Physical Function and Strength in Relation to Inflammation in Older Adults with Obesity and Increased Cardiometabolic Risk.

BACKGROUND: Inflammation is implicated in functional decline and the development of disability in aging. This study aimed to investigate the association of inflammation with physical function and muscle strength in older adults with obesity and increased cardiometabolic risk. DESIGN: In baseline assessments from the CROSSROADS randomized controlled trial, serum interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) and C-reactive protein (hs-CRP) were assayed in 163 older adults (37% males, 24% African American, BMI 34±3, age 70±5yrs) with hypertension, dyslipidemia and/or diabetes. Physical function was assessed by six-minute walk test (6MWT), chair sit-and-reach (CSR), hand-grip and knee-extension strength; specific-strength as muscle strength/mass ratio. Analyses included ANCOVA and multiple linear regression adjusted for thigh skeletal muscle (MRI), arm lean mass (DXA) and moderate-to-vigorous intensity physical activity (MVPA; accelerometry). RESULTS: Higher hs-CRP (p<0.01) and IL-6 (p=0.07) were associated with lower 6MWT and CSR, respectively. A composite inflammation score combining all 3 inflammatory markers showed the strongest inverse association with 6MWT (p<0.01). MVPA moderated associations such that amongst participants who engaged in low MVPA, 6MWT distances and CSR scores were significantly lower in those with high IL-6 and TNFα (p<0.05), respectively. In participants with high MVPA, higher hs-CRP (p<0.05) and TNFα (p=0.07) were associated with poorer upper-extremity specific-strength. CONCLUSIONS: Chronic inflammation was associated with poorer physical function and specific strength in older adults with obesity and increased cardiometabolic risk. This association was strongest in participants with multiple elevated inflammatory markers. Physical activity levels below current recommendations mitigated the deleterious effects of inflammation on lower body mobility, underscoring the benefits of exercise for preserving physical function with age.

Effects of a Standard American Diet and an anti-inflammatory diet in male and female mice.

BACKGROUND: Obesity and chronic pain are prevalent concerns. Pain is frequently experienced in weight-bearing joints, but is common in other areas of the body as well, suggesting other factors. Poor diet often contributes to obesity and can directly influence the immune system. We have shown that poor diet prolongs recovery from inflammatory injury. Therefore, our goal was to determine whether poor-quality diet-induced consequences could be prevented or reversed by an anti-inflammatory diet (AID). METHODS: A Standard American Diet (SAD) was developed to investigate the effects of poor diet on pain. The SAD includes amounts of refined sugar, carbohydrates and fats that better model the typical American diet, as compared to high-fat diets. We developed an AID to explore whether the effects of the SAD could reverse or whether the AID would enhance recovery prophylactically. The AID was developed using ingredients (epigallocatechin gallate, sulforaphane, resveratrol, curcumin and ginseng) with known anti-inflammatory properties. Following 15 weeks of diet [SAD, AID or regular (REG)] exposure, male and female mice underwent inflammatory injury, at which point some animals had their diets switched for the remainder of the study. RESULTS: Animals who consumed the SAD showed longer recovery compared to the AID- and REG-fed animals. Animals switched off the SAD had faster recovery times, with AID-fed animals recovering as fast as REG-fed animals. CONCLUSIONS: Poor diet prolonged recovery from inflammatory injury. Substitution of SAD with AID or REG promoted faster recovery. These findings suggest diet can be used as a non-pharmacological intervention following injury. SIGNIFICANCE: Obesity may increase susceptibility to chronic pain often due to poor diet. Diet has potential to be used as treatment for pain. This study investigates the use of a novel translatable diet to act as a preventative (i.e. prior to surgery) or an intervention (i.e. following an injury).

Effects of 6-month supplementation with ß-hydroxy-ß-methylbutyrate, glutamine and arginine on vascular endothelial function of older adults.

