The influence of obesity and consequent insulin resistance on coronary risk factors in medically treated patients with coronary disease.

OBJECTIVE: Obesity promotes the development and progression of coronary heart disease (CHD), in part, through its association with hyperlipidemia, hypertension, clotting abnormalities and insulin resistance. We assessed whether these relationships persist in patients with established CHD treated with evidence-based preventive pharmacologic therapies. DESIGN AND SUBJECTS: We performed a cross-sectional study of 74 adults with CHD and a body mass index (BMI) of >27 kg m(-2) (mean 32+/-4). The mean age of subjects was 64+/-9 years (range 44-84 years). MEASUREMENTS: Obesity measures included weight, BMI, waist, fat mass, intra-abdominal fat and subcutaneous fat. Risk factor measures included insulin sensitivity, fasting insulin level, lipid profiles, blood pressure, C-reactive protein (hs-CRP), plasminogen activator inhibitor (PAI-1) and platelet reactivity. Medication use included aspirin (99%), statin (84%), beta-blocker (71%), ACE inhibitor or blocker (37%) and clopidogrel (28%). RESULTS: There was no direct relationship between obesity parameters and risk factor measures of lipid concentrations, blood pressure, clotting abnormalities or platelet reactivity except for a modest relationship between visceral fat and hs-CRP (r=0.30, P=0.02). However, increased BMI, waist circumference, fat mass, total abdominal fat and abdominal subcutaneous fat all correlated with insulin sensitivity (r-values -0.30 to -0.45, P-values 0.01 to <0.001) and insulin concentrations. Insulin sensitivity, in turn, was the best predictor of PAI-1, triglycerides, high-density lipoprotein (HDL) levels, cholesterol/HDL levels (all P<0.01) and platelet reactivity (R=0.34, P=0.02). CONCLUSIONS: Use of preventive pharmacologic therapies obviated the expected relationship between adiposity and CHD risk factors. However, a residual effect of insulin resistance is left untreated. Total adiposity and central adiposity were strong predictors of insulin sensitivity, which in turn predicted cardiac risk factors such as lipid concentrations, PAI-1 and platelet reactivity. Thus, while evidence-based pharmacologic treatments may diminish the statistical relationship between obesity and many cardiac risk factors, adiposity negatively impacts CHD risk by reducing tissue insulin sensitivity.

Identification of SCAN dimerization domains in four gene families.

Zinc-finger transcription factors are often accompanied by modular sequence motifs such as the Kruppel-associated box (KRAB) and the SCAN domain. The KRAB domain mediates transcriptional repression while the SCAN domain mediates selective protein dimerization. The hypoalphalipoproteinemia susceptibility gene ZNF202 encodes a SCAN box and a KRAB domain followed by eight Cys2-His2 zinc-finger motifs. In order to identify the existence of genes which encode proteins of structural homology to ZNF202, a mouse lambda library was screened with a human ZNF202 cDNA probe. The isolated cDNA clones represented three SCAN-domain-encoding gene families. We purified three novel cDNAs that encode a SCAN-KRAB-(Cys2-His2)x domain alignment and one cDNA that encodes a SCAN-(Cys2-His2)x domain alignment. In addition, we identified one cDNA sequence with a predicted protein sequence containing a KRAB-SCAN-KRAB-(Cys2-His2)x domain alignment. Therefore, when combined with the recently discovered family of isolated SCAN-domain-encoding genes, four SCAN domain gene families can be distinguished. The consensus sequences for the murine SCAN and KRAB domains are highly conserved within the mammalian phylogenetic tree which may be useful in elucidating the biological function of these protein modules and the crucial residues responsible for their binding specificity.

Daily energy expenditure is related to plasma leptin concentrations in older African-American women but not men.

