Regulation of metabolic health by dietary histidine in mice.

Low-protein (LP) diets are associated with a decreased risk of diabetes in humans, and promote leanness and glycaemic control in both rodents and humans. While the effects of an LP diet on glycaemic control are mediated by reduced levels of the branched-chain amino acids, we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to an LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces the weight gain of young, lean male mice, reducing both adipose and lean mass without altering glucose metabolism, and rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity. This normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. Surprisingly, the effects of histidine restriction do not require the energy balance hormone Fgf21. Histidine restriction that was started in midlife promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary histidine may be a translatable option for the treatment of obesity. KEY POINTS: Protein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan. Restriction of specific individual essential amino acids can recapitulate the benefits of PR. Reduced histidine promotes leanness and increased energy expenditure in male mice. Reduced histidine does not extend the lifespan of mice when begun in midlife. Dietary levels of histidine are positively associated with body mass index in humans.

A Comparison of Self- and Proxy-Reported Subjective Sleep Durations With Objective Actigraphy Measurements in a Survey of Wisconsin Children 6-17 Years of Age.

Children's sleep quality and duration are important to overall development, health, and wellbeing. However, measuring children's sleep is challenging, especially in situations where objective assessment is impractical. This study aimed to assess age and proxy effects in comparing subjective sleep duration with objective measures, in a community-based sample of Wisconsin children (aged 6-17 years), recruited from 2014-2017. The sample participants had a mean age of 11.4 (standard deviation, 3.3) years and 52% of them were male. We used linear mixed effects models to test for age effects in proxy- and self-report groups separately, and a quasiexperimental regression discontinuity approach to compare subjective sleep duration with objective actigraphy estimates across proxy- and self-report groups. We found evidence of systematic overestimation of sleep duration when using subjective measurements but did not find evidence of age effects in either group. Based on these analyses, we found evidence of differential overestimation by proxy- or self-report condition. Proxy reporters overestimated sleep duration by 2.3 hours (95% confidence interval: 2.2, 2.4), compared with 1.0 hour (95% confidence interval: 0.7, 1.2) for self-reporters. These findings suggest that proxy- versus self-reporting conditions are an important consideration when designing a study, and that it might be beneficial to reduce the age at which children self-report.

Using recursive feature elimination in random forest to account for correlated variables in high dimensional data.

BACKGROUND: Random forest (RF) is a machine-learning method that generally works well with high-dimensional problems and allows for nonlinear relationships between predictors; however, the presence of correlated predictors has been shown to impact its ability to identify strong predictors. The Random Forest-Recursive Feature Elimination algorithm (RF-RFE) mitigates this problem in smaller data sets, but this approach has not been tested in high-dimensional omics data sets. RESULTS: We integrated 202,919 genotypes and 153,422 methylation sites in 680 individuals, and compared the abilities of RF and RF-RFE to detect simulated causal associations, which included simulated genotype-methylation interactions, between these variables and triglyceride levels. Results show that RF was able to identify strong causal variables with a few highly correlated variables, but it did not detect other causal variables. CONCLUSIONS: Although RF-RFE decreased the importance of correlated variables, in the presence of many correlated variables, it also decreased the importance of causal variables, making both hard to detect. These findings suggest that RF-RFE may not scale to high-dimensional data.

Food insecurity and dyslipidemia in a representative population-based sample in the US.

OBJECTIVE: The association of food insecurity with dyslipidemia has not been firmly established. The main objective of this study was to assess whether food insecurity was associated with dyslipidemia. METHOD: A population-based sample of 1,663 adults from the 2008-2011 Survey of the Health of Wisconsin was used. Food insecurity was defined as an affirmative response to either of the questions: (1) "In the last 12months, have you been concerned about having enough food for you or your family?" (2) "In the last 12months, have your food choices been limited because there wasn't enough money?" High total cholesterol was defined as total cholesterol (TC) >240mg/dL or taking prescribed lipid-lowering medication. Low high-density lipoprotein cholesterol (HDL-C) was defined as <40mg/dL in men and <50mg/dL in women. RESULTS: Food insecurity was not associated with high TC either among men or women. Food insecurity was associated with a higher likelihood of low HDL-C among women (adjusted odds ratio [AOR]: 2.31 {95% confidence interval [CI]: 1.42, 3.76}), but not among men. Obesity appears to be a partial mediator of the association among women (P from the Sobel test=0.01). CONCLUSION: These findings suggest that food insecurity may contribute to an increased risk of low HDL-C in women.

