Oxidative costs of reproduction: Oxidative stress in mice fed standard and low antioxidant diets.

Lactation is one of the most energetically expensive behaviours, and trade-offs may exist between the energy devoted to it and somatic maintenance, including protection against oxidative damage. However, conflicting data exist for the effects of reproduction on oxidative stress. In the wild, a positive relationship is often observed, but in laboratory studies oxidative damage is often lower in lactating than in non-breeding animals. We hypothesised that this discrepancy may exist because during lactation food intake increases many-fold resulting in a large increase in the intake of dietary antioxidants which are typically high in laboratory rodent chow where they are added as a preservative. We supplied lactating and non-breeding control mice with either a standard or low antioxidant diet and studied how this affected the activity of endogenous antioxidants (catalase, superoxide dismutase; SOD, and glutathione peroxidise; GPx) and oxidative damage to proteins (protein carbonyls, PC) in liver and brain tissue. The low antioxidant diet did not significantly affect activities of antioxidant enzymes in brain or liver, and generally did not result in increased protein damage, except in livers of control mice on low antioxidant diet. Catalase activity, but not GPx or SOD, was decreased in both control and lactating mice on the low antioxidant diet. Lactating mice had significantly reduced oxidative damage to both liver and brain compared to control mice, independent of the diet they were given. In conclusion, antioxidant content of the diet did not affect oxidative stress in control or reproductive mice, and cannot explain the previously observed reduction in oxidative stress in lactating mammals studied in the laboratory. The reduced oxidative stress in the livers of lactating mice even under low antioxidant diet treatment was consistent with the 'shielding' hypothesis.

Genetic association analysis of 30 genes related to obesity in a European American population.

OBJECTIVE: Obesity, which is frequently associated with diabetes, hypertension and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). METHODS: We reanalyzed 355 common genetic variants of 30 candidate genes in seven molecular pathways related to obesity in 1982 unrelated European Americans from the New York Cancer Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates, including age, age(2), gender and diabetes status. The single-nucleotide polymorphisms (SNPs) were modeled as additive effects. RESULTS: With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: ghrelin (GHRL; rs35683), agouti-related peptide (AGRP; rs5030980), carboxypeptidase E (CPE; rs1946816 and rs4481204), glucagon-like peptide-1 receptor (GLP1R; rs2268641), serotonin receptors (HTR2A; rs912127), neuropeptide Y receptor (NPY5R;Y5R1c52), suppressor of cytokine signaling 3 (SOCS3; rs4969170) and signal transducer and activator of transcription 3 (STAT3; rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. CONCLUSION: Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake, and thus these associations are mechanistically plausible in this context.

Body mass index and mortality rate among Hispanic adults: a pooled analysis of multiple epidemiologic data sets.

OBJECTIVE: To evaluate the association between body mass index (BMI, kg m⁻²) and mortality rate among Hispanic adults. METHODS AND PROCEDURES: Analysis of five data sets (total N=16,798) identified after searching for publicly available, prospective cohort data sets containing relevant information for at least 500 Hispanic respondents (≥18 years at baseline), at least 5 years of mortality follow-up, and measured height and weight. Data sets included the third National Health and Nutrition Examination Survey, the Puerto Rico Heart Health Program (PRHHP), the Hispanic Established Population for Epidemiologic Studies of the Elderly (HEPESE), the San Antonio Heart Study (SAHS) and the Sacramento Area Latino Study on Aging. RESULTS: Cox proportional hazards regression models, adjusting for sex and smoking, were fit within three attained-age strata (18 to younger than 60 years, 60 to younger than 70 years, and 70 years and older). We found that underweight was associated with elevated mortality rate for all age groups in the PRHHP (hazard ratios [HRs]=1.38-1.60) and the SAHS (HRs=1.88-2.51). Overweight (HRs=0.38 and 0.84) and obesity grade 2-3 (HRs=0.75 and 0.60) associated with reduced mortality rate in the HEPESE dataset for those in the 60 to younger than 70 years, and 70 years and older attained-age strata. Weighted estimates combining the HRs across the data sets revealed a similar pattern. CONCLUSION: Among Hispanic adults, there was no clear evidence that overweight and obesity associate with elevated mortality rate.

Putative contributors to the secular increase in obesity: exploring the roads less traveled.