Recent research suggests that leptin may control body weight by regulating energy expenditure and energy intake in mice. To explore the possible role of leptin in the regulation of energy expenditure in humans, we used doubly-labeled water methodology to determine whether fasting plasma leptin concentrations were related to total daily energy expenditure (TEE) and its components, resting energy expenditure (REE) and physical activity energy expenditure (PAEE), in free-living older African-American men (n = 21) and women (n = 25). Plasma leptin concentrations were higher in women than men, even after the adjustment for differences in fat mass (28 +/- 3 ng/ml for women vs. 17 +/- 3 ng/ml for men; P < 0.01). The logarithm of plasma leptin concentrations correlated with fat mass in both women (r = 0.80) and men (r = 0.78) (P < 0.0001). After statistical adjustment for sex differences in fat-free mass and fat mass, women had lower TEE (22%) and REE (15%) (P < 0.01) and a trend (P = 0.08) toward lower PAEE, compared with men. After controlling for the effects of fat-free mass on energy expenditure, plasma leptin concentrations were related to REE (r = 0.68, P < 0.001) and tended to be related to TEE (r = 0.37, P = 0.07) in African-American women but not men (r = 0.18 and -0.03, respectively). Plasma leptin concentrations were not related to PAEE in either men or women. These results suggest that leptin may contribute to the regulation of TEE in older African-American women through its effects on resting energy metabolism, but the role of leptin in the regulation of energy expenditure is less apparent in older African-American men.

Evidence for a unique first position codon-anticodon mismatch in vivo.

The Ser68(AGC) codon of the beta-lactamase gene was changed to the glycine codons GGA and GGC. With glycine at position 68, beta-lactamase is inactive because it does not have a nucleophilic side-chain to function in the reaction mechanism. The mutant SG68(GGA) allele had no detectable beta-lactamase activity; however, the mutant SG68(GGC) did produce a small amount of activity. Both mutant alleles produce comparable amounts of beta-lactamase protein in a maxi-cell system. To identify why these two "same-sense" beta-lactamase mutants differ phenotypically, we introduced the alleles into Escherichia coli strains with mutations that affect translational fidelity. The rpsD mutation, which decreases fidelity, significantly increased activity with the SG68(GGC) allele, while the rpsL mutation, which increases translational fidelity, had little effect on the beta-lactamase activity. The rpsD and rpsL alleles had no effect on the SG68(GGA) allele. From the allele specificity of the activity produced by the bla mutants, and from the differential effect of translational fidelity on the activity of the SG68(GGC) allele, we infer that tRNA(GCU)Ser, the AGU/C reading tRNA(Ser), mistranslates SG68(GGC) at a frequency of about 0.1%, and subsequently produces active beta-lactamase. This is the first observation of an A/G wobble with a wild-type tRNA at the first position of the codon-anticodon interaction.

Physiological predictors of increasing total and central adiposity in aging men and women.

BACKGROUND: Increasing levels of total and central body fat with advancing age contribute to the development of cardiovascular and metabolic disease. We examined gender-related differences and physiological predictors of the rate of increase in total and central body fat in men and women. METHODS: We studied 427 healthy men (age range, 17 to 90 years) and 293 women (age range, 18 to 88 years). We measured body fatness by hydrostatic weighing, central adiposity from the waist circumference, peak volume of oxygen utilization (VO2) from a treadmill test, leisure time physical activity (LTA) from a questionnaire, resting metabolic rate and respiratory quotient from indirect calorimetry, and energy intake from 3-day food diaries. RESULTS: Fat mass increased with age, and the rate was greater in women (r = .61; slope = 0.25 kg/y; P < .01) than in men (r = .43; slope = 0.16 kg/y; P < .01). Increasing fat mass in men and women was most strongly associated with declines in peak VO2 and LTA. Controlling for these variables reduced the increase in fat mass from 17% to 3% per decade in men and from 26% to 5% per decade in women. The increase in waist circumference with age was also greater in women (r = .53; slope = 0.28 cm/y) than in men (r = .39; slope = 0.18 cm/y; P < .01). Increasing waist circumference with age in men and women was most strongly associated with declines in LTA and peak VO2, respectively. Control for these variables reduced the age-related increase in waist circumference from 2% to 1% per decade in men and from 4% to 1% per decade in women. We observed no independent contribution of resting metabolic rate, respiratory quotient, menopause status, energy, or macronutrient intake to the age-related increase in fat mass and waist circumference. CONCLUSIONS: Our findings suggest that (1) the age-related increase in fat mass and waist circumference is greater in women than in men and (2) the physiological characteristics that reflect a decline in physical activity-related energy expenditure, rather than resting energy expenditure, are important predictors of the increases in total and central fatness. Lifestyle changes that increase the level of physical activity may be advantageous in blunting age-related increases in total and central body fatness.