The association between neighborhood economic hardship, the retail food environment, fast food intake, and obesity: findings from the Survey of the Health of Wisconsin.

BACKGROUND: Neighborhood-level characteristics such as economic hardship and the retail food environment are assumed to be correlated and to influence consumers' dietary behavior and health status, but few studies have investigated these different relationships comprehensively in a single study. This work aims to investigate the association between neighborhood-level economic hardship, the retail food environment, fast food consumption, and obesity prevalence. METHODS: Linking data from the population-based Survey of the Health of Wisconsin (SHOW, n = 1,570, 2008-10) and a commercially available business database, the Wisconsin Retail Food Environment Index (WRFEI) was defined as the mean distance from each participating household to the three closest supermarkets divided by the mean distance to the three closest convenience stores or fast food restaurants. Based on US census data, neighborhood-level economic hardship was defined by the Economic Hardship Index (EHI). Relationships were analyzed using multivariate linear and logistic regression models. RESULTS: SHOW residents living in neighborhoods with the highest economic hardship faced a less favorable retail food environment (WRFEI = 2.53) than residents from neighborhoods with the lowest economic hardship (WRFEI = 1.77; p-trend < 0.01). We found no consistent or significant associations between the WRFEI and obesity and only a weak borderline-significant association between access to fast food restaurants and self-reported fast food consumption (≥ 2 times/week, OR = 0.59-0.62, p = 0.05-0.09) in urban residents. Participants reporting higher frequency of fast food consumption (≥ 2 times vs. <2 times per week) were more likely to be obese (OR = 1.35, p = 0.06). CONCLUSION: This study indicates that neighborhood-level economic hardship is associated with an unfavorable retail food environment. However inconsistent or non-significant relationships between the retail food environment, fast food consumption, and obesity were observed. More research is needed to enhance methodological approaches to assess the retail food environment and to understand the complex relationship between neighborhood characteristics, health behaviors, and health outcomes.

The Wisconsin Assessment of the Social and Built Environment (WASABE): a multi-dimensional objective audit instrument for examining neighborhood effects on health.

BACKGROUND: Growing evidence suggests that mixed methods approaches to measuring neighborhood effects on health are needed. The Wisconsin Assessment of the Social and Built Environment (WASABE) is an objective audit tool designed as an addition to a statewide household-based health examination survey, the Survey of the Health of Wisconsin (SHOW), to objectively measure participant's neighborhoods. METHODS: This paper describes the development and implementation of the WASABE and examines the instrument's ability to capture a range of social and built environment features in urban and rural communities. A systematic literature review and formative research were used to create the tool. Inter-rater reliability parameters across items were calculated. Prevalence and density of features were estimated for strata formed according to several sociodemographic and urbanicity factors. RESULTS: The tool is highly reliable with over 81% of 115 derived items having percent agreement above 95%. It captured variance in neighborhood features in for a diverse sample of SHOW participants. Sidewalk density in neighborhoods surrounding households of participants living at less than 100% of the poverty level was 67% (95% confidence interval, 55-80%) compared to 34% (25-44%) for those living at greater than 400% of the poverty level. Walking and biking trails were present in 29% (19-39%) of participant buffer in urban areas compared to only 7% (2-12%) in rural communities. Significant environmental differences were also observed for white versus non-white, high versus low income, and college graduates versus individuals with lower level of education. CONCLUSIONS: The WASABE has strong inter-rater reliability and validity properties. It builds on previous work to provide a rigorous and standardized method for systematically gathering objective built and social environmental data in a number of geographic settings. Findings illustrate the complex milieu of built environment features found in participants neighborhoods and have relevance for future research, policy, and community engagement purposes.

Urban-rural and regional variability in the prevalence of food insecurity: the survey of the health of Wisconsin.

