduction in Addition to Increased Systemic Inflammation in Diet-Induced Obesity.

Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB1). This research aimed to determine if treatment with the global CB1 antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a "browning" of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB1 ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders.

The effect of dietary supplementation with blueberry, cyanidin-3-O-ß-glucoside, yoghurt and its peptides on gene expression associated with glucose metabolism in skeletal muscle obtained from a high-fat-high-carbohydrate diet induced obesity model.

Obesity is a leading global health problem contributing to various chronic diseases, including type II diabetes mellitus (T2DM). The aim of this study was to investigate whether blueberries, yoghurt, and their respective bioactive components, Cyanidin-3-O-ß-glucoside (C3G) and peptides alone or in combinations, alter the expression of genes related to glucose metabolism in skeletal muscles from diet-induced obese mice. In extensor digitorum longus (EDL), yoghurt up-regulated the expression of activation of 5'adenosine monophosphate-activated protein kinase (AMPK), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3 kinase (PI3K) and glucose transporter 4 (GLUT4), and down-regulated the expression of angiotensin II receptor type 1 (AGTR-1). The combination of blueberries and yoghurt down-regulated the mRNA expression of AGTR-1 and Forkhead box protein O1 (FoxO1) in the EDL. Whereas the combination of C3G and peptides down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression in the EDL. In the soleus, blueberries and yoghurt alone, and their combination down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression. In summary blueberries and yoghurt, regulated multiple genes associated with glucose metabolism in skeletal muscles, and therefore may play a role in the management and prevention of T2DM.

The effect of malting on phenolic compounds and radical scavenging activity in grains and breakfast cereals.

Breakfast cereals are popular grain foods and sources of polyphenols. Malting alters polyphenol content and activity; however, effects are varied. The total polyphenol content (TPC), radical scavenging activity (RSA), and polyphenol profile were analyzed in unmalted and malted grains (wheat, barley, and sorghum) and breakfast cereals (wheat, barley) by Folin Ciocalteu Reagent (FCR), % inhibition of the free radical 2,2-diphenyl-1-picryl-hydrazyl, and high performance liquid chromatography. Higher TPC was observed in all malted grains and breakfast cereals compared with unmalted samples (p < 0.05). Higher RSA was also observed in all malted samples compared to unmalted samples (p < 0.05) except for wheat grain to malted wheat grain. In this study, malting induced additional polyphenols and antioxidant activity in grains and cereal products. Malted grain breakfast cereals may be practical sources of polyphenol antioxidants. PRACTICAL APPLICATION: This study utilized malting in a unique way to investigate potential health benefits of polyphenols and antioxidant activity in grains (wheat, barley, and sorghum) and ready-to-eat breakfast cereals (wheat and barley). This study found that grains and breakfast cereals are important sources of antioxidant polyphenols, and these were significantly increased in malted varieties. Understanding this is important as grains and breakfast cereals are widely consumed staple foods. Consuming healthier grain products may be a practical strategy in reducing the risk of noncommunicable diseases such as colorectal cancer and type-2 diabetes, where wholegrain consumption may be important in prevention.