Sex hormone-binding globulin levels in middle-aged premenopausal women. Associations with visceral obesity and metabolic profile.

OBJECTIVE: Low sex hormone-binding globulin (SHBG) levels in women are associated not only with hyperinsulinemia, increased risk for cardiovascular disease, and type 2 diabetes but also with excess body fatness and abdominal obesity. We tested the hypothesis that an elevated total or intra-abdominal adipose tissue accumulation mediates the relationship between low SHBG levels and an altered metabolic profile. RESEARCH DESIGN AND METHODS: We measured body composition (dual-energy X-ray absorptiometry [DEXA]) and body fat distribution (computed tomography) in 52 middle-aged (46.7 +/- 0.4, mean +/- SEM) premenopausal women. Insulin and glucose responses to a 75-g oral glucose load and plasma lipid-lipoprotein levels were also measured. RESULTS: Low plasma SHBG concentrations were associated with increased total body fat mass (r = -0.41, P < 0.005) and subcutaneous abdominal (r = -0.39, P < 0.005) and intra-abdominal (r = -0.37, P < 0.008) adipose tissue area. Low SHBG was also associated with a greater insulin response to oral glucose (r = -0.40, P < 0.005), higher triglyceride levels (r = -0.29, P < 0.05), higher cholesterol/HDL cholesterol ratio (r = -0.51, P < 0.005), but lower HDL cholesterol concentrations (r = 0.65, P < 0.005). When matched for intra-abdominal fat or total fat mass, subjects with either low or high SHBG showed no difference in the insulin response to an oral glucose challenge. Statistical adjustment for differences in intra-abdominal adipose tissue accumulation or total body fat mass also eliminated the associations between SHBG levels and metabolic variables, with the exception of the association between SHBG and HDL cholesterol levels (r = 0.52, P < 0.005). CONCLUSIONS: Our results suggest that the previously reported relationship between low SHBG levels and increased metabolic disease risk in women is mediated, to a large extent, by concomitant variation in body fatness and intra-abdominal adipose tissue accumulation.

Effect of menopausal status on insulin-stimulated glucose disposal: comparison of middle-aged premenopausal and early postmenopausal women.

OBJECTIVE: Studies in animal models suggest that ovarian hormone deficiency is associated with the development of insulin resistance. In women, ovarian hormone levels are dramatically reduced after the menopause transition. However, the effect of the menopause transition on insulin sensitivity is unclear. Thus, we examined the effect of menopausal status on insulin sensitivity. RESEARCH DESIGN AND METHODS: Insulin-stimulated glucose disposal was measured in 43 middle-aged premenopausal women (47 +/- 3 years of age) during the luteal phase of the menstrual cycle and 40 early postmenopausal women (51 +/- 4 years; time since menopause, 21 +/- 13 months) using the hyperinsulinemic-euglycemic clamp technique. Body composition was measured by dual-energy X-ray absorptiometry and abdominal fat distribution by computed tomography RESULTS: No difference in fat-free mass (FFM) was found between groups. Total body (P < 0.01), subcutaneous abdominal (P < 0.05), and intra-abdominal (P < 0.01) adiposity were greater in postmenopausal women compared with premenopausal women. No differences in insulin-stimulated glucose disposal were found between premenopausal and postmenopausal women on an absolute basis (pre, 436 +/- 130 vs. post, 446 +/- 120 mg/min), when expressed relative to FFM (pre, 10.7 +/- 3.0 vs. post, 11.5 +/- 3.6 mg x kg(-1) FFM x min(-1)) or when statistically adjusted for FFM (pre, 436 +/- 125 vs. post, 445 +/- 126 mg/min). CONCLUSIONS: These results suggest that menopausal status does not affect insulin sensitivity, as measured by the hyperinsulinemic-euglycemic clamp technique.

Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy nonobese women.

OBJECTIVE: We examined the hypothesis that an age-related increase in the compartments of visceral fat would account, in part, for the deleterious changes in insulin sensitivity and blood lipid profile in nonobese women. RESEARCH DESIGN AND METHODS: We directly assessed visceral and subcutaneous abdominal adipose tissue areas (computed tomography), glucose disposal (hyperinsulinemic-euglycemic clamp), body composition (dual energy X-ray absorptiometry), blood-lipid profile, and aerobic fitness (VO2max) in 178 nonobese women categorized into four age groups: group 1, 28 +/- 4 years, n = 88; group 2, 46 +/- 2 years, n = 38; group 3, 53 +/- 2 years, n = 31; and group 4. 67 +/- 6 years, n = 21. RESULTS: Visceral abdominal adipose tissue area increased with age (2.36 cm2 per year, P < 0.0001). We noted an age-related increase in total cholesterol (P < 0.0003), triglycerides (P < 0.0009), LDL cholesterol (P < 0.027), and the ratio of total cholesterol to HDL cholesterol (P < 0.042). However, age-related changes in insulin sensitivity exhibited a different age-related pattern. That is, insulin sensitivity, expressed on an absolute basis or indexed per kilogram of fat-free mass, was lowest in group 4 but was not significantly different among groups 1, 2, and 3. After statistical control for visceral fat, lower insulin sensitivity persisted in group 4, although differences were diminished relative to other groups. However, the effect of visceral fat on age-related changes in the blood-lipid profile was stronger. That is, differences in visceral and deep subcutaneous adipose tissue area abolished age-related differences in total cholesterol, triglycerides, and LDL cholesterol. No independent effects of VO2max or leisure-time physical activity on age-related changes in insulin sensitivity or on the blood-lipid profile were noted. CONCLUSIONS: We conclude that 1) visceral fat shows an increase with advancing age, whereas a decrease in insulin sensitivity was noted only in older women; 2) age-related differences in visceral fat explain only a modest part of the decline in insulin sensitivity in nonobese women; and 3) unfavorable changes in plasma lipids were strongly associated with the age-related increase in visceral abdominal adipose tissue.

The pharmacophore of the human C5a anaphylatoxin.

We have determined which amino acids contribute to the pharmacophore of human C5a, a potent inflammatory mediator. A systematic mutational analysis of this 74-amino acid protein was performed and the effects on the potency of receptor binding and of C5a-induced intracellular calcium ion mobilization were measured. This analysis included the construction of hybrids between C5a and the homologous but unreactive C3a protein and site-directed mutagenesis. Ten noncontiguous amino acids from the structurally well-defined 4-helix core domain (amino acids 1-63) and the C-terminal arginine-containing tripeptide were found to contribute to the pharmacophore of human C5a. The 10 mostly charged amino acids from the core domain generally made small incremental contributions toward binding affinity, some of which were independent. Substitutions of the C-terminal amino acid Arg 74 produced the largest single effect. We also found the connection between these 2 important regions to be unconstrained.

Sodium-potassium pump activity contributes to the age-related decline in resting metabolic rate.