OBJECTIVE: To investigate plausible contributors to the obesity epidemic beyond the two most commonly suggested factors, reduced physical activity and food marketing practices. DESIGN: A narrative review of data and published materials that provide evidence of the role of additional putative factors in contributing to the increasing prevalence of obesity. DATA: Information was drawn from ecological and epidemiological studies of humans, animal studies and studies addressing physiological mechanisms, when available. RESULTS: For at least 10 putative additional explanations for the increased prevalence of obesity over the recent decades, we found supportive (although not conclusive) evidence that in many cases is as compelling as the evidence for more commonly discussed putative explanations. CONCLUSION: Undue attention has been devoted to reduced physical activity and food marketing practices as postulated causes for increases in the prevalence of obesity, leading to neglect of other plausible mechanisms and well-intentioned, but potentially ill-founded proposals for reducing obesity rates.

Association of K121Q polymorphism in ENPP1 (PC-1) with BMI in Caucasian and African-American adults.

OBJECTIVE: To test for association of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) K121Q polymorphism with body mass index (BMI) and diabetes in a large sample of Caucasians and African-Americans by selectively genotyping individuals at the extremes of the phenotypic distribution. SUBJECTS: Subsets comprising the extremes of the BMI distribution (10th-20th and above the 90th BMI percentile for Caucasians and between the 10th-30th and above the 80th percentile for African-Americans) from a group of 10,260 Caucasian and 2268 African-American adults participating in New York Cancer Project were studied. METHODS: Subjects were genotyped for the ENPP1 K121Q polymorphism by pyrosequencing and tested for association with BMI and diabetes by regression analysis. RESULTS: Regression analysis with BMI as the dependent variable demonstrated a significant association (P = 0.02) of genotype at K121Q with BMI, with no significant race-by-genotype interaction (P = 0.30). Compared with Q/Q or Q/K individuals, the K/K individuals had a BMI approximately 1.3 kg/m2 higher, without effects of age, gender or race. By logistic regression analysis, the K121Q alleles had no significant effect on diabetes status (P = 0.37) in obese subjects. CONCLUSION: In both Caucasians and African-Americans, the K121 polymorphism in ENPP1 was associated with increased BMI, but not with diabetes.

PYY3-36 as an anti-obesity drug target.

The neuropeptide Y (NPY)/peptide YY (PYY) system has been implicated in the physiology of obesity for several decades. More recently ignited enormous interest in PYY3-36, an endogenous Y2-receptor agonist, as a promising anti-obesity compound. Despite this interest, there have been remarkably few subsequent reports reproducing or extending the initial findings, while at the same time studies finding no anti-obesity effects have surfaced. Out of 41 different rodent studies conducted (in 16 independent labs worldwide), 33 (83%) were unable to reproduce the reported effects and obtained no change or sometimes increased food intake, despite use of the same experimental conditions (i.e. adaptation protocols, routes of drug administration and doses, rodent strains, diets, drug vendors, light cycles, room temperatures). Among studies by authors in the original study, procedural caveats are reported under which positive effects may be obtained. Currently, data speak against a sustained decrease in food intake, body fat, or body weight gain following PYY3-36 administration and make the previously suggested role of the hypothalamic melanocortin system unlikely as is the existence of PYY deficiency in human obesity. We review the studies that are in the public domain which support or challenge PYY3-36 as a potential anti-obesity target.

Obesity and prostate cancer screening in the USA.

OBJECTIVE: To estimate the association between body mass index (BMI: kg/m2) and prostate-specific antigen (PSA) cancer screening in a nationally representative sample of US men aged 50 years and older using data from the 2001 Behavioral Risk Factor Surveillance Survey. RESPONDENTS: Men aged 50 years or older classified by BMI as healthy weight range (18.5-24.9), overweight (25-29.9), obese class I (30-34.9), obese class II (35-39.9), and obese class III (> or =40). OUTCOME MEASURES: Interval since most recent screening for PSA. RESULTS: Adjusting for age, race, smoking, education, employment, income and health insurance status, we found that, compared with men in the healthy weight range, men in the overweight [odds ratio (OR)=1.13; 95% confidence interval (95% CI)=1.04-1.35], obese class I (OR=1.26; 95% CI=1.06-1.36) and obese class II (OR=1.14, 95% CI=1.02-1.26) categories were significantly more likely to have obtained a PSA test within the previous year. A similar pattern was observed when we examined other screening intervals (e.g. within past 2 years, within past 3 years, etc.). CONCLUSIONS: Among men aged 50 years and older, overweight and obesity is associated with obtaining a PSA test.