Transforming growth factor ß1 impairs the transcriptomic response to contraction in myotubes from women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterised by a hormonal imbalance affecting the reproductive and metabolic health of reproductive-aged women. Exercise is recommended as a first-line therapy for women with PCOS to improve their overall health; however, women with PCOS are resistant to the metabolic benefits of exercise training. Here, we aimed to gain insight into the mechanisms responsible for such resistance to exercise in PCOS. We employed an in vitro approach with electrical pulse stimulation (EPS) of cultured skeletal muscle cells to explore whether myotubes from women with PCOS have an altered gene expression signature in response to contraction. Following EPS, 4719 genes were differentially expressed (false discovery rate <0.05) in myotubes from women with PCOS compared to 173 in healthy women. Both groups included genes involved in skeletal muscle contraction. We also determined the effect of two transforming growth factor ß (TGFß) ligands that are elevated in plasma of women with PCOS, TGFß1 and anti-Müllerian hormone (AMH), alone and on the EPS-induced response. While AMH (30 ng/ml) had no effect, TGFß1 (5 ng/ml) induced the expression of extracellular matrix genes and impaired the exercise-like transcriptional signature in myotubes from women with and without PCOS in response to EPS by interfering with key processes related to muscle contraction, calcium transport and actin filament. Our findings suggest that while the fundamental gene expression responses of skeletal muscle to contraction is intact in PCOS, circulating factors like TGFß1 may be responsible for the impaired adaptation to exercise in women with PCOS. KEY POINTS: Gene expression responses to in vitro contraction (electrical pulse stimulation, EPS) are altered in myotubes from women with polycystic ovary syndrome (PCOS) compared to healthy controls, with an increased expression of genes related to pro-inflammatory pathways. Transforming growth factor ß1 (TGFß1) upregulates genes related to extracellular matrix remodelling and reduces the expression of contractile genes in myotubes, regardless of the donor's health status. TGFß1 alters the gene expression response to EPS, providing a possible mechanism for the impaired exercise adaptations in women with PCOS.

High-intensity training elicits greater improvements in cardio-metabolic and reproductive outcomes than moderate-intensity training in women with polycystic ovary syndrome: a randomized clinical trial.

STUDY QUESTION: Does 12 weeks of high-intensity interval training (HIIT) result in greater improvements in cardio-metabolic and reproductive outcomes compared to standard moderate-intensity continuous training (MICT) in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: HIIT offers greater improvements in aerobic capacity, insulin sensitivity and menstrual cyclicity, and larger reductions in hyperandrogenism compared to MICT. WHAT IS KNOWN ALREADY: Exercise training is recognized to improve clinical outcomes in women with PCOS, but little is known about whether HIIT results in greater health outcomes compared to standard MICT. STUDY DESIGN, SIZE, DURATION: This was a two-armed randomized clinical trial enrolling a total of 29 overweight women with PCOS between May 2016 and November 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS aged 18-45 years were randomly assigned to 12 weeks of either MICT (60-75% peak heart rate, N = 14) or HIIT (>90% peak heart rate, N = 15), each completed three times per week. The primary clinical outcomes were aerobic capacity (VO2peak) and insulin sensitivity (euglycaemic-hyperinsulinaemic clamp). Secondary outcomes included hormonal profiles, menstrual cyclicity and body composition. MAIN RESULTS AND THE ROLE OF CHANCE: Both HIIT and MICT improved VO2peak (HIIT; Δ 5.8 ± 2.6 ml/kg/min, P < 0.001 and MICT; Δ 3.2 ± 2 ml/kg/min, P < 0.001), however, the HIIT group had a greater improvement in aerobic capacity compared to MICT (ß = 2.73 ml/kg/min, P = 0.015). HIIT increased the insulin sensitivity index compared to baseline (Δ 2.3 ± 4.4 AU, P = 0.007) and MICT (ß = 0.36 AU, P = 0.030), and caused higher increases in sex hormone-binding globulin compared to MICT (ß = 0.25 nmol/l, P = 0.002). HIIT participants were 7.8 times more likely to report improved menstrual cyclicity than those in the MICT group (odds ratio 7.8, P = 0.04). LIMITATIONS, REASONS FOR CAUTION: This study has a small sample size and the findings of the effect of the exercise interventions are limited to overweight reproductive-aged women, who do not have any co-existing co-morbidities that require medication. WIDER IMPLICATIONS OF THE FINDINGS: Exercise, regardless of intensity, has clear health benefits for women with PCOS. HIIT appears to be a more beneficial strategy and should be considered for promoting health and reducing cardio-metabolic risk in overweight women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a Project Support Grant from the Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence in PCOS. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: ACTRN12615000242527. TRIAL REGISTRATION DATE: 19 February 2015. DATE OF FIRST PATIENT'S ENROLMENT: 27 May 2016.

Eight weeks of combined exercise training do not alter circulating microRNAs-29a, -133a, -133b, and -155 in young, healthy men.