We examined the hypothesis that a decline in Na-K pump activity contributes to the lower resting metabolic rate (RMR) in older males, independent of the loss of fat-free mass. Plasma and erythrocyte Na and K concentrations were measured using flame photometry. Changes in these concentrations after incubation with and without ouabain were used to calculate erythrocyte Na-K pump rate and rate constant in 27 younger (28 +/- 7 yr) and 25 older (67 +/- 6 yr) men. Older men showed an 18% lower erythrocyte Na-K pump rate constant (0.32 +/- 0.09 vs. 0.39 +/- 0.10 h-1; P < 0.01), a 12% lower RMR (1.10 +/- 0.14 vs. 1.25 +/- 0.14 kcal/min; P < 0.01) and an 8% lower level of fat-free mass (61.7 +/- 5.8 vs. 67.4 +/- 8.1 kg; P < 0.01) relative to younger men. A lower RMR persisted in older men (1.14 +/- 0.12 kcal/min) compared to younger men (1.21 +/- 0.12 kcal/min; P < 0.05) after control for the effect of fat-free mass. No differences in RMR were found, however, between older (1.17 +/- 0.13 kcal/min) and younger men (1.20 +/- 0.13 kcal/min) after controlling for both fat-free mass and the erythrocyte Na-K pump rate constant. A positive relation was noted between RMR and the erythrocyte Na-K pump rate constant, after removing the effects of fat-free mass (partial r = 0.30; P < 0.05). Our results support the conclusions that: 1) the in vivo activity of the Na-K pump is related to RMR, and 2) the age-related reduction in Na-K pump activity is a partial contributor to the decline in RMR in older men.

Hormonal and physiological correlates of energy expenditure and substrate oxidation in middle-aged, premenopausal women.

An understanding of the hormonal and physiological correlates of energy expenditure and substrate oxidation in middle-aged women will increase our knowledge of factors that promote changes in energy balance and adiposity. We measured resting and postprandial energy expenditure and substrate oxidation in 59 middle-aged, premenopausal women (mean+/-sD age, 47+/-2 yr) to examine the hormonal and physiological correlates of energy and substrate metabolism. Energy expenditure and substrate oxidation were measured at rest using indirect calorimetry and urinary nitrogen excretion and for 180 min after the ingestion of a liquid meal (10 kcal/kg fat-free mass; 410+/-44 Cal). Fasting hormone levels were measured by RIA, glucose tolerance was determined by a 75-g oral glucose tolerance test, body composition was measured by dual energy x-ray absorptiometry, and peak aerobic capacity was determined by a treadmill test. Using stepwise regression analysis, we found that resting energy expenditure was predicted by fat-free mass and serum leptin concentration (r2 = 66%; P < 0.01), fat oxidation was predicted by resting energy expenditure (r2 = 17%; P < 0.01), and carbohydrate oxidation was predicted by serum leptin and appendicular skeletal muscle mass (r2 = 21%;P < 0.01). Novariables were related to postprandial energy expenditure or substrate oxidation. We conclude that in middle-aged, premenopausal women, variation in resting energy expenditure and substrate oxidation is primarily explained by fat-free mass and serum leptin levels. Thus, changes in metabolically active tissue mass or leptin concentration may partially contribute to changes in resting energy expenditure or substrate oxidation in middle-aged women.

Racial differences in plasma leptin concentrations in obese postmenopausal women.

