Detrimental Changes in Health during Menopause: The Role of Physical Activity.

Midlife women experience changes in cardiometabolic, physical, and psychosocial health during menopause that negatively impacts their overall quality of life. Factors that contribute to these increases in cardiometabolic risk include weight gain as well as increases in fat mass (particularly abdominal adiposity), insulin resistance, and vascular dysfunction. Other deleterious changes in physical health (e. g. reduced sleep health, bone density, and balance) as well as changes in psychosocial health (e. g. mood, anxiety, and depression) often coincide and are linked to these increases in cardiometabolic risk. Physical activity and exercise are important lifestyle components that have been demonstrated to improve cardiometabolic, physical, and psychosocial health, yet physical activity and exercise is known to decline during perimenopause and into the postmenopausal years. In this narrative review, we summarize these changes in overall health during menopause as well as how declining physical activity contributes to these changes. Additionally, we discuss how incorporating physical activity and exercise during menopause can potentially ameliorate health declines. We conclude that there exists a significant, positive impact of physical activity on cardiometabolic, physical, and psychological health among midlife women, particularly if undertaken during the perimenopausal and postmenopausal years.

Two weeks of moderate hypoxia improves glucose tolerance in individuals with type 2 diabetes.

We previously showed that nightly exposure to moderate hypoxia reduces fasting glucose levels and improves both whole-body skeletal muscle and hepatic insulin sensitivity in individuals with obesity. The goal of this study was to extend this observation in an "at home" setting and determine if nightly exposure to moderate hypoxia improves glucose tolerance in individuals with type 2 diabetes. Eight adults, ages 20-65 years with type 2 diabetes enrolled in our study and slept for 14 consecutive nights at home in a hypoxic tent maintained at 15% O2 (~2400 m). The primary endpoint was insulin sensitivity (Matsuda Index) calculated from a 75-g oral glucose tolerance test. Secondary endpoints included calculations of insulin secretion and beta-cell function, including the area-under-the-curve (AUC) for glucose and insulin, the Insulinogenic Index, and the Disposition Index. We observed the Matsuda Index trended towards a 29% increase following 14 nights of moderate hypoxia (from 1.7 ± 0.7 to 2.2 ± 1.7; p = 0.06). Two-hour glucose AUC was significantly reduced from 501 ± 99 to 439 ± 65 mg/dL × h (p = 0.01). We conclude that 14 nights of moderate hypoxia improves glucose tolerance in individuals with type 2 diabetes. Future studies should confirm whether exposure to moderate hypoxia consistently improves glucose homeostasis in larger sample sizes.

Racial differences in body composition and cardiometabolic risk during the menopause transition: a prospective, observational cohort study.

BACKGROUND: Obesity disproportionately affects more women than men. The loss of ovarian function during the menopause transition coincides with weight gain, increases in abdominal adiposity, and impaired metabolic health. Racial differences in obesity prevalence that results from the menopause transition are not well understood. OBJECTIVE: The purpose of the study was to assess longitudinal changes in body composition and cardiometabolic risk among black and white women during the menopausal transition. STUDY DESIGN: In a secondary analysis of a prospective, observational cohort study (the Healthy Transitions study), 161 women ≥43 years old with a body mass index of 20-40 kg/m2 and who had not yet transitioned through menopause were enrolled at Pennington Biomedical Research Center. Women were seen annually for body composition by dual-energy X-ray absorptiometry, for abdominal adipose tissue distribution by computed tomography, for sex steroid hormones, and for cardiometabolic risk factors that include fasting glucose, insulin, and lipids. Surrogate measures of insulin sensitivity were also calculated. RESULTS: Ninety-four women (25 black, 69 white) transitioned through menopause and were included within the analyses. At menopause onset, black women weighed more (77.8±3.0 vs 70.8±1.8 kg) and had a higher systolic (125±16 vs 118±14 mm Hg) and diastolic (80±8 vs 74±7 mm Hg) blood pressure compared with white women (all P≤.05). No other differences in body composition, sex steroid hormones, or cardiometabolic risk factors were observed at menopause onset. Before menopause, white women gained significant weight (3 kg), total body adiposity (6% percent body fat, 9% fat mass, 12% trunk fat mass) and abdominal adipose tissue (19% subcutaneous fat, 15% visceral fat, 19% total adipose tissue), which coincided with significant decreases in estradiol, sex hormone-binding globulin, and estrone sulfate and increases in follicle-stimulating hormone, total cholesterol, and low-density lipoprotein cholesterol. Conversely, black women had more abdominal adipose tissue before menopause, which was maintained across the menopause transition. Black women also had significant decreases in estrone sulfate and total testosterone and increases in follicle-stimulating hormone before menopause. In the postmenopausal years, abdominal subcutaneous adipose tissue, total adipose tissue, follicle-stimulating hormone, total cholesterol, and low-density and high-density lipoprotein cholesterol increased only in white women. CONCLUSION: White women gained more abdominal adiposity during the menopause transition compared with black women, which, in part, may be due to differences in the pattern of sex steroid hormone changes between women of different racial backgrounds. The gains in abdominal adiposity in white women were observed in tandem with increased cardiometabolic risk factors. Future studies should consider comprehensive lifestyle approaches to target these increased gains in abdominal adiposity (ie, nutrition and physical activity coaching), while taking into account the potential interactions of race, body adiposity, sex steroid hormones, and their influence on cardiometabolic risk.