BACKGROUND: Food insecurity is a public health concern estimated to affect 18 million American households nationally, which can result in chronic nutritional deficiencies and other health risks. The relationships between food insecurity and specific demographic and geographic factors in Wisconsin are not well documented. The goals of this paper are to investigate sociodemographic and geographic features associated with food insecurity in a representative sample of Wisconsin adults. METHODS: This study used data from the Survey of the Health of Wisconsin (SHOW). SHOW annually collects health-related data on a representative sample of Wisconsin residents. Between 2008-2012, 2,947 participants were enrolled in the SHOW study. The presence of food insecurity was defined based on the participant's affirmative answer to the question "In the last 12 months, have you been concerned about having enough food for you or your family?" RESULTS: After adjustment for age, race, and gender, 13.2% (95% CI, 10.8%-15.1%) of participants reported food insecurity, 56.7% (95% CI, 50.6%-62.7%) of whom were female. Food insecurity did not statistically differ by region (P = 0.30). The adjusted prevalence of food insecurity in the urban core, other urban, and rural areas was 14.1%, 6.5%, and 10.5%, respectively. These differences were not statistically significant (P = 0.13) and, for urban core and rural areas, persisted even when accounting for level of economic hardship in the community. CONCLUSIONS: The prevalence of food insecurity is substantial, affecting an estimated 740,000 or more Wisconsin residents. The prevalence was similarly high in all urbanicity levels and across all state public health regions in Wisconsin. Food insecurity is a common problem with potentially serious health consequences affecting populations across the entire state.

Overall prescription medication use among adults: findings from the Survey of the Health of Wisconsin.

PURPOSE: To analyze overall prescription medication use patterns among study participants in a representative statewide sample of Wisconsin adults. METHODS: We analyzed data on 1572 participants from the 2008-2010 cycles of the Survey of the Health of Wisconsin (SHOW). SHOW is a statewide population-based survey that collects health information, including prescription medications, from 21 to 74 year olds. Prescription medication use was examined according to demographic and socioeconomic characteristics. RESULT: Almost 55% of participants reported using at least 1 medication in the past month and 14% reported using at least 5 medications. The top 5 medications reported were lisinopril, hydrochlorothiazide, simvastatin, levothyroxine, and metoprolol. Overall prescription medication use increased significantly with age. Medication use was greater among females, former smokers, adults with body mass index (BMI) ≥ 30, or with low family income, and non-hispanic blacks. Adults having health insurance, drug coverage, or a regular source of care were more likely to report medication use. CONCLUSION: The prevalence of prescription medication use in a general population sample in Wisconsin was high. Age, gender, race, BMI, family income, smoking history, health insurance, prescription drug coverage, and having a regular source of health care were associated with prescription medication use.

Associations of gut microbiome richness and diversity with objective and subjective sleep measures in a population sample.

STUDY OBJECTIVES: Alterations in gut microbiota composition have been associated with several conditions, and there is emerging evidence that sleep quantity and quality are associated with the composition of the gut microbiome. Therefore, this study aimed to assess the associations between several measures of sleep and the gut microbiome in a large, population-based sample. METHODS: Data were collected from participants in the Survey of the Health of Wisconsin from 2016 to 2017 (N = 720). Alpha diversity was estimated using Chao1 richness, Shannon's diversity, and Inverse Simpson's diversity. Beta diversity was estimated using Bray-Curtis dissimilarity. Models for each of the alpha-diversity outcomes were calculated using linear mixed effects models. Permutational multivariate analysis of variance tests were performed to test whether gut microbiome composition differed by sleep measures. Negative binomial models were used to assess whether sleep measures were associated with individual taxa relative abundance. RESULTS: Participants were a mean (SD) age of 55 (16) years and 58% were female. The sample was 83% non-Hispanic white, 10.6% non-Hispanic black, and 3.5% Hispanic. Greater actigraphy-measured night-to-night sleep duration variability, wake-after-sleep onset, lower sleep efficiency, and worse self-reported sleep quality were associated with lower microbiome richness and diversity. Sleep variables were associated with beta-diversity, including actigraphy-measured night-to-night sleep duration variability, sleep latency and efficiency, and self-reported sleep quality, sleep apnea, and napping. Relative abundance of several taxa was associated with night-to-night sleep duration variability, average sleep latency and sleep efficiency, and sleep quality. CONCLUSIONS: This study suggests that sleep may be associated with the composition of the gut microbiome. These results contribute to the body of evidence that modifiable health habits can influence the human gut microbiome.

Socioecologic Factors and Racial Differences in Breast Cancer Multigene Prognostic Scores in US Women.