Leptin may play an important role in the regulation of body weight by influencing energy intake and expenditure. Differences in body composition, resting energy expenditure (REE), and physical activity between African-American and Caucasian women could be reflective of racial differences in plasma leptin concentrations. Thus, we examined racial differences in leptin levels and the relationships of leptin to body composition and resting metabolism in obese postmenopausal African-American (n = 28) and Caucasian (n = 29) women matched for level of body fat. African-American and Caucasian women were similar in age (64.1 +/- 1.3 vs. 63.2 +/- 1.0 yr), body weight (84.7 +/- 3.3 vs. 80.4 +/- 1.3 kg), adipose tissue mass (39.7 +/- 2.8 vs. 38.0 +/- 1.0 kg), waist to hip ratio (0.81 +/- 0.02 vs. 0.81 +/- 0.01), and maximal aerobic capacity (1.5 +/- 0.05 vs. 1.6 +/- 0.05 L/min). African-American women had greater lean tissue mass than Caucasian women (41.8 +/- 1.1 vs. 39.3 +/- 0.6 kg; P = 0.05). The leptin concentration was 20% lower in African-American than Caucasian women (36.0 +/- 4.8 vs. 45.8 +/- 3.5; P < 0.05), whereas REE values were similar. Leptin correlated strongly with percent body fat in African-American (r = 0.71; P < 0.0001) and Caucasian women (r = 0.61; P < 0.001) and with REE in African-American (r = 0.58; P < 0.001), but not Caucasian, women (r = 0.08). These findings suggest racial differences in plasma leptin levels and in leptin's role in the regulation of REE, which may play a role in the greater incidence of obesity in the African-American compared to the Caucasian population.

Regulation of protein metabolism in middle-aged, premenopausal women: roles of adiposity and estradiol.

The age-related loss of fat-free mass (FFM) is accelerated in women during the middle-age years and continues at an increased rate throughout the postmenopausal period. Because protein is the primary structural component of fat-free tissue, changes in FFM are largely due to alterations in protein metabolism. Knowledge of the hormonal and physiological correlates of protein metabolism in middle-aged women, therefore, has important implications for understanding the mechanisms underlying changes in FFM. We measured leucine kinetics (expressed relative to FFM: micromol/kg FFM/h) in 46 middle-aged, premenopausal women (mean +/- SD, 47 +/- 3 yr) after an overnight fast (i.e. basal) and during euglycemic hyperinsulinemia (40 mU/m2/min) using a 5.5-h infusion of [1-13C]leucine. Additionally, we measured insulin-stimulated glucose disposal by euglycemic hyperinsulinemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution by computed tomography, and hormone levels by RIA as possible correlates of protein metabolism. Under basal conditions, stepwise regression analysis showed that leucine appearance (i.e. protein breakdown) was related to percent body fat and serum estradiol (r2 = 40%; P < 0.01), and leucine oxidation was related to serum estradiol and percent body fat (r2 = 26%; P < 0.05). Under euglycemic hyperinsulinemic conditions, no variables correlated with the percent change in leucine appearance. The percent change in leucine oxidation was related to intraabdominal adipose tissue area and glucose disposal rate (r2 = 48%; P < 0.01). Correlates and r2 values for nonoxidative leucine disposal (i.e. protein synthesis) under basal and euglycemic hyperinsulinemic conditions were similar to those observed for leucine appearance. From these results, we conclude that adiposity and/or serum estradiol may contribute to the regulation of protein metabolism and FFM in middle-aged, premenopausal women.

Energy requirements and physical activity of older free-living African-Americans: a doubly labeled water study.

We examined daily energy requirements and determinants of physical activity in older, free-living African-American women (n = 37; age, 64 +/- 8 yr) and men (n = 28; age, 64 +/- 7 yr). Total daily energy expenditure and its components [i.e. resting metabolic rate (RMR) and physical activity energy expenditure] were determined using doubly labeled water and indirect calorimetry. Body composition from dual energy x-ray absorptiometry, maximal oxygen consumption from a graded treadmill test, and leisure time physical activity from a structured interview were determined. Total daily energy expenditure adjusted for body composition was lower (P < 0.05) for women (2198 +/- 621 kcal/d) than for men (2633 +/- 669 kcal/d) due to a lower RMR (1431 +/- 240 vs. 1576 +/- 259 kcal/d; P = 0.07) and physical activity energy expenditure (548 +/- 559 vs. 794 +/- 603 kcal/d; P = 0.19), respectively. The physical activity level ratio (i.e. total daily energy expenditure/RMR) was not different from Food and Agriculture Organization/World Health Organization/United Nations University recommendations (i.e. 1.51) for women (1.51 +/- 0.25), but was higher for men (1.71 +/- 0.32). The strongest correlates with physical activity energy expenditure were age for women (r = -0.44; P < 0.01) and maximal oxygen consumption for men (r = 0.39; P < 0.05). These data show that daily energy requirements are significantly lower in African-American women compared to men, primarily due to lower levels of physical activity energy expenditure. Furthermore, lower levels of cardiovascular fitness in men and advancing age in women are associated with lower physical activity energy expenditure.

