Nathalie Boisseau

Alcohol and bone: review of dose effects and mechanisms

Alcohol is widely consumed across the world. It is consumed in both social and cultural settings. Until recently, two types of alcohol consumption were recognized: heavy chronic alcohol consumption or light consumption. Today, there is a new pattern of consumption among teenagers and young adults namely: binge drinking. Heavy alcohol consumption is detrimental to many organs and tissues, including bones, and is known to induce secondary osteoporosis. Some studies, however, have reported benefits from light alcohol consumption on bone parameters. To date, little is known regarding the effects of binge drinking on bone health. Here, we review the effects of three different means of alcohol consumption: light, heavy, and binge drinking. We also review the detailed literature on the different mechanisms by which alcohol intake may decrease bone mass and strength. The effects of alcohol on bone are thought to be both direct and indirect. The decrease in bone mass and strength following alcohol consumption is mainly due to a bone remodeling imbalance, with a predominant decrease in bone formation. Recent studies, however, have reported new mechanisms by which alcohol may act on bone remodeling, including osteocyte apoptosis, oxidative stress, and Wnt signalling pathway modulation. The roles of reduced total fat mass, increased lipid content in bone marrow, and a hypoleptinemia are also discussed.

Circulating Androgens in Women: Exercise-Induced Changes

Physical exercise is known to strongly stimulate the endocrine system in both sexes. Among these hormones, androgens (e.g. testosterone, androstenedione, dehydroepiandrosterone) play key roles in the reproductive system, muscle growth and the prevention of bone loss. In female athletes, excessive physical exercise may lead to disorders, including delay in the onset of puberty, amenorrhoea and premature osteoporosis. The free and total fractions of circulating androgens vary in response to acute and chronic exercise/ training (depending on the type), but the physiological role of these changes is not completely understood. Although it is commonly accepted that only the free fraction of steroids has a biological action, this hypothesis has recently been challenged. Indeed, a change in the total fraction of androgen concentration may have a significant impact on cells (inducing genomic or nongenomic signalling). The purpose of this review, therefore, is to visit the exercise-induced changes in androgen concentrations and emphasize their potential effects on female physiology. Despite some discrepancies in the published studies (generally due to differences in the types and intensities of the exercises studied, in the hormonal status of the group of women investigated and in the methods for androgen determination), exercise is globally able to induce an increase in circulating androgens. This can be observed after both resistance and endurance acute exercises. For chronic exercise/training, the picture is definitely less clear and there are even circumstances where exercise leads to a decrease of circulating androgens. We suggest that those changes have significant impact on female physiology and physical performance.

Low bone accrual is associated with osteocyte apoptosis in alcohol-induced osteopenia.

INTRODUCTION Alcohol is known to decrease bone mineral density (BMD) and to induce trabecular microarchitecture deterioration. However, little is known about the effects of chronic alcohol consumption on osteocytes in situ. The aim of this study was to assess the effects of a high alcohol dose on osteocytes in an alcohol-induced osteopenia model. MATERIALS AND METHODS 24 male Wistar rats, 2-months old were separated in 2 groups: Control (C) or Alcohol (A35). The rats in the A35 group drank a beverage composed of 35% ethanol v/v mixed to water for 17 weeks. BMD was assessed by DXA, while the microarchitecture was analyzed using μCT. Bone remodeling was studied measuring serum concentration of osteocalcin, NTx and TRAP. Bone marrow adiposity, osteoblastic lineage differentiation, osteocyte morphology and apoptosis were assessed using bright field, epifluorescence, transmission electron and confocal microscopy. RESULTS BMD, trabecular thickness, TRAP and NTx concentration were significantly decreased in A35, while cortical thickness was thinner. There were 10 fold more cells stained with cleaved caspase-3, and 35% more empty lacunae in A35, these data indicating a large increase in osteocyte apoptosis in the A35 group. The number of lipid droplets in the marrow was increased in A35 (7 fold). Both the osteocyte apoptosis and the fat bone marrow content strongly correlated with femur BMD (p=0.0017, r = -0.72 and p=0.002, r = -0.70) and whole body BMD. CONCLUSION These data suggest that low BMD is associated with osteocyte apoptosis and bone marrow fat content in alcohol-induced osteopenia.