Importance: Disproportionately aggressive tumor biology among non-Hispanic Black women with early-stage, estrogen receptor (ER)-positive breast cancer contributes to racial disparities in breast cancer mortality. It is unclear whether socioecologic factors underlie racial differences in breast tumor biology. Objective: To examine individual-level (insurance status) and contextual (area-level socioeconomic position and rural or urban residence) factors as possible mediators of racial and ethnic differences in the prevalence of ER-positive breast tumors with aggressive biology, as indicated by a high-risk gene expression profile. Design, Setting, and Participants: This retrospective cohort study included women 18 years or older diagnosed with stage I to II, ER-positive breast cancer between January 1, 2007, and December 31, 2015. All data analyses were conducted between December 2022 and April 2023. Main Outcomes and Measures: The primary outcome was the likelihood of a high-risk recurrence score (RS) (≥26) on the Oncotype DX 21-gene breast tumor prognostic genomic biomarker. Results: Among 69 139 women (mean [SD] age, 57.7 [10.5] years; 6310 Hispanic [9.1%], 274 non-Hispanic American Indian and Alaskan Native [0.4%], 6017 non-Hispanic Asian and Pacific Islander [8.7%], 5380 non-Hispanic Black [7.8%], and 51 158 non-Hispanic White [74.0%]) included in our analysis, non-Hispanic Black (odds ratio [OR], 1.33; 95% CI, 1.23-1.43) and non-Hispanic American Indian and Alaska Native women (OR, 1.38; 95% CI, 1.01-1.86) had greater likelihood of a high-risk RS compared with non-Hispanic White women. There were no significant differences among other racial and ethnic groups. Compared with non-Hispanic White patients, there were greater odds of a high-risk RS for non-Hispanic Black women residing in urban areas (OR, 1.35; 95% CI, 1.24-1.46), but not among rural residents (OR, 1.05; 95% CI, 0.77-1.41). Mediation analysis demonstrated that lack of insurance, county-level disadvantage, and urban vs rural residence partially explained the greater odds of a high-risk RS among non-Hispanic Black women (proportion mediated, 17%; P < .001). Conclusions and Relevance: The findings of this cohort study suggest that the consequences of structural racism extend beyond inequities in health care to drive disparities in breast cancer outcome. Additional research is needed with more comprehensive social and environmental measures to better understand the influence of social determinants on aggressive ER-positive tumor biology among racial and ethnic minoritized women from disadvantaged and historically marginalized communities.

Dietary isoleucine content defines the metabolic and molecular response to a Western diet.

The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, it is unknown how sex, strain, and dietary isoleucine intake may interact to impact the response to a Western Diet (WD). Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain- independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, we find that foods contain a range of isoleucine levels, and that consumption of dietary isoleucine is lower in humans with healthy eating habits. Our results demonstrate that the dietary level of isoleucine is critical in the metabolic and molecular response to a WD, and suggest that lowering dietary levels of isoleucine may be an innovative and translatable strategy to protect from the negative metabolic consequences of a WD.

Sense of community and mental health: a cross-sectional analysis from a household survey in Wisconsin.

BACKGROUND: In the USA, one in five adults live with a mental illness, and researchers have estimated that nearly half of the population will have a mental illness over the course of their lifetime. Research has shown significant associations between social relationships and mental health outcomes at the individual and population levels. This study aims to examine whether sense of community, a type of social capital, is associated with mental health. METHODS: In a cross-sectional analysis, multiple logistic regression models were used to examine whether sense of community was associated with symptoms of depression, anxiety and stress reported over the last week. The analysis used data from the Survey of the Health of Wisconsin collected between 2014 and 2016. A total of 1647 observations are included in the analyses. RESULTS: Compared with those who report a positive sense of community, those with a negative sense of community had a significantly higher odds of reporting depression, anxiety and stress symptoms. Socioeconomic status is negatively associated with depression and anxiety, but not with stress. Women were more likely to experience moderate, severe, or extremely severe anxiety and stress, compared with men. CONCLUSION: This study extends current understanding of health benefits of social capital and found that individuals' sense of community is associated with reduced symptoms of depression, anxiety and stress. Further research examining mechanisms to support improved sense of community and other types of social capital could benefit health equity research.

Psychological distress and well-being among sensory impaired individuals during COVID-19 lockdown measures.