Single-nucleotide polymorphisms in the C-reactive protein (CRP) gene promoter that affect transcription factor binding, alter transcriptional activity, and associate with differences in baseline serum CRP level.

To investigate whether functional polymorphisms exist in the C-reactive protein (CRP) gene, i.e., ones that contribute directly to differences in baseline CRP among individuals, we sequenced a 1,156-nucleotide-long stretch of the CRP gene promoter in 287 ostensibly healthy people. We identified two single-nucleotide polymorphisms (SNPs), a bi-allelic one at nucleotide -409 (G-->A), and a tri-allelic one at -390 (C-->T-->A), both resident within the hexameric core of transcription factor binding E-box elements. Electrophoretic mobility shift assays confirmed that the SNP within the sequence (-412)CACGTG(-407) (E-box 1) modulates transcription factor binding, and that the one within (-394)CACTTG(-389) (E-box 2) supports transcription factor binding only when the -390 T allele is present. The commonest of four E-box 1/E-box 2 haplotypes (-409G/-390T) identified in the population supported highest promoter activity in luciferase reporter assays, and the rarest one (-409A/-390T) supported the least. Importantly, serum CRP in people with these haplotypes reproduced this rank order, i.e., people with the -409G/-390T haplotype had the highest baseline serum CRP (mean +/- SEM 10.9 +/- 2.25 microg/ml) and people with the -409A/-390T haplotype had the lowest (5.01 +/- 1.56 microg/ml). Furthermore, haplotype-associated differences in baseline CRP were not due to differences in age, sex, or race, and were still apparent in people with no history of smoking. At least two other SNPs in the CRP promoter lie within E-box elements (-198 C-->T, E-box 4, and -861 T-->C, E-box 3), indicating that not only is the quality of E-box sites in CRP a major determinant of baseline CRP level, but also that the number of E-boxes may be important. These data confirm that the CRP promoter does encode functional polymorphisms, which should be considered when baseline CRP is being used as an indicator of clinical outcome. Ultimately, development of genetic tests to screen for CRP expression variants could allow categorization of healthy people into groups at high versus low future risk of inflammatory disease.

Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids.

BACKGROUND: Human adenovirus-36 (Ad-36) increases adiposity and paradoxically lowers serum cholesterol and triglycerides in chickens, mice, and non-human primates. The role of Ad-36 in human obesity is unknown. OBJECTIVES: To determine the prevalence of Ad-36 antibodies in obese and nonobese humans. To evaluate the association of Ad-36 antibodies with body mass index (BMI) and serum lipids. DESIGN: Cohort study. Volunteers from obesity treatment programs, communities, and a research study. SUBJECTS: Obese and nonobese volunteers at the University of Wisconsin, Madison, WI, and the Bowen Center, Naples, Florida. Obese and thin volunteer research subjects and 89 twin pairs at Columbia University, New York. INTERVENTIONS: Study 1: 502 subjects; serum neutralization assay for antibodies to Ad-2, Ad-31, Ad-36, and Ad-37; serum cholesterol and triglycerides assays. Study 2: BMI and %body fat in 28 twin pairs discordant for Ad-36 antibodies. MAIN OUTCOME MEASURES: Presence of antibodies to adenoviruses, BMI, serum cholesterol and triglycerides levels. RESULTS: Significant (P < 0.001) association of obesity and positive Ad-36 antibody status, independent of age, sex, and collection site. Ad-36 antibodies in 30% of obese, 11% of nonobese. Lower serum cholesterol and triglycerides (P < 0.003) in Ad-36 antibody-positive vs -negative subjects. Twin pairs: antibody-positive twins had higher BMIs (24.5+/-5.2 vs 23.1+/-4.5 kg/m2, P < 0.03) and %body fat (29.6+/-9.5% vs 27.5+/-9.9%, P < 0.04). No association of Ad-2, Ad-31, or Ad-37 antibodies with BMI or serum lipids. CONCLUSIONS: Ad-36 is associated with increased body weight and lower serum lipids in humans. Prospective studies are indicated to determine if Ad-36 plays a role in the etiology of human obesity.

Differential associations of body mass index and adiposity with all-cause mortality among men in the first and second National Health and Nutrition Examination Surveys (NHANES I and NHANES II) follow-up studies.