Mathematical ratios lead to spurious conclusions regarding age- and sex-related differences in resting metabolic rate.

Resting metabolic rate (RMR) data have been normalized by dividing RMR by fat-free mass (FFM) (ie, ratio method), or by using a regression-based approach. We compared both data-normalization procedures on age- and sex-related differences in RMR. The ratio method showed no differences in adjusted RMR between older men (0.084 +/- 0.004 kJ.FFM-1.min-1) and younger men (0.082 +/- 0.003 kJ.FFM-1.min-1), whereas analysis of covariance showed a lower (P < 0.01) adjusted RMR in older men (4.81 +/- 0.04 kJ/min) than in younger men (5.14 +/- 0.04 kJ/min). In another example, the ratio method showed that women had a higher (P < 0.05) adjusted RMR (0.10 +/- 0.004 kJ/min) than did men (0.08 +/- 0.003 kJ/min), whereas analysis of covariance showed a lower (P < 0.01) adjusted RMR in women (4.45 +/- 0.03 kJ/min) than in men (4.62 +/- 0.03 kJ/min). The ratio method provides misleading conclusions regarding sex- and age-related differences in RMR when compared with a regression-based approach.

Free-living daily energy expenditure in patients with Parkinson's disease.

Previous studies have suggested that elevated resting energy expenditure contributes to weight loss in patients with Parkinson's disease (PD). Body weight is, however, ultimately determined by variation in daily energy expenditure and not just resting energy expenditure. Therefore, we examined the hypothesis that PD patients are characterized by elevated daily energy expenditure. Sixteen patients with levodopa responsive PD and 46 healthy elderly controls were characterized for daily energy expenditure and its components (resting and physical activity energy expenditure) using a combination of the doubly labeled water technique (over 10 days) and resting indirect calorimetry. Fat-free mass and fat mass were measured by dual energy x-ray absorptiometry. Results showed that fat mass and fat-free mass did not differ between groups. Daily energy expenditure was 15% lower (2214 +/- 460 vs. 2590 +/- 497 kcal/d; p < 0.01) in PD patients compared to controls. This was primarily due to lower physical activity energy expenditure (339 +/- 366 vs. 769 +/- 412 kcal/d; P < 0.01) in PD patients as resting energy expenditure was not different between groups (1655 +/- 283 vs. 1561 +/- 219 kcal/d). These results show that daily energy expenditure is lower in PD patients compared to healthy elderly, primarily due to reduced physical activity energy expenditure. These results argue against the hypothesis that an abnormally elevated daily energy expenditure contributes to weight loss in PD.

Daily energy expenditure in free-living non-institutionalized Alzheimer's patients: a doubly labeled water study.