Oral contraception but not menstrual cycle phase is associated with increased free cortisol levels and low hypothalamo-pituitary-adrenal axis reactivity

Background: In females, estrogen is a potential modulator of cortisol response to stressors. The aim of this study was to determine the influence of menstrual cycle phase, oral contraception (OC) use and exercise training on hypothalamo-pituitary-adrenal (HPA) axis activity and reactivity after physical stress. Aim: We investigated the effects of the menstrual cycle and OC use on exhaustive exercise-induced changes in free salivary cortisol concentrations and free urinary cortisol/cortisone excretion in healthy young women. Materials and subjects: Twenty-eight women were allocated to an untrained group (no.=16) or a trained group (no.=12), depending on their physical training background. The untrained group was composed of nine OC users (UNT-OC+) and seven eumenorrheic women (UNT-OC−) tested in the follicular and luteal phases, while the trained group was entirely composed of OC+ subjects (T-OC+). Methods: Three laboratory sessions were conducted in a randomised order: a prolonged exercise test, a short-term exercise test, and a control session. For each session, urine and saliva specimens were collected at rest (09: 00 h) and then, 30, 60 and 90 min later. Results: Estradiol fluctuation during the menstrual cycle phase did not alter free cortisol baseline values and responses to exercise. OC use was associated with increased free resting salivary concentrations and urinary cortisol excretion with blunted salivary cortisol response to prolonged exercise stimulation. No training effect was noted. Conclusions: OC but not menstrual cycle phase is associated with increased free cortisol levels and low HPA axis reactivity.

Influence of Hormonal Status on Substrate Utilization at Rest and during Exercise in the Female Population

During exercise, substrate utilization plays a major role in performance and disease prevention. The contribution of fat and carbohydrates to energy expenditure during exercise is modulated by several factors, including intensity and duration of exercise, age, training and diet, but also gender. Because sex hormone levels change throughout a woman’s lifetime (in connection with puberty, the menstrual cycle, use of oral contraceptives and menopause), the female population has to be considered specifically in terms of substrate utilization, and metabolic and hormonal responses to exercise. Before puberty, there is no difference between males and females when it comes to substrate oxidation during exercise. This is not the case during adulthood, since women are known to rely more on fat than men for the same relative intensity of exercise. Among adult women, the menstrual cycle and use of oral contraceptives may influence substrate oxidation. While some authors have noted that the luteal phase of the menstrual cycle is connected with greater lipid oxidation, compared with the follicular stage, other authors have found no difference. Among oral contraceptive users, fat oxidation is sometimes increased during prolonged exercise with a concomitant rise in lipolytic hormones, as well as growth hormone. If this result is not always observed, the type of oral contraceptive (monophasic vs triphasic) and hormone doses may be implicated.Menopause represents a hormonal transition in a woman’s life, leading to a decline in ovarian hormone production. A decrease in fat oxidation is consequently observed, and some studies have demonstrated a similar respiratory exchange ratio during prolonged exercise in postmenopausal women and in men. As is the case during puberty, no sex difference should thus appear after menopause in the absence of hormonal replacement therapy (HRT). Results concerning women who take HRT remain conflicting. HRT may act on fat loss by increasing lipid metabolism, but this depends on how the treatment is administered (orally vs transdermally). To better understand the role of ovarian hormones in substrate oxidation, studies have made use of animal protocols to investigate cellular mechanisms. Estradiol and progesterone seem to have opposite effects, with greater lipid oxidation when estradiol is used alone. However, the concentrations used (physiological levels or pharmacological doses) may considerably modify fuel selection. In cases where conflicting data are observed in studies of substrate utilization and prolonged exercise in women, methodological reasons must be called into question. Too many parameters, which oftentimes are not specified, may modulate substrate utilization and metabolic and hormonal responses to prolonged exercise. Although information is generally provided about the type of exercise, its duration and the subjects’ training level, detailed information is not always given about the subjects’ nutritional state and, more specifically, the hormonal status of female subjects. The primary purpose of this review was to identify the impact of hormonal status on substrate oxidation among female subjects at rest and during exercise. A second aim was to describe gender differences in substrate utilization during exercise.