BACKGROUND/OBJECTIVES: Vascular endothelial function declines with advancing age, due in part to increased oxidative stress and inflammation, and this age-related vascular dysfunction has been identified as an independent risk factor for cardiovascular diseases. This double-blind, placebo-controlled trial investigated the effects of a dietary supplement containing ß-hydroxy-ß-methylbutyrate (HMB), glutamine and arginine on endothelial-dependent vasodilation of older adults. SUBJECTS/METHODS: A total of 31 community-dwelling men and women aged 65-87 years were randomly assigned to two groups. The treatment group received two doses of the supplement daily (totaling 3 g HMB, 14 g glutamine and 14 g arginine) for 6 months, whereas the control group received an isocaloric placebo. At baseline and week 24, vascular endothelial function was measured by flow-mediated dilation of the brachial artery, and fasting blood samples were obtained to measure high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor-α (TNF-α). RESULTS: Paired sample t-tests revealed a 27% increase in flow-mediated dilation among the treatment group (P=0.003), whereas no change was observed in the placebo group (P=0.651). Repeated-measures analysis of variance verified a significant time by group interaction (P=0.038). Although no significant changes were observed for hsCRP or TNF-α, a trend was observed for increasing hsCRP among the placebo group only (P=0.059). CONCLUSIONS: These results suggest that dietary supplementation of HMB, glutamine and arginine may favorably affect vascular endothelial function in older adults. Additional studies are needed to elucidate whether reduced inflammation or other mechanisms may underlie the benefits of supplementation.

Longitudinal study on pubertal insulin resistance.

Previous cross-sectional studies show that puberty is associated with a reduction in insulin sensitivity (S(I)), but no longitudinal studies have examined this change in detail. This study is a longitudinal study in 60 children (33 male and 27 female subjects; 32 Caucasian and 28 African-American) examined at Tanner stage I (age 9.2 +/- 1.4 years) and after 2.0 +/- 0.6 years of follow-up, by which time 29 children remained at Tanner stage I and 31 had progressed to Tanner stage III or IV. Tanner stage was assessed by physical examination. S(I), the acute insulin response (AIR), and the disposition index (DI) were determined by the tolbutamide-modified intravenous glucose tolerance test and minimal modeling, body fat mass was assessed by dual-energy X-ray absorptiometry, visceral fat was determined by computed tomography, and fasting blood was analyzed for hormone levels. In children progressing to Tanner stage III, S(I) fell significantly by 32% (4.4 +/- 3.0 to 3.0 +/- 1.7 x 10(-4)min(-1)/[microIU/ml]), AIR increased by 30%, DI fell by 27%, and there was a significant increase in fasting glucose (93.5 +/- 5.0 to 97.0 +/- 4.1 mg/dl) and insulin (14.3 +/- 8.1 to 18.6 +/- 11.0 microIU/ml). In children remaining at Tanner stage I, there was a slight increase in S(I) (6.4 +/- 3.1 to 7.4 +/- 3.5 x 10(-4)min(-1)/[microIU/ml]) with no significant change in AIR or fasting glucose and insulin. The pubertal fall in S(I) was more consistent in African-Americans; remained significant after controlling for age, sex, and change in fat mass, visceral fat, and fat-free mass; and was similar in children at low, medium, and high body fat. Change in S(I) was not significantly related to change in fasting hormone levels, but change in AIR was significantly related to change in androstendione (r = 0.39; P = 0.04). Pubertal transition from Tanner stage I to Tanner stage III was associated with a 32% reduction in S(I,) and increases in fasting glucose, insulin, and AIR. These changes were similar across sex, ethnicity, and obesity. The significant fall in DI suggests conservation in beta-cell function or an inadequate beta-cell response to the fall in S(I). The fall in S(I) was not associated with changes in body fat, visceral fat, IGF-I, androgens, or estradiol.

Levels of progesterone, testosterone, and estradiol, and androstenedione metabolism in the gonads of Lytechinus variegatus (Echinodermata:echinoidea).

Levels of progesterone (P4), testosterone (T) and estradiol (E2) indicated significant variation among individual echinoids during the annual cycle, reflecting generally the variation in gamete development that can be observed among individuals. Testosterone and E2 levels in both the ovaries and testes were higher during the period of gonadal growth. Levels of all steroids were greatly reduced compared to those levels reported for asteroids. Differences in the levels of P4, T, and estrogens between asteroids and Lytechinus variegatus may be related to differences in gonad morphology and nutrient storage capacity between asteroids and echinoids. It was hypothesized that the low levels of steroids detected in L. variegatus reflect paracrine-like mechanisms in cell signaling as compared to endocrine-like mechanisms proposed to be involved in regulating gonad function in asteroids. Both the ovaries and testes of L. variegatus had the capacity to synthesize T and a variety of 5alpha-reduced androgens including 5alpha-androstane-3beta,17beta-diol and 5alpha-androstane-3alpha,17beta-diol (5alpha-adiols) from androstenedione (AD) in 8 h. Estrogen synthesis was not detected. The sex-specific pattern of accumulation of 5alpha-adiols in the ovaries and testes suggests that the 5alpha-adiols may affect processes related to reproduction in L. variegatus.