PURPOSE: Individuals with a family history of type 2 diabetes (FH +) have an increased risk of developing type 2 diabetes. Circulating microRNAs (miRNAs) have been implicated as biomarkers of type 2 diabetes risk. Here, we investigated if four circulating miRNAs related to glucose metabolism were altered in men with a FH + and we conducted a preliminary analysis to determine if miRNA expressions were responsive to 8 weeks of combined exercise training. METHODS: Sixteen young healthy men (mean ± SD; age 22.5 ± 2.5; BMI 26.4 ± 4.0) with FH + or without a family history of type 2 diabetes (FH -) underweight 8 weeks of combined endurance and resistance exercise training (n = 8 FH -; n = 8 FH +). The expression of miR-29a, miR-133a, miR-133b, and miR-155 were measured in serum before and after exercise training. QIAGEN's Ingenuity® Pathway Analysis was used to examine miRNA target genes and their involvement in glucose metabolism signaling pathways. RESULTS: There were no differences in miRNA expressions between FH - and FH + . Exercise training did not alter miRNA expressions in either FH - or FH + despite improvements in insulin sensitivity, aerobic capacity, and muscular strength. miR-29a and miR-155 were inversely related to fasting glucose, and miR-133a and miR-133b were negatively correlated with glucose tolerance; however, correlations were not observed with insulin sensitivity. CONCLUSIONS: The circulating miRNAs- miR-29a, miR-133a, miR-133b, and miR-155 are related to measures of glucose metabolism in healthy, normoglycemic men, but do not reflect peripheral insulin sensitivity or improvements in metabolic health following 8 weeks of combined exercise training.

Four weeks of electrical stimulation improves glucose tolerance in a sedentary overweight or obese Hispanic population.

Introduction/purpose: Most US adults (54%) do not meet the minimum exercise recommendations by the American College of Sports Medicine. Neuromuscular electrical stimulation (NMES) is a novel alternate strategy to induce muscle contraction. However, the effectiveness of NMES to improve insulin sensitivity and energy expenditure is unclear. The purpose of this study was to investigate the effects of 4 weeks of NMES on glucose tolerance in a sedentary overweight or obese population. Methods: Participants (n = 10; age: 36.8 ± 3.8 years; BMI = 32 ± 1.3 kg/m2) were randomized into either control or NMES group. All participants received bilateral quadriceps stimulation (12 sessions; 30 min/session; three times/week at 50 Hz and 300 µs pulse width) altering pulse amplitude to either provide low-intensity sensory level (control; tingling sensation) or at high-intensity neuromuscular level (NMES; maximum tolerable levels with visible muscle contraction). Glucose tolerance was assessed by a 3-h oral glucose tolerance test (OGTT), and substrate utilization was measured by indirect calorimetry and body composition via dual X-ray absorptiometry at baseline and after 4 weeks of NMES intervention. Results: Control and NMES groups had comparable fasting blood glucose, glucose tolerance, substrate utilization, and muscle mass at baseline. Four weeks of NMES resulted in a significant improvement in glucose tolerance measured by OGTT, whereas no change was observed in the control group. There was no change in substrate utilization and muscle mass in both control and NMES groups. Conclusion: NMES is a novel and effective strategy to improve glucose tolerance in an at-risk overweight or obese sedentary population.

The mitochondrial profile in women with polycystic ovary syndrome: impact of exercise.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting pre-menopausal women and involves metabolic dysregulation. Despite the high prevalence of insulin resistance, the existence of mitochondrial dysregulation and its role in the pathogenesis of PCOS is not clear. Exercise is recommended as the first-line therapy for women with PCOS. In particular, high-intensity interval training (HIIT) is known to improve metabolic health and enhance mitochondrial characteristics. In this narrative review, the existing knowledge of mitochondrial characteristics in skeletal muscle and adipose tissue of women with PCOS and the effect of exercise interventions in ameliorating metabolic and mitochondrial health in these women are discussed. Even though the evidence on mitochondrial dysfunction in PCOS is limited, some studies point to aberrant mitochondrial functions mostly in skeletal muscle, while there is very little research in adipose tissue. Although most exercise intervention studies in PCOS report improvements in metabolic health, they show diverse and inconclusive findings in relation to mitochondrial characteristics. A limitation of the current study is the lack of comprehensive mitochondrial analyses and the diversity in exercise modalities, with only one study investigating the impact of HIIT alone. Therefore, further comprehensive large-scale exercise intervention studies are required to understand the association between metabolic dysfunction and aberrant mitochondrial profile, and the molecular mechanisms underlying the exercise-induced metabolic adaptations in women with PCOS.