Repeatability and relative validity of a quantitative food-frequency questionnaire among French adults

Background A 50-item self-administered food frequency questionnaire (FFQ) was developed for French adults, to assess the intake of energy, 10 macronutrients, 11 vitamins, and 11 minerals, and to be used in the context of a medical consultation. Objective To assess the repeatability and relative validity of this FFQ compared to a 7-day diet record (7-DR). Design A total of 54 and 100 French adults were included in the repeatability and validation studies, respectively. Repeatability was assessed using two FFQs, the second carried out 3 weeks after the first. In the validation study, subjects first completed the FFQ, then the 7-DR the following week. Energy and nutrient intakes were compared using Pearson correlation. The degree of misclassification by the FFQ, compared to the 7-DR, was calculated by a contingency table of quintiles. Bland–Altman plots assessed the correlation between FFQ and 7-DR across the intake range. Results Repeatability for intake, explored by Pearson correlation, was 0.62–0.90 (median: 0.81). Relative validity, as determined by Pearson correlation for the nutrient intake derived from the FFQ and 7-DR, was 0.36–0.80 (0.64). The FFQ tended to report higher fiber and micronutrient intake than 7-DR. Misclassification into opposite quintiles ranged 0–6% (1%), whereas classification into same or adjacent quintiles ranged 59–83% (74%). Bland–Altman plots showed good agreement for most nutrients across the range of intake. Conclusion This new FFQ showed a high repeatability and good relative validity, and thanks to its short length, should be a useful tool for rapidly evaluating the nutrient intake of French adults.

High-intensity interval training reduces abdominal fat mass in postmenopausal women with type 2 diabetes.

AIM This study compared the effect of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) for 16 weeks on whole-body and abdominal fat mass (FM) in postmenopausal women with type 2 diabetes (T2D). METHODS Seventeen women (69±1 years; BMI: 31±1kg.m-2) were randomly assigned to either a HIIT [60×(8s at 77-85% HRmax, 12s of active recovery)] or MICT (40min at 55-60% of their individual HRR) cycling program for 16 weeks, 2 days/week. Dual-energy X-ray absorptiometry was used to measure whole-body and regional FM content, including abdominal adiposity and visceral adipose tissue. Plasma cholesterol, HDL, LDL, triglycerides, glucose and HbA1c levels were measured. Levels of nutritional intake and physical activity were evaluated by 7-day self-reports. RESULTS Dietary energy (caloric) intake, physical activity level and total body mass did not vary in either group from the beginning to the end of the training intervention. Overall, total FM decreased and total fat-free mass significantly increased over time (by around 2-3%). Total FM reduction at the end of the intervention was not significantly different between groups. However, significant loss of total abdominal (-8.3±2.2%) and visceral (-24.2±7.7%) FM was observed only with HIIT. Time effects were noted for HbA1c and total cholesterol/HDL ratio. CONCLUSION With no concomitant caloric restriction, an HIIT program in postmenopausal women with T2D (twice a week for 16 weeks) appeared to be more effective for reducing central obesity than MICT, and could be proposed as an alternative exercise training program for this population.