Leptin in postmenopausal women: influence of hormone therapy, insulin, and fat distribution.

Whether use of hormone-replacement therapy (HRT) influences menopause-related changes in body weight is unclear. HRT may affect energy balance by influencing synthesis of the adipocyte-derived hormone leptin. The objectives of this study were to: 1) identify factors influencing circulating leptin in postmenopausal women; 2) determine whether HRT influences serum leptin after adjusting for confounding factors; and, 3) identify potential independent effects of HRT or leptin on resting energy expenditure (REE). Subjects were 54 postmenopausal women, 45-55 yr old, 35 of whom used HRT (estrogen plus progestin). Total and regional body composition and fat distribution were determined by dual-energy x-ray absorptiometry and computed tomography; fasting serum leptin and insulin, by RIA; and REE, by indirect calorimetry. Stepwise multiple linear regression analysis indicated that serum leptin could best be predicted from total fat mass, fasting serum insulin, and total lean mass [log leptin = 1.08 x log fat mass) + (0.46 x log insulin) + (-1.25 x log lean mass) + 1.88; model R2 = 0.78, P < 0.001]. Multiple linear regression analysis indicated that visceral fat was independently related to leptin (parameter estimate = 0.23, P < 0.05), after adjusting for s.c. abdominal fat and leg fat, as well as lean mass and insulin. After adjusting for total fat mass, total lean mass, and fasting insulin, serum leptin did not differ between users and nonusers of HRT (21.7 +/- 1.0 vs. 20.2 +/- 1.3 ng/mL, P = 0.369, adjusted mean +/- SE, respectively). Serum estradiol was inversely correlated with (adjusted) leptin in non-HRT users (r = -0.50), suggesting that ovarian senescence may lead to an increase in leptin. Multiple linear regression analysis indicated that REE (adjusted for fat mass, fat-free mass, and ethnicity) was not associated with leptin (P = 0.298) or hormone use status (P = 0.999; 1323 +/- 31 vs. 1316 +/- 42 kcal/day, adjusted mean +/- SE for users and nonusers, respectively). These results indicate that, in postmenopausal women: 1) total fat mass, lean mass, and fasting insulin, but not HRT, are significant determinants of serum leptin; 2) visceral and s.c. fat contribute to serum leptin; and, 3) neither HRT nor leptin is independently related to REE.

Associations among oral estrogen use, free testosterone concentration, and lean body mass among postmenopausal women.

Circulating concentrations of sex hormone-binding globulin (SHBG) are increased by use of oral estrogen. The objective of this study was to determine whether postmenopausal women who used oral estrogen had higher serum concentrations of SHBG and lower serum concentrations of free testosterone (T) than nonusers, and whether free T was associated with lean body mass, particularly skeletal muscle mass. Subjects were 70 postmenopausal women, 46-55 yr old, 46 of whom used oral estrogen. Total and regional body composition were determined by dual-energy x-ray absorptiometry. Serum concentrations of SHBG, total T, and estradiol (E(2)) were determined by RIA. Free T was calculated from concentrations of total T and SHBG. Hormone users had higher serum concentrations of E(2) and SHBG (182.0 +/- 58. 5 vs. 82.9 +/- 41.1 nmol/L, mean +/- SD, P: < 0.001) and lower concentrations of free T (3.7 +/- 2.2 vs. 7.9 +/- 4.1 pmol/L, mean +/- SD, P: < 0.001); total T did not differ. Total lean mass and leg lean mass were significantly correlated with free, but not total T [r values of 0.29 (P: < 0.05) and 0.31 (P: < 0.01) for total and leg lean mass, respectively, vs. free T]; arm lean mass was not correlated with either measure of T. Serum E(2) was significantly correlated with SHBG (r = 0.50, P: < 0.001) and free T (r = -0.33, P: < 0.01). These observations imply that, by reducing the concentration of bioavailable T, oral estrogen therapy may accelerate or augment lean mass loss among postmenopausal women. This conclusion awaits confirmation by longitudinal observation.

Do hormonal indices of maturation explain energy expenditure differences in African American and Caucasian prepubertal children?