OBJECTIVE: The frequently observed U-shaped relationship between body mass index (BMI; kg/m(2)) and mortality rate may be due to the opposing effects of fat mass (FM) and fat-free mass (FFM) components of BMI on mortality rate. The purpose is to test the hypothesis stated above. DESIGN: Longitudinal prospective cohort studies. The mortality follow-up of the first and second National Health and Nutrition Examination Surveys (NHANES I and NHANES II). SUBJECTS: A total of 10 169 male subjects aged 25-75 who participated in NHANES I and II were selected for analyses. Follow-up continued until 1992. The mean follow-up time was 14.6 y for NHANES I and 12.9 y for NHANES II. Ninety-eight percent of the participants were successfully followed representing a total of 3722 deaths. MEASUREMENTS: Subscapular and triceps skinfolds thickness were used as FM indicators, whereas upper arm circumference was used as a FFM indicator. The Cox proportional hazards model tested the relationships of BMI, FM and FFM with all-cause mortality adjusting for age, smoking status, race and education levels. RESULTS: BMI had a U-shaped relationship with mortality, with a nadir of approximately 27 kg/m(2). However, when indicators of FM and FFM were added to the model, the relationship between BMI and mortality became more nearly monotonic increasing. Moreover, the relationship between FM indicator and mortality was monotonic increasing and the relationship between FFM indicator and mortality was monotonic decreasing. CONCLUSION: These results support the hypothesis that the apparently deleterious effects of marked thinness may be due to low FFM and that, over the observed range of the data, marked leanness (as opposed to thinness) has beneficial effects.

Body weight and cancer screening among women.

Obesity increases cancer risk, yet small-scale surveys indicate that obese women delay or avoid cancer screening even more so than do nonobese women. We sought to estimate the association between body mass index (BMI) (kg/m(2)) and delayed cancer screening among adult women in a population-based survey. Subjects were women classified by BMI as underweight (<18.5), desirable weight (18.5-24.9), overweight (25-29.9), obese class I (30-34.9), obese class II (35-39.9), and obese class III (> or =40). Outcome measures were intervals (0 for < or =2 years versus 1 for >2 years) since most recent screening for Papanicolaou (Pap) smear, mammography, and clinical breast examination (CBE). Adjusting for age, race, smoking, and health insurance, we observed J-shaped associations between BMI and screening. Compared with desirable weight women, underweight women (odds ratios [OR] = 1.21, 95% confidence interval [95% CI] 1.09-1.34), overweight women (OR = 1.13, 95% CI 1.07-1.18), and obese women (OR range 1.22-1.69) were significantly more likely to delay Pap smear testing for >2 years. Underweight (OR = 1.32, 95% CI 1.13-1.54), obesity class I (OR = 1.12, 95% CI 1.02-1.23), and obesity class III women (OR = 1.32, 95% CI 1.10-1.54) were more likely to delay mammography, and overweight (OR = 1.10, 95% CI 1.01-1.19), obesity class I (OR = 1.18, 95% CI 1.08-1.30), and obesity class III women (OR = 1.47, 95% CI 1.23-1.75) were more likely to delay CBE. White women were more likely to delay CBE as a function of BMI than were non-white women. Weight may be an important correlate of cancer screening behavior, particularly for white women.

Metabolic disharmony and mortality.

The concept of 'metabolic harmony' is introduced and conceptualized as the state in which indices of metabolic activity (i.e., serum glucose, cholesterol, systolic and diastolic blood pressure, body mass index) within an individual attain their expected values given the individual values on related variables. Its complement, 'metabolic disharmony' (i.e., the extent to which an individual's 'profile' of metabolic variables is jointly unusual in relation to their expected values) is operationalized via Mahalanbis' D(2 )statistic calculated on these indices of metabolic activity (plus age and sex). Analysis of a large (N = 5209) longitudinal (32 years) cohort study shows that, independent of the linear and quadratic effects of the aforementioned metabolic variables, the disharmony index (DI) significantly and strongly predicted hazard of death (chi(2)(1) = 20.05, P < 0.00005). That is, each 10 percentile increase in DI was associated with a 6.9% increase in the hazard rate. The association of DI to hazard rate was not materially altered when potential confounders (e.g., smoking status) were added to the model or when all subjects were included by imputing missing data. These results demonstrate that metabolic disharmony is associated with, and may cause, an increased hazard of death.

Annual deaths attributable to obesity in the United States.