The Panacea of Human Aging: Calorie Restriction Versus Exercise.

Primary aging is the progressive decline in health and fitness and depends on metabolic rate and oxidative stress. Untoward changes in body composition and metabolic function characterize secondary aging. We hypothesize that both exercise and calorie restriction (CR) improve secondary aging, but only CR improves primary. However, CR followed with exercise is a superior strategy to maintain overall health and quality of life with age.

Is activation of human brown adipose tissue a viable target for weight management?

To date, human studies show that brown adipose tissue (BAT) contributes a small yet highly variable amount to overall energy expenditure. No studies have shown a decrease in body weight with cold-induced BAT activation, and existing pharmacological studies suggest that BAT activation via the sympathetic nervous system may result in increased heart rate and systolic blood pressure. Furthermore, even though the amount and/or activity of BAT have been shown to vary with seasons, such variation does not seem to be translated into weight changes. Collectively, these findings do not support the use of BAT activation for weight loss in humans; however, the potential role of BAT in counteracting the metabolic adaptation observed with weight loss is suggested. Although the role of BAT in weight control is currently unsubstantiated, BAT may play a role in improving insulin sensitivity in humans.

Childhood wrist circumference is not a predictor of insulin resistance in adulthood.

We sought to determine whether childhood wrist circumference predicts insulin resistance in adulthood. Measures were taken in prepubertal children and then approximately 30 years later in the same subjects as adults. Our findings suggest that wrist circumference in childhood is not a predictor of insulin resistance in adulthood.

Sleep Duration Alters Overfeeding-mediated Reduction in Insulin Sensitivity.

CONTEXT: Weight gain and sleep restriction both reduce insulin sensitivity. However, it is not known if sleep duration alters glucose metabolism in response to overfeeding. OBJECTIVE: To examine the effect of sleep duration on overfeeding-mediated alterations in carbohydrate metabolism and insulin sensitivity. METHODS: Retrospective exploratory analysis of a longitudinal overfeeding study in healthy participants (n = 28, age: 26.9 ± 5.5 years, body mass index: 25.74 ± 2.45 kg/m2). After providing baseline study measures, participants were overfed 40% above weight maintenance calorie requirements for 8 weeks. Insulin sensitivity was determined by a 2-step hyperinsulinemic-euglycemic clamp. Baseline habitual sleep duration was estimated by accelerometry, and sleep groups were created based on median sleep duration (5.2 hours/night). RESULTS: Overfeeding led to an average body weight gain of 7.3 ± .4 kg. Habitual sleep duration did not alter overfeeding-mediated body weight gain, fat gain, and fat distribution (all P > .15). Compared to participants with more sleep, fasting insulin (P = .01) and homeostatic model assessment for insulin resistance (P = .02) increased while fasting glucose remained unchanged (P = .68) with overfeeding in participants with shorter sleep duration. Glucose infusion rate during high insulin dose was reduced with overfeeding in participants with short sleep duration but not in participants with more sleep (P < .01). CONCLUSION: Overfeeding mediated weight gain reduced liver, adipose, and whole-body insulin sensitivity prominently in individuals with short sleep duration but not in individuals with longer sleep duration. This suggests that promoting adequate sleep during short periods of overeating may prevent detrimental effects on glucose metabolism.

Impact of pubertal development on endothelial function and arterial elasticity.