PURPOSE: Hearing and vision impairment are prevalent chronic conditions associated with poorer mental health. Limitations of in-person contacts during COVID-19-related lockdown measures may affect those with sensory impairments more severely exacerbating mental health problems. We aimed to determine whether hearing and/or visual impairment were associated with more psychological distress during a time of lockdown measures in Spring/Summer 2020 in Wisconsin. METHODS: We included 1341(64% women, aged 20-92 years) Survey of the Health of Wisconsin COVID-19 survey participants (May 2020-July,2020). We assessed self-reported current mental health and well-being and vision and hearing impairment. Logistic regression models with sensory impairments as determinants and mental health outcomes were adjusted for age, gender, race, education, heart disease, hypertension, hyperlipidemia, and diabetes. RESULTS: Vision impairment was associated with increased odds of generalized anxiety disorder (odds ratio = 2.10; 95% confidence interval = 1.32-3.29) and depressive symptoms (2.57;1.58-4.11), greater likelihood to report loneliness (1.65;1.00-2.64) and hopelessness (1.45;1.01-2.08). Hearing impaired individuals reported more loneliness (1.80;1.05-2.98) and hopelessness (1.42;0.99-2.03). Exploratory analyses revealed that sensory impaired individuals less often chose walking as a coping strategy during the pandemic. CONCLUSIONS: Individuals with sensory impairment may represent a particularly vulnerable population during the COVID-19 pandemic. Future research should determine underlying reasons and interventions to mitigate this populations' disadvantages.

Biomonitoring of perfluoroalkyl and polyfluoroalkyl substances (PFAS) from the Survey of the Health of Wisconsin (SHOW) 2014-2016 and comparison with the National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a growing class of manufactured chemical compounds found in a variety of consumer products. PFAS are ubiquitous in the environment and were found in many humans sampled in the United States (U.S.). Yet, significant gaps in understanding statewide levels of exposure to PFAS remain. OBJECTIVE: The goals of this study are to establish a baseline of exposure at the state level by measuring PFAS serum levels among a representative sample of Wisconsin residents and compare to United States National Health and Nutrition Examination Survey (NHANES). METHODS: The study sample included 605 adults (18+ years of age) selected from the 2014-2016 sample of the Survey of the Health of Wisconsin (SHOW). Thirty-eight PFAS serum concentrations were measured using high-pressure liquid chromatography coupled with tandem mass spectrometric detection (HPLC-MS/MS) and geometric means were presented. Weighted geometric mean serum values of eight PFAS analytes from SHOW were compared to U.S. national levels from the NHANES 2015-2016 sample (PFOS, PFOA, PFNA, PFHxS, PFHpS, PFDA, PFUnDA), and the 2017-2018 sample for Me-PFOSA, PFHPS using the Wilcoxon rank-sum test. RESULTS: PFOS, PFHxS, PFHpS, PFDA, PFNA, and PFOA were detected in over 96% of SHOW participants. In general, SHOW participants had lower serum levels across all PFAS when compared to NHANES. Serum levels increased with age and were higher among males and whites. Similar trends were seen in NHANES, except non-whites had higher PFAS levels at higher percentiles in NHANES. IMPACT STATEMENT: The present study conducts biomonitoring of 38 PFAS among representative sample of residents in the state of Wisconsin. Results suggest that while the majority of Wisconsin residents tested have detectable levels of PFAS in their blood serum, they may have a lower body burden of some PFAS compared to a nationally representative sample. Older adults, males, and whites may have a higher body burden of PFAS relative to other groups, both in Wisconsin and the wider United States.

Evaluating effects of statewide smoking regulations on smoking behaviors among participants in the Survey of the Health of Wisconsin.

BACKGROUND: Studies have shown that laws banning smoking in public places reduce exposure to secondhand smoke, but the impact of such laws on exposure to smoke outside the home and on household smoking policies has not been well documented. The goal of this study was to evaluate the effects of 2009 Wisconsin Act 12, a statewide smoke-free law enacted in July 2010, among participants in the Survey of the Health of Wisconsin (SHOW). METHODS: Smoking history and demographic information was gathered from 1341 survey participants from 2008 to 2010. Smoking behaviors of independent samples of participants surveyed before and after the legislation was enacted were compared. RESULTS: The smoking ban was associated with a reduction of participants reporting exposure to smoke outside the home (from 55% to 32%; P<0.0001) and at home (13% to 7%; P=0.002). The new legislation was associated with an increased percentage of participants with no-smoking policies in their households (from 74% to 80%; P=.04). The results were stronger among participants who were older, wealthier, and more educated. CONCLUSION: Smoke-free legislation appears to reduce secondhand smoke exposure and to increase no-smoking policies in households. Further research should be conducted to see if these effects are maintained.

Assessing the relationship between physical activity and the gut microbiome in a large, population-based sample of Wisconsin adults.