Weight loss is common in Alzheimer's disease (AD), but its pathogenesis is poorly understood. It is unclear whether an elevated daily energy expenditure contributes to the weight loss. We tested the hypothesis that daily energy expenditure is higher in AD patients compared to healthy elderly. Thirty AD (73 +/- 8 years; Mini-Mental State Examination score: 16 +/- 8) and 103 healthy elderly (69 +/- 7 years) were characterized for daily energy expenditure and its components (resting and free-living physical activity energy expenditure) from doubly labeled water and indirect calorimetry. Fat-free mass and fat mass were measured from dual energy X-ray absorptiometry. Fat-free mass tended to be lower in AD patients (45 +/- 9 kg) versus healthy elderly (49 +/- 10 kg; p = 0.07), whereas no differences were noted in fat mass between groups. Daily energy expenditure was 14% lower in AD (1901 +/- 517 kcal/d) compared to healthy elderly (2213 +/- 513 kcal/d; p < 0.001), due to lower resting (1287 +/- 227 versus 1418 +/- 246 kcal/d; p < 0.01) and physical activity energy expenditures (425 +/- 317 versus 574 +/- 342 kcal/d; p < 0.05). No differences in energy expenditure were noted between groups after controlling for differences in body composition. Daily energy expenditure was examined in a subgroup (n = 11) of AD patients who lost significant body weight (5.6 +/- 2.3 kg) within the past year. There was a lower daily energy expenditure in cachectic AD patients (1799 +/- 474 kcal/d) versus non-cachectic patients (1960 +/- 544 kcal/d) and healthy elderly (2213 +/- 513 kcal/d; p < 0.01). Similarly, no differences in energy expenditure were noted between groups after controlling for differences in body composition. We conclude that absolute levels of daily energy expenditure are lower in AD patients due to their lower body mass. However, after taking into account differences in body composition, daily energy expenditure in AD patients is appropriate for their metabolic size. The hypothesis that elevated daily energy expenditure contributes to weight loss in AD is not supported by these findings.

Relationship between physical activity and HDL-cholesterol in healthy older men and women: a cross-sectional and exercise intervention study.

We used cross-sectional and exercise intervention studies to examine whether physical activity levels or increases in peak aerobic capacity (peak VO2) explain variation in high density lipoprotein cholesterol (HDL-C) levels in older men and women. In the cross-sectional study, 307 older individuals (169 men; 138 women; 67 +/- 7 years) were characterized for HDL-C, leisure time physical activity, peak VO2, body composition, body fat distribution and dietary intake. HDL-C was 19% higher (P < 0.001) in women (57 +/- 14 mg/dl) versus men (48 +/- 14 mg/dl). Thirty-two percent of the variation in HDL-C in older men was explained by the waist circumference (r2 = 16%), percent dietary intake of alcohol (r2 = 11%), and carbohydrate (r2 = 6%). Waist circumference was also the best predictor of HDL-C in older women, (r2 = 7%); with percent dietary intake of carbohydrate adding an additional 6% to the model. Neither peak VO2 nor leisure time physical activity were independent predictors of HDL-C. Statistical control for the aforementioned variables diminished, but did not abolish gender differences in HDL-C. Thirty-seven older individuals (23 men; 14 women) participated in a 2-month exercise program in which individuals by week eight were expending approximately 900 kcal per week in exercise energy expenditure. Subjects were maintained in energy balance throughout the exercise program. Endurance training significantly increased peak VO2 by 15% in both men and women, and by design, body composition and body fat distribution did not change. No changes in HDL-C levels were noted. In conclusion, variations in leisure time physical activity or increases in peak VO2 are not independent predictors of HDL-C levels in healthy older men and women. Instead, central adiposity, as estimated by the waist circumference, and to a lesser extent, dietary intake of carbohydrate and alcohol, are significant predictors of variation in plasma HDL-C levels. Furthermore, short-term exercise training, generating less than 900 kcal per week in exercise energy expenditure, in the absence of weight loss, fails to influence HDL-C levels.

Skeletal muscle atrophy and peak oxygen consumption in heart failure.

We measured skeletal muscle mass and peak oxygen consumption (VO2) in 13 cachectic heart failure patients, 14 noncachectic patients, and in 52 healthy controls to examine skeletal muscle atrophy and its relation to low peak VO2 in heart failure patients. Our results show that skeletal muscle atrophy is associated with prior weight loss and is related to low peak VO2 in heart failure patients.

Energy expenditure and symptom severity in men with heart failure.

Our results demonstrate a graded increase in resting metabolic rate based on symptom severity as reflected in the New York Heart Association classification. This finding supports the hypothesis that clinical severity of illness corresponds to the magnitude of the increase in resting energy demands.