OBJECTIVES: Little is known about the relation of pubertal development on endothelial function and arterial elasticity in children and adolescents; therefore, we compared brachial artery flow-mediated dilation and carotid artery elasticity across Tanner (pubertal) stages in children and adolescents. STUDY DESIGN: Blood pressure, fasting lipids, glucose and insulin, body fat, insulin sensitivity adjusted for lean body mass, brachial flow-mediated dilation (percent dilation and area under the curve), endothelium-independent dilation (peak dilation and area under the curve), and carotid artery elasticity were evaluated across pubertal stages (Tanner I vs Tanner II-IV vs Tanner V) in 344 children and adolescents (184 males, 160 females; ages 6 to 21 years). RESULTS: One hundred twenty-four subjects (mean age 8.23 ± 0.15 years; 52 females) were Tanner stage I; 105 subjects (mean age 13.19 ± 0.17 years; 47 females) were Tanner stages II-IV; and 115 subjects (mean age 17.19 ± 0.16 years; 61 females) were Tanner stage V. There were no significant differences for any of the measures of vascular structure and function across pubertal stages. CONCLUSION: Results of the current study indicate that smooth-muscle and endothelial function, as well as carotid artery elasticity, do not differ throughout pubertal development and that accounting for pubertal stage when reporting vascular data in children and adolescents may be unnecessary.

The influence of gender on carotid artery compliance and distensibility in children and adults.

PURPOSE: Given the role of arterial wall elasticity in the development of cardiovascular disease, carotid artery compliance and distensibility have been used commonly over the last decade as predictors of cardiovascular risk, although their gender differences remain unknown. The purpose of our study was to evaluate the impact of gender on carotid arterial elasticity in a large sample of children and adults. METHODS: Carotid artery compliance and distensibility were measured with ultrasonography in 294 children (157 boys, 137 girls; ages 6-18 years) and 604 adults (291 men, 311 women; ages 18-49 years) previously recruited for a study investigating cardiovascular risk factors. An independent sample t test was used to compare demographic and carotid artery elasticity values by age and gender. RESULTS: No significant gender difference in carotid arterial compliance and distensibility was observed in children. Women had significantly greater cross-sectional compliance than men (0.004 ± 0.000 versus 0.003 ± 0.000 1/mmHg, p = 0.041). CONCLUSIONS: We found significant gender difference in carotid compliance in adults, but not in children, suggesting that gender differences in arterial stiffness are not present early in life but emerge later in adulthood.

"Weight loss is my goal and being healthy is my goal I can get over the hot flashes": a qualitative exploration of menopausal transition experiences and preferences for weight management among White women.

OBJECTIVES: A qualitative research study design was used to (1) describe experiences of White women during the menopausal transition, and (2) identify barriers and facilitators for participating in a lifestyle program targeting weight management. METHODS: Perimenopausal and postmenopausal White women who self-reported a desire to lose or maintain weight participated in focus groups. Women were queried about their past diet, exercise, and weight management practices; menopausal transition; and specific components and considerations for developing a lifestyle program for weight management. Thematic analysis was conducted on coded transcripts and four main themes emerged, each containing three to six subthemes. RESULTS: Twenty-eight White women (age 54 ± 3 y, body mass index 31.4 ± 9.5 kg/m 2 ) were enrolled. Overall, women felt menopause was a major life event that coincided with weight gain and frustrating body changes. Women already engaged in many different types of exercises and diets to lose weight. Women also talked to healthcare professionals about menopause but were disappointed in the support they received. Women were interested in a lifestyle program that included menopause-specific education, which focused on results beyond weight, which was flexible to their busy lifestyle, and which provided opportunities to build camaraderie among other women experiencing menopause. CONCLUSIONS: This cohort of White women were interested in receiving menopause information and improving their overall health as part of a lifestyle program targeting weight management during this transition. Building camaraderie with other women affected by menopause is important to women, as is creating a lifestyle program that is flexible with daily life.

Metabolic Adaptations and Substrate Oxidation are Unaffected by Exogenous Testosterone Administration during Energy Deficit in Men.