OBJECTIVE: To examine the relationships between hormonal indices of maturation and total, resting and physical activity-related energy expenditure (TEE, REE and AEE) in African American and Caucasian prepubertal children. DESIGN: Cross-sectional study. SUBJECTS: Sixty-four African American and 48 Caucasian prepubertal children. MEASUREMENTS: TEE (by doubly labeled water), REE (by indirect calorimetry), fat mass and fat-free mass (by dual-energy X-ray absorptiometry), fasting serum dehydroepiandrosterone-sulfate (DHEAS), androstenedione, and estrone-sulfate (by radioimmunoassay). RESULTS: Serum concentrations of hormones correlated significantly with REE and TEE (r values range from 0.33 to 0.76, P<0.001). Only androstenedione correlated significantly with AEE (r = 0.23, P<0.05). However, these correlations were no longer significant after adjusting energy expenditure components for fat-free mass. In multiple regression models, ethnicity was not a significant determinant of any energy expenditure component after adjusting for body composition and hormone concentrations. CONCLUSION: Hormonal indices of maturation do not influence energy expenditure in this group of African American and Caucasian prepubertal children.

Effect of photoperiod, testosterone, and estradiol on body mass, bifid claw size, and pelage color in collared lemmings (Dicrostonyx groenlandicus).

Collared lemmings undergo several photoperiod-mediated seasonal physiological changes. When exposed to short photoperiod, lemmings increase in size, develop a bifid claw, and molt to a white pelage. Previous data indicate that body mass, claw size, and pelage color are influenced by hormones of testicular origin, suggesting that, on a seasonal basis, changes in production of, or sensitivity to, testicular hormones may play a role in the development of the phenotype characteristic of the ambient photoperiod. The present study was designed to determine if the active testicular hormone(s) is testosterone (T) and/or estradiol (E2) and if seasonally changing physiological traits in female lemmings are also influenced by gonadal status. Fifty-day-old lemmings, reared in 22L:2D (long day), 16L:8D (intermediate day), or 8L:16D (short day), were either gonadectomized or sham operated and given either empty Silastic implants or implants containing T (4 or 10 mm; castrated males), E2 (4 mm undiluted or diluted 1:4 with cholesterol; ovariectomized females), the aromatase inhibitor ATD (androsta-1,4,6-triene-3,17-dione; 2 x 20 mm; intact animals of both sexes), or ATD plus a 10-mm T implant (castrated males). After a 6-week treatment period, changes in body mass, bifid claw width, pelage color stage, and serum prolactin (PRL) were assessed. The effects of gonadectomy and steroid treatment depended upon photoperiod. Whereas gonadectomy increased mass gained by both sexes under intermediate and short day, under long day only females showed the positive mass response to gonadectomy. Treatment with T and E2 reversed the effect of gonadectomy on body mass under intermediate day and decreased the amount of mass gained under short day. Treatment with ATD (males) and E2 (females) indicated that E2 was the hormone responsible for the tonic, inhibitory effect of the gonads on body mass in both sexes. Claw size was most sensitive to steroid manipulation in animals housed in long day, in which all treatments had a negative influence. Gonadectomy under short day resulted in the development of a whiter pelage in both sexes. The effect of gonadectomy on pelage in female lemmings, and its reversal by E2 treatment, may have been partially due to alteration of serum PRL.

16-unsaturated C 19 3-oxo steroids as metabolic intermediates in boar testis.

1. The formation of the two 16-unsaturated alcohols 5alpha-androst-16-en-3alpha-ol and 5alpha-androst-16-en-3beta-ol from [5alpha-(3)H]5alpha-androst-16-en-3-one has been demonstrated in boar testis homogenates. 2. The optimum yield (23%) of the 3alpha-alcohol was obtained in the presence of NADPH, whereas that for the 3beta-alcohol (74%) was obtained when NADH was the added cofactor. 3. The two alcohols were not interconvertible. 4. Prolonged storage of boar testis tissue at -20 degrees C abolished the ability to form all androst-16-enes except androsta-4,16-dien-3-one from [4-(14)C]progesterone. 5. The production of 5alpha-androst-16-en-3-one and the two alcohols from [7alpha-(3)H]androsta-4,16-dien-3-one only occurred when fresh tissue was used, whereas reduction of [5alpha-(3)H]5alpha-androst-16-en-3-one was unaffected by storage of testis at -20 degrees C. 6. NADPH was the preferred cofactor for the reduction of androsta-4,16-dien-3-one. 7. The previously established conversion of androsta-5,16-dien-3beta-ol into androsta-4,16-dien-3-one was shown to be reversible, NADH and NADPH being equally effective cofactors. 8. Pathways of biosynthesis of 5alpha-androst-16-en-3alpha- and 3beta-ols, with the C(19) 3-oxo steroids as intermediates, are presented.