Maternal diet high in linoleic acid alters offspring fatty acids and cardiovascular function in a rat model.

Linoleic acid (LA), an essential n-6 fatty acid (FA), is critical for fetal development. We investigated the effects of maternal high LA (HLA) diet on offspring cardiac development and its relationship to circulating FA and cardiovascular function in adolescent offspring, and the ability of the postnatal diet to reverse any adverse effects. Female Wistar Kyoto rats were fed low LA (LLA; 1·44 % energy from LA) or high LA (HLA; 6·21 % energy from LA) diets for 10 weeks before pregnancy and during gestation/lactation. Offspring, weaned at postnatal day 25, were fed LLA or HLA diets and euthanised at postnatal day 40 (n 6-8). Maternal HLA diet decreased circulating total cholesterol and HDL-cholesterol in females and decreased total plasma n-3 FA in males, while maternal and postnatal HLA diets decreased total plasma n-3 FA in females. α-Linolenic acid (ALA) and EPA were decreased by postnatal but not maternal HLA diets in both sexes. Maternal and postnatal HLA diets increased total plasma n-6 and LA, and a maternal HLA diet increased circulating leptin, in both male and female offspring. Maternal HLA decreased slopes of systolic and diastolic pressure-volume relationship (PVR), and increased cardiac Col1a1, Col3a1, Atp2a1 and Notch1 in males. Maternal and postnatal HLA diets left-shifted the diastolic PVR in female offspring. Coronary reactivity was altered in females, with differential effects on flow repayment after occlusion. Thus, maternal HLA diets impact lipids, FA and cardiac function in offspring, with postnatal diet modifying FA and cardiac function in the female offspring.

Seasonal Change in Body Composition and Physique of Team Sport Athletes.

ABSTRACT: Walker, EJ, Aughey, RJ, McLaughlin, P, and McAinch, AJ. Seasonal change in body composition and physique of team sport athletes. J Strength Cond Res 36(2): 565-572, 2022-Body composition of team sport athletes was measured at 3 points across the preseason and competitive season. This repeated-measures study was conducted in 46 professional Australian football (AF) (age 23.8 ± 3.8 years), 26 soccer (age 22.7 ± 4.7 years), and 33 rugby union players (age 28.1 ± 4.2 years). A mixed-design analysis of variance was used to determine change across the season, and Pearson's correlation was used to determine the relationship between different measures. Anthropometry, dual-energy x-ray absorptiometry (DXA), and 3-dimensional (3D) scan technology were used in AF and soccer, whereas only DXA was used in rugby. Body mass remained unchanged for both AF and soccer with gains in lean mass (p < 0.01), from preseason to early in the competitive season. Skinfold measures declined in AF (p < 0.001) and soccer (p < 0.05) across the season, whereas DXA-measured fat mass only declined in soccer (p < 0.01). Rugby backs (p < 0.01) and forwards (p < 0.001) reduced body fat and gained lean mass from preseason to in-season with forwards having greater relative and absolute changes as measured by DXA. 3D technology did not show change across the season. Dual-energy x-ray absorptiometry body fat percent and the sum of skinfold correlation were large (r = 0.74 [p < 0.001, CI 0.67-0.81]). The greatest change in body composition occurs from the beginning of preseason to the start of competition, with changes returning to baseline levels toward the end of season. Dual-energy x-ray absorptiometry and skinfold measures were moderately correlated, providing a good alternative to track change in subcutaneous fat in AF and soccer athletes.