INTRODUCTION/PURPOSE: The effects of testosterone on energy and substrate metabolism during energy deficit are unknown. The objective of this study was to determine the effects of weekly testosterone enanthate (TEST; 200 mg·wk -1 ) injections on energy expenditure, energy substrate oxidation, and related gene expression during 28 d of energy deficit compared with placebo (PLA). METHODS: After a 14-d energy balance phase, healthy men were randomly assigned to TEST ( n = 24) or PLA ( n = 26) for a 28-d controlled diet- and exercise-induced energy deficit (55% below total energy needs by reducing energy intake and increasing physical activity). Whole-room indirect calorimetry and 24-h urine collections were used to measure energy expenditure and energy substrate oxidation during balance and deficit. Transcriptional regulation of energy and substrate metabolism was assessed using quantitative reverse transcription-polymerase chain reaction from rested/fasted muscle biopsy samples collected during balance and deficit. RESULTS: Per protocol design, 24-h energy expenditure increased ( P < 0.05) and energy intake decreased ( P < 0.05) in TEST and PLA during deficit compared with balance. Carbohydrate oxidation decreased ( P < 0.05), whereas protein and fat oxidation increased ( P < 0.05) in TEST and PLA during deficit compared with balance. Change (∆; deficit minus balance) in 24-h energy expenditure was associated with ∆activity factor ( r = 0.595), but not ∆fat-free mass ( r = 0.147). Energy sensing (PRKAB1 and TP53), mitochondria (TFAM and COXIV), fatty acid metabolism (CD36/FAT, FABP, CPT1b, and ACOX1) and storage (FASN), and amino acid metabolism (BCAT2 and BCKHDA) genes were increased ( P < 0.05) during deficit compared with balance, independent of treatment. CONCLUSIONS: These data demonstrate that increased physical activity and not exogenous testosterone administration is the primary determinate of whole-body and skeletal muscle metabolic adaptations during diet- and exercise-induced energy deficit.

Effect of sleep restriction on insulin sensitivity and energy metabolism in postmenopausal women: A randomized crossover trial.

OBJECTIVE: The aim of this study was to investigate the effect of sleep restriction (SR) on insulin sensitivity and energy metabolism in postmenopausal women. METHODS: In a randomized crossover trial, 14 women underwent four nights of habitual sleep (HS, 100% normal sleep) and SR (60% of HS) while following a eucaloric diet. Outcomes included the following: (1) insulin sensitivity by hyperinsulinemic-euglycemic clamp, defined as the glucose infusion rate (GIR); (2) resting metabolism and substrate oxidation by indirect calorimetry; and (3) glucose, insulin, and C-peptide concentrations following a standard meal test. RESULTS: Nine postmenopausal women (mean [SD], age 59 [4] years, BMI 28.0 [2.6] kg/m2 ) were analyzed. Accelerometer-determined total time in bed was 8.4 ± 0.6 hours during HS versus 5.0 ± 0.4 hours during SR (38% reduction, p < 0.0001). SR reduced low-dose insulin GIR by 20% (HS: 2.55 ± 0.22 vs. SR: 2.03 ± 0.20 mg/kg/min; p = 0.01) and high-dose insulin GIR by 12% (HS: 10.48 ± 0.72 vs. SR: 9.19 ± 0.72 mg/kg/min; p < 0.001). SR reduced fat oxidation during high-dose insulin infusion (p < 0.01), and it did not alter resting energy metabolism. CONCLUSIONS: Four nights of SR reduced insulin sensitivity and fat oxidation in postmenopausal women. These findings underscore the role of insufficient sleep in metabolic dysfunction following menopause. Larger trials investigating how sleep disturbances cause metabolic dysfunction during menopause are needed across all stages of menopause.

"It just seems like people are talking about menopause, but nobody has a solution": A qualitative exploration of menopause experiences and preferences for weight management among Black women.

OBJECTIVES: A qualitative study was performed to characterize experiences of women going through menopause, as well as to identify barriers and facilitators for participating in a lifestyle program targeting weight management during menopause. STUDY DESIGN: Perimenopausal and postmenopausal Black women with a self-reported desire to lose or maintain weight during menopause participated in a total of six focus groups. MAIN OUTCOME MEASURES: Women were asked about their past experiences with diet, exercise, and weight management; their menopause experiences; as well as specific components and considerations for developing a lifestyle program for weight management. Thematic analysis was conducted on coded transcripts and four main themes emerged, each containing three to seven subthemes. RESULTS: Twenty-seven Black women (age 54±4 years, BMI 35.1 ± 9.0 kg/m2) were enrolled. Overall, women felt unprepared for the changes they experienced during menopause and had difficulty maintaining or losing weight. While women were receptive to trying different diets and exercises, they wanted a diet that was flexible with their lifestyle and exercises that considered their existing health status. Women were also interested in learning about menopause alongside other women, stating that medical professionals did not provide them with adequate information or help. Social support, accountability, and seeing results were perceived critical to achieve long-lasting behavioral change. CONCLUSIONS: Women were interested in receiving menopause information and improving their overall health as part of a lifestyle program during menopause. Associating with other women affected by menopause will allow for the creation of more sustainable lifestyle programs during menopause. Clinicaltrials.gov identifier: NCT04487782.