Neuregulin 1 Improves Glucose Tolerance in db/db Mice

In vitro experiments using rodent skeletal muscle cells suggest that neuregulin 1 (NRG1) is involved in glucose metabolism regulation, although no study has evaluated the role of NRG1 in systemic glucose homeostasis. The purpose of this study was to investigate the effect of chronic and acute NRG1 treatment on glucose homeostasis in db/db mice. To this aim, glucose tolerance tests were performed in 8-week-old male db/db mice after treatment with NRG1 (50μg.kg-1) or saline 3 times per week for 8 weeks. In other experiments, glucose tolerance and pyruvate tolerance tests were performed in db/db mice 15 minutes after a single NRG1 (50μg.kg-1) or saline injection. Liver, adipose tissue, hypothalamus and skeletal muscle were also collected 30 minutes after acute NRG1 (50μg.kg-1) or saline treatment, and the phosphorylation status of the ERBB receptors, AKT (on Ser473) and FOXO1 (on Ser256) was assessed by western blotting. Chronic treatment (8 weeks) with NRG1 improved glucose tolerance in db/db mice. Acute treatment also lowered glycemia and insulinemia during glucose or pyruvate tolerance tests. NRG1 acute injection induced activation of ERBB3 receptors and phosphorylation of AKT and FOXO1 only in liver. Altogether, this study shows that acute and chronic NRG1 treatments improve glucose tolerance in db/db mice. This effect could be mediated through inhibition of hepatic gluconeogenesis.

Regular exercise limits alcohol effects on trabecular, cortical thickness and porosity, and osteocyte apoptosis in the rat

INTRODUCTION Excessive alcohol consumption is known to be a cause of secondary osteoporosis whereas physical activity is recommended in prevention of osteoporosis. This study was designed to analyze the effects of physical exercise on bone parameters in chronic alcohol-fed rats. METHODS Forty-eight male Wistar rats were divided in four groups: Control (C), Alcohol (A), Exercise (E) and Alcohol+Exercise (AE). A and AE groups drank a solution composed of ethanol and water (35% volume/volume for 17 weeks). E and AE groups were submitted to treadmill training for 14 weeks (60 min/day, 5 times/week). Bone mineral density (BMD) was assessed by DXA, the trabecular and cortical microarchitectural parameters by microCT and serum osteocalcin, NTx and leptin concentrations by ELISA assays. Bone mechanical parameters were evaluated through mechanical testing. Osteocyte apoptosis was analyzed with cleaved caspase-3 immunostaining. RESULTS Alcohol-fed rats had significantly lower body weight (-28%), fat (-46%) and lean mass (-25%) compared to controls. BMD (-8%), trabecular (-12%) and cortical thickness (-27%) were significantly lower with alcohol whereas porosity (+38%) and pore number (+42%) were higher. Exercise combined with alcohol prevented lower Tb.Th (+20%), Ct.Th (+30%), stress (+26%) and higher Ct.Po (-24%) and osteocyte apoptosis (-91%) compared to A. However, WB BMD (-4%) and femur BMD were still lower in AE versus C. CONCLUSION Regular physical activity has beneficial effects on some microarchitectural parameters in alcohol-fed rats. However, regular treadmill exercise does not compensate for the effects of heavy chronic alcohol consumption on whole body bone density.

Neuregulin 1 improves glucose tolerance in adult and old rats

AIM Studies both in vitro and ex vivo of rodent skeletal muscle have highlighted the potential involvement of neuregulin 1 (NRG1) in glucose metabolism regulation, yet nothing is known of the role of NRG1 in systemic glucose homoeostasis. For this reason, it was hypothesized that systemic delivery of NRG1 might improve glucose tolerance and that the effect might be age-dependent. METHODS Glucose tolerance tests were performed in 6-month-old (adult) and 22-month-old (old) male Wistar rats 15min after a single injection of either NRG1 (50μg/kg) or saline (controls). Skeletal muscle and liver samples were also collected 30min after the acute NRG1 or saline treatment, while the phosphorylation status of ErbB receptors and AKT was assessed by Western blotting. RESULTS Acute NRG1 treatment decreased the glycaemic response to an oral glucose load in both adult and old rats. NRG1 injection did not activate ErbB receptors in skeletal muscle, whereas phosphorylation of ErbB3 and AKT was markedly increased in the liver of NRG1-treated adult and old rats compared with controls. CONCLUSION This study shows that NRG1 has a possible glucose-lowering effect in the liver and via an ErbB3/AKT signaling pathway. This NRG1 effect is also maintained in old rats, suggesting that the NRG1/ErbB signaling pathway might represent a promising therapeutic target in insulin resistance states.