Non-cell autonomous mechanisms control mitochondrial gene dysregulation in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance and impaired energy metabolism in skeletal muscle, the aetiology of which is currently unclear. Here, we mapped the gene expression profile of skeletal muscle from women with PCOS and determined if cultured primary myotubes retain the gene expression signature of PCOS in vivo. Transcriptomic analysis of vastus lateralis biopsies collected from PCOS women showed lower expression of genes associated with mitochondrial function, while the expression of genes associated with the extracellular matrix was higher compared to controls. Altered skeletal muscle mRNA expression of mitochondrial-associated genes in PCOS was associated with lower protein expression of mitochondrial complex II-V, but not complex I, with no difference in mitochondrial DNA content. Transcriptomic analysis of primary myotube cultures established from biopsies did not display any differentially expressed genes between controls and PCOS. Comparison of gene expression profiles in skeletal muscle biopsies and primary myotube cultures showed lower expression of mitochondrial and energy metabolism-related genes in vitro, irrespective of the group. Together, our results show that the altered mitochondrial-associated gene expression in skeletal muscle in PCOS is not preserved in cultured myotubes, indicating that the in vivo extracellular milieu, rather than genetic or epigenetic factors, may drive this alteration. Dysregulation of mitochondrial-associated genes in skeletal muscle by extracellular factors may contribute to the impaired energy metabolism associated with PCOS.

Role for animal models in understanding essential fatty acid deficiency in cystic fibrosis.

Essential fatty acid deficiency has been observed in most patients with Cystic Fibrosis (CF); however, pancreatic supplementation does not restore the deficiency, suggesting a different pathology independent of the pancreas. At this time, the underlying pathological mechanisms are largely unknown. Essential fatty acids are obtained from the diet and processed by organs including the liver and intestine, two organs significantly impacted by mutations in the cystic fibrosis transmembrane conductance regulator gene (Cftr). There are several CF animal models in a variety of species that have been developed to investigate molecular mechanisms associated with the CF phenotype. Specifically, global and systemic mutations in Cftr which mimic genotypic changes identified in CF patients have been generated in mice, rats, sheep, pigs and ferrets. These mutations produce CFTR proteins with a gating defect, trafficking defect, or an absent or inactive CFTR channel. Essential fatty acids are critical to CFTR function, with a bidirectional relationship between CFTR and essential fatty acids proposed. Currently, there are limited analyses on the essential fatty acid status in most of these animal models. Of interest, in the mouse model, essential fatty acid status is dependent on the genotype and resultant phenotype of the mouse. Future investigations should identify an optimal animal model that has most of the phenotypic changes associated with CF including the essential fatty acid deficiencies, which can be used in the development of therapeutics.

Sex-Specific Differences in Lysine, 3-Hydroxybutyric Acid and Acetic Acid in Offspring Exposed to Maternal and Postnatal High Linoleic Acid Diet, Independent of Diet.

BACKGROUND: Linoleic acid (LA) is an essential polyunsaturated fatty acid (PUFA) that is required for foetal growth and development. Excess intake of LA can be detrimental for metabolic health due to its pro-inflammatory properties; however, the effect of a diet high in LA on offspring metabolites is unknown. In this study, we aimed to determine the role of maternal or postnatal high linoleic acid (HLA) diet on plasma metabolites in adult offspring. METHODS: Female Wistar Kyoto (WKY) rats were fed with either low LA (LLA) or HLA diet for 10 weeks prior to conception and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), treated with either LLA or HLA diets and sacrificed at PN180. Metabolite analysis was performed in plasma samples using Nuclear Magnetic Resonance. RESULTS: Maternal and postnatal HLA diet did not alter plasma metabolites in male and female adult offspring. There was no specific clustering among different treatment groups as demonstrated by principal component analysis. Interestingly, there was clustering among male and female offspring independent of maternal and postnatal dietary intervention. Lysine was higher in female offspring, while 3-hydroxybutyric acid and acetic acid were significantly higher in male offspring. CONCLUSION: In summary, maternal or postnatal HLA diet did not alter the plasma metabolites in the adult rat offspring; however, differences in metabolites between male and female offspring occurred independently of dietary intervention.