Body composition and cardiometabolic health across the menopause transition.

Every year, 2 million women reach menopause in the United States, and they may spend 40% or more of their life in a postmenopausal state. In the years immediately preceding menopause-known as the menopause transition (or perimenopause)-changes in hormones and body composition increase a woman's overall cardiometabolic risk. In this narrative review, we summarize the changes in weight, body composition, and body fat distribution, as well as the changes in energy intake, energy expenditure, and other cardiometabolic risk factors (lipid profile, glucose metabolism, sleep health, and vascular function), that occur during the menopause transition. We also discuss the benefits of lifestyle interventions in women in the earlier stages of menopause before these detrimental changes occur. Finally, we discuss how to include perimenopausal women in research studies so that women across the life-span are adequately represented.

NAMS 2021 Utian Translational Science SymposiumSeptember 2021, Washington, DCCharting the path to health in midlife and beyond: the biology and practice of wellness.

ABSTRACT: Charting the Path to Health in Midlife and Beyond: The Biology and Practice of Wellness was a Translational Science Symposium held on Tuesday, September 21, 2021. Foundational psychosocial and behavioral approaches to promote healthy aging and strategies to disseminate this information were discussed. The following synopsis documents the conversation, describes the state of the science, and outlines a path forward for clinical practice. Wellness, in its broadest sense, prioritizes an orientation toward health, and an embrace of behaviors that will promote it. It involves a journey to improve and maintain physical and mental health and overall well-being to fully engage and live one's best life. It is more about recognizing and optimizing what one can do than what one cannot do and emphasizes the individual's agency over changing what they are able to change. Wellness is therefore not a passive state but rather an active goal to be sought continually. When viewed in this fashion, wellness is accessible to all. The conference addressed multiple aspects of wellness and embraced this philosophy throughout.

Overfeeding-induced weight gain elicits decreases in sex hormone-binding globulin in healthy males-Implications for body fat distribution.

OBJECTIVE: Obesity and upper-body fat elevates cardiometabolic risk. However, mechanisms predisposing to upper-body fat accumulation are not completely understood. In males, low testosterone (T) frequently associates with obesity, and estrogen deficiency may contribute to upper-body adiposity. This study examines the effects of overfeeding-induced weight gain on changes in gonadal hormones in healthy males and its association with regional fat depots. METHODS: Twenty-five males (age: 29.7 ± 6.9 years; BMI: 24.7 ± 3.1 kg/m2 ) were overfed for 8 weeks to gain approximately 5% body weight. Changes in total and regional fat depots were assessed using dual-energy x-ray absorptiometry and abdominal computed tomography scans. Circulating T, estrone (E1), 17-ß estradiol (E2), and sex hormone-binding globulin (SHBG) concentrations were measured at baseline and after weight gain. RESULTS: Overfeeding resulted in 3.8 (3.3, 4.9) kg weight gain with increased total body fat. Weight gain did not alter circulating T (p = 0.82), E1 (p = 0.52), or E2 (p = 0.28). However, SHBG decreased (p = 0.04) along with consequent increases in T/SHBG (p = 0.02) and E2/SHBG (p = 0.03) ratios. Importantly, baseline E2/SHBG ratio was inversely associated with increases in upper-body fat mass (ρ = -0.43, p = 0.03). CONCLUSIONS: Modest weight gain does not alter circulating gonadal hormones in males but may increase bioavailability of T and E2 via decreases in SHBG. The association between baseline E2/SHBG and regional fat mass suggests that higher levels of bioavailable E2 may protect from upper-body fat accumulation during overfeeding-induced modest weight gain in healthy males. Our study suggests a complex relationship between adipose tissue, gonadal hormones, and fat accumulation in males.

Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding.