CONTEXT: Obesity is a major health problem in the United States, but the number of obesity-attributable deaths has not been rigorously estimated. OBJECTIVE: To estimate the number of deaths, annually, attributable to obesity among US adults. DESIGN: Data from 5 prospective cohort studies (the Alameda Community Health Study, the Framingham Heart Study, the Tecumseh Community Health Study, the American Cancer Society Cancer Prevention Study I, and the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study) and 1 published study (the Nurses' Health Study) in conjunction with 1991 national statistics on body mass index distributions, population size, and overall deaths. SUBJECTS: Adults, 18 years or older in 1991, classified by body mass index (kg/m2) as overweight (25-30), obese (30-35), and severely obese (>35). MAIN OUTCOME MEASURE: Relative hazard ratio (HR) of death for obese or overweight persons. RESULTS: The estimated number of annual deaths attributable to obesity varied with the cohort used to calculate the HRs, but findings were consistent overall. More than 80% of the estimated obesity-attributable deaths occurred among individuals with a body mass index of more than 30 kg/m2. When HRs were estimated for all eligible subjects from all 6 studies, the mean estimate of deaths attributable to obesity in the United States was 280184 (range, 236111-341153). Hazard ratios also were calculated from data for nonsmokers or never-smokers only. When these HRs were applied to the entire population (assuming the HR applied to all individuals), the mean estimate for obesity-attributable death was 324 940 (range, 262541-383410). CONCLUSIONS: The estimated number of annual deaths attributable to obesity among US adults is approximately 280000 based on HRs from all subjects and 325000 based on HRs from only nonsmokers and never-smokers.

Meta-analysis of the effect of excluding early deaths on the estimated relationship between body mass index and mortality.

OBJECTIVES: Prospective cohort studies typically observe U- or J-shaped relationships between body mass index (BMI) (kg/m2) and mortality. However, some studies suggest that the elevated mortality at lower BMIs is due to confounding by pre-existing occult disease and recommend eliminating subjects who die during the first several (k) years of follow-up. This meta-analysis tests the effects of such early death exclusion on the BMI-mortality association. RESEARCH METHODS AND PROCEDURES: Studies identified from MEDLINE, review articles, ancestry analyses, and the "invisible college." INCLUDED STUDIES: 1) measured relative body weight at baseline; 2) included at least 1000 subjects; 3) reported results with and without early-death exclusion, or relevant data; and 4) did not study exclusively diseased populations. Blank tables were mailed to 131 investigators covering 59 databases. Completed tables (n = 16 databases), electronic raw data (n = 7 databases), and original articles (n = 6 databases) provided final data. Meta-analytic regressions compared the BMI-mortality association with and without early death exclusion. The sample included 29 studies and 1,954,345 subjects. RESULTS: The effect of eliminating early deaths was statistically significant but minuscule in magnitude. Implementation of early death exclusion was estimated to shift the BMI associated with minimum mortality only 0.4 units for men and 0.6 units for women at age 50. Even at a BMI 16, the estimated relative risk (compared to BMI 25) decreased only 0.008 units for men and 0.076 units for women at age 50. DISCUSSION: Results indicate that either pre-existing disease does not confound the BMI-mortality association or eliminating early deaths is inefficient for reducing that confounding.

Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent: a randomized controlled trial.

CONTEXT: Hydroxycitric acid, the active ingredient in the herbal compound Garcinia cambogia, competitively inhibits the extramitochondrial enzyme adenosine triphosphate-citrate (pro-3S)-lyase. As a citrate cleavage enzyme that may play an essential role in de novo lipogenesis inhibition, G cambogia is claimed to lower body weight and reduce fat mass in humans. OBJECTIVE: To evaluate the efficacy of G cambogia for body weight and fat mass loss in overweight human subjects. DESIGN: Twelve-week randomized, double-blind, placebo-controlled trial. SETTING: Outpatient weight control research unit. PARTICIPANTS: Overweight men and women subjects (mean body mass index [weight in kilograms divided by the square of height in meters], approximately 32 kg/m2). INTERVENTION: Subjects were randomized to receive either active herbal compound (1500 mg of hydroxycitric acid per day) or placebo, and both groups were prescribed a high-fiber, low-energy diet. The treatment period was 12 weeks. Body weight was evaluated every other week and fat mass was measured at weeks 0 and 12. MAIN OUTCOME MEASURES: Body weight change and fat mass change. RESULTS: A total of 135 subjects were randomized to either active hydroxycitric acid (n = 66) or placebo (n = 69); 42 (64%) in the active hydroxycitric acid group and 42 (61%) in the placebo group completed 12 weeks of treatment (P = .74). Patients in both groups lost a significant amount of weight during the 12-week treatment period (P<.001); however, between-group weight loss differences were not statistically significant (mean [SD], 3.2 [3.3] kg vs 4.1 [3.9] kg; P = .14). There were no significant differences in estimated percentage of body fat mass loss between treatment groups, and the fraction of subject weight loss as fat was not influenced by treatment group. CONCLUSIONS: Garcinia cambogia failed to produce significant weight loss and fat mass loss beyond that observed with placebo.