Over the past 10 to 15 years, intermittent fasting has emerged as an unconventional approach to reduce body weight and improve metabolic health beyond simple calorie restriction. In this review, we summarize findings related to Ramadan and Sunnah fasting. We then discuss the role of caloric restriction not only as an intervention for weight control, but importantly, as a strategy for healthy aging and longevity. Finally, we review the four most common intermittent fasting (IF) strategies used to date for weight management and to improve cardiometabolic health. Weight loss is common after IF but does not appear to be different than daily caloric restriction when compared directly. IF may also provide additional cardiometabolic benefit, such as insulin sensitization, that is independent from weight loss. While no specific fasting regimen stands out as superior at this time, there is indeed heterogeneity in responses to these different IF diets. This suggests that one dietary regimen may not be ideally suited for every individual. Future studies should consider strategies for tailoring dietary prescriptions, including IF, based on advanced phenotyping and genotyping prior to diet initiation.

A Novel Approach to Assess Metabolic Flexibility Overnight in a Whole-Body Room Calorimeter.

OBJECTIVE: This study aimed to investigate a novel approach for determining the effects of energy-standardized dinner meals (high-fat and low-fat) on respiratory exchange ratio (RER) dynamics and metabolic flexibility. METHODS: Using a randomized crossover study design, energy expenditure, RER, and macronutrient oxidation rates were assessed in response to a single dinner meal during an overnight stay in a whole-body room calorimeter. Eight healthy adults completed two overnight chamber stays while fed either a high-fat (60% fat, 20% carbohydrate [CHO], 20% protein; food quotient [FQ] = 0.784) or low-fat (20% fat, 60% CHO, 20% protein; FQ = 0.899) dinner containing 40% of daily energy requirements. RESULTS: Following the low-fat meal, CHO oxidation first increased before decreasing, resulting in a 12-hour RER:FQ ratio close to 1.0 (0.986 ± 0.019, P = 0.06) and therefore resulting in a 12-hour equilibrated fat balance (29 ± 76 kcal/12 hours). Following the high-fat meal, participants had a RER:FQ ratio above 1.0 (1.061 ± 0.017, P < 0.01), resulting in a significant positive 12-hour fat balance of 376 ± 142 kcal/12 hours. Various RER trajectory parameters were significantly different following the high-fat and low-fat meals. CONCLUSIONS: This proof-of-concept study provides an alternative approach to quantify metabolic flexibility in response to a high-fat dinner and it can be used to derive indexes of metabolic flexibility, such as the 12-hour RER:FQ ratio or the 12-hour fat balance.

Reproducibility of a ramping protocol to measure cerebral vascular reactivity using functional magnetic resonance imaging.

Though individual differences in arterial carbon dioxide and oxygen levels inherently exist, the degree of their influence on cerebral vascular reactivity (CVR) is less clear. We examined the reproducibility of BOLD signal changes to an iso-oxic ramping Pet CO2 protocol. CVR changes were induced by altering Pet CO2 while holding Pet O2 constant using a computer-controlled sequential gas delivery (SGD) device. Two MRI scans, each including a linear change in Pet CO2 , were performed using a 3-Tesla (3T) scanner. This ramp sequence consisted of 1 min at 30 mmHg followed by 4 min period during where Pet CO2 was linearly increased from 30 to 50 mmHg, 1 min at 51 mmHg, and concluded with 4 min at baseline. The protocol was repeated at a separate visit with 3 days between visits (minimum). Intraclass correlation coefficients (ICC) and coefficients of variation (CV) were used to verify reproducibility. Eleven subjects (6 females; mean age 26.5 ± 5.7 years) completed the full testing protocol. Good reproducibility was observed for the within-visit ramp sequence (Visit 1: ICC = 0.82, CV = 6.5%; Visit 2: ICC = 0.74, CV = 6.4%). Similarly, ramp sequence were reproducible between visits (Scan 1: ICC = 0.74, CV = 6.5%; Scan 2: ICC = 0.66, CV = 6.1%). Establishing reproducible methodologies for measuring BOLD signal changes in response to Pet CO2 alterations using a ramp protocol will allow researchers to study CVR functionality. Finally, adding a ramping protocol to CVR studies could provide information about changes in CVR over a broad range of Pet CO2 .

Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women.

OBJECTIVE: Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. DESIGN: Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50-60 years, BMI 30-40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS). RESULTS: CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05). CONCLUSIONS: A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.