Body weight and health care among women in the general population.

OBJECTIVE: To examine the relation between body mass index ([BMI] calculated as weight in kilograms divided by the square of height in meters) and the use of medical care services among a nationally representative sample of women. DESIGN AND SETTING: Multistage cluster-area probability sampling survey. Data are from the Cancer Control and Health Insurance supplements of the 1992 National Health Interview Survey conducted by the National Center for Health Statistics. Respondents were 6981 women aged 18 years or older residing in the United States who self-reported sociodemographic information and the use of health care services. MAIN OUTCOME MEASURES: Interval (< or = 3 years vs > 3 years) since most recent mammography, clinical breast examination, gynecologic examination, and Papanicolaou smear and the number of physician visits in the year before the survey. RESULTS: When age, race, income, education, smoking, and health insurance status were adjusted for, the BMI was directly related to delaying clinical breast examinations, gynecologic examinations, and Papanicolaou smears. Obese women (BMI of 35) were more likely than nonobese women (BMI of 25) to delay clinical breast examinations (odds ratio, 1.26; 95% confidence interval, 1.00-1.58), gynecologic examinations (odds ratio, 1.39; 95% confidence interval, 1.15-1.69), and Papanicolaou smears (odds ratio, 1.29; 95% confidence interval, 1.04-1.58). The BMI was not significantly related to delays in mammography. It was also related to increased physician visits (P = .001). CONCLUSION: Among women, an increased BMI is associated with decreased preventive health care services, which may exacerbate or even account for some of the increased health risks of obesity.

Body mass index, smoking, and mortality among older American women.

The relationship among body mass index (BMI, kg/m2), smoking status, and overall mortality remains controversial. To assess this relationship in a representative sample of older women, we used data from the Panel Study of Income Dynamics (PSID). The PSID (begun in 1968) is a prospective longitudinal cohort study designed to examine economic and demographic behavior. Respondents were 1355 women age > or = 50 when they initially completed the Self-Administered Health Questionnaire in 1990. Data collected included self-reported height and weight, years of completed education, smoking status (never versus ever), and responses to four health-related questions (e.g., retired due to ill health, difficulty eating). Respondents were followed, including the date of death if respondent died, through 1994. Cox proportional hazard regression revealed a U-shaped relationship irrespective of whether smoking was included in the model. The base of the curve was fairly wide, suggesting that a broad range of BMI is well tolerated by older women. The minimum mortality (estimated from fitted proportional hazard models) for both the smoking and nonsmoking models occurred at a BMI of approximately 34. When interactions between smoking status and BMI terms were added to the model, the interactions were not jointly significant (p = 0.071). Moreover an exploratory plot of the BMI-mortality curve among never smokers (n = 800) revealed a curve that moved away from being U-shaped toward being more monotonically decreasing. It is concluded that these data suggest that there is no evidence that the U-shaped BMI-mortality relationship observed is caused by confounding by smoking status.

Hypothesis concerning the U-shaped relation between body mass index and mortality.

Numerous studies have documented a U- or J-shaped association between body mass index (BMI) (kg/m2) and mortality, such that increased mortality rate is associated with relatively low and high BMI values. It has been argued elsewhere that the elevated mortality rate observed at lower BMI values actually results from the effects of unmeasured confounding variables, in particular smoking status and preexisting disease. In this paper, the authors present an additional explanation for the phenomenon, i.e., nonspecific measurement. They propose that differential health consequences of fat mass and fat-free mass can be masked by the use of BMI when studied in relation to mortality. To illustrate this point, they use body composition data from 1,137 healthy adults and specify a hypothetical underlying BMI-mortality model in which the logit of death increased linearly with fat mass and decreased linearly with fat-free mass, and % fat increased monotonically with BMI. The results indicate that, even under these specifications, the authors can recover a U-shaped association between BMI and mortality. Consistent with previous suggestions in the literature, future epidemiologic studies that examine the association between adiposity and mortality should prioritize the use of body composition measures.