The gut microbiome is an important factor in human health and disease. While preliminary studies have found some evidence that physical activity is associated with gut microbiome richness, diversity, and composition, this relationship is not fully understood and has not been previously characterized in a large, population-based cohort. In this study, we estimated the association between several measures of physical activity and the gut microbiota in a cohort of 720 Wisconsin residents. Our sample had a mean age of 55 years (range: 18, 94), was 42% male, and 83% of participants self-identified as White. Gut microbial composition was assessed using gene sequencing of the V3-V4 region of 16S rRNA extracted from stool. We found that an increase of one standard deviation in weekly minutes spent in active transportation was associated with an increase in alpha diversity, particularly in Chao1's richness (7.57, 95% CI: 2.55, 12.59) and Shannon's diversity (0.04, 95% CI: 0.0008, 0.09). We identified interactions in the association between Inverse Simpson's diversity and physical activity, wherein active transportation for individuals living in a rural environment was associated with additional increases in diversity (4.69, 95% CI: 1.64, 7.73). We also conducted several permutational ANOVAs (PERMANOVA) and negative binomial regression analyses to estimate the relationship between physical activity and microbiome composition. We found that being physically active and increased physical activity time were associated with increased abundance of bacteria in the family Erysipelotrichaceae. Active transportation was associated with increased abundance of bacteria in the genus Phascolarctobacterium, and decreased abundance of Clostridium. Minutes in active transportation was associated with a decreased abundance of the family Clostridiaceae.

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.

Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.

The Survey of the Health of Wisconsin (SHOW), a novel infrastructure for population health research: rationale and methods.

BACKGROUND: Evidence-based public health requires the existence of reliable information systems for priority setting and evaluation of interventions. Existing data systems in the United States are either too crude (e.g., vital statistics), rely on administrative data (e.g., Medicare) or, because of their national scope (e.g., NHANES), lack the discriminatory power to assess specific needs and to evaluate community health activities at the state and local level. This manuscript describes the rationale and methods of the Survey of the Health of Wisconsin (SHOW), a novel infrastructure for population health research. METHODS/DESIGN: The program consists of a series of independent annual surveys gathering health-related data on representative samples of state residents and communities. Two-stage cluster sampling is used to select households and recruit approximately 800-1,000 adult participants (21-74 years old) each year. Recruitment and initial interviews are done at the household; additional interviews and physical exams are conducted at permanent or mobile examination centers. Individual survey data include physical, mental, and oral health history, health literacy, demographics, behavioral, lifestyle, occupational, and household characteristics as well as health care access and utilization. The physical exam includes blood pressure, anthropometry, bioimpedance, spirometry, urine collection and blood draws. Serum, plasma, and buffy coats (for DNA extraction) are stored in a biorepository for future studies. Every household is geocoded for linkage with existing contextual data including community level measures of the social and physical environment; local neighborhood characteristics are also recorded using an audit tool. Participants are re-contacted bi-annually by phone for health history updates. DISCUSSION: SHOW generates data to assess health disparities across state communities as well as trends on prevalence of health outcomes and determinants. SHOW also serves as a platform for ancillary epidemiologic studies and for studies to evaluate the effect of community-specific interventions. It addresses key gaps in our current data resources and increases capacity for etiologic, applied and translational population health research. It is hoped that this program will serve as a model to better support evidence-based public health, facilitate intervention evaluation research, and ultimately help improve health throughout the state and nation.

Effective environmental public health surveillance programs: a framework for identifying and evaluating data resources and indicators.

The complexity and multidisciplinary nature of environmental public health (EPH) surveillance call for a systematic framework and a concrete set of criteria to guide development, selection, and evaluation of environmental public health indicators. Environmental public health indicators are the foundation of a comprehensive EPH surveillance system, providing quantitative summary measures and descriptive information about spatial and temporal trends of hazard, exposure, and health effects over person, place, and time. A case-synthesis review of environmental regulatory and public health indicator models was employed to develop a framework and outline a methodological approach to EPH surveillance system development, including the selection of content areas and the corresponding data and environmental public health indicators. The framework is organized around three assessment phases: (1) scientific basis and relevance, (2) analytic soundness, and (3) feasibility, interpretation and utility. By outlining a process and identifying important constructs and criteria, the framework provides practitioners with an effective and systematic tool for making scientifically valid programmatic decisions about EPH content development. Improved decision making ensures more effective EPH surveillance systems and enhanced opportunities to understand and protect the public health from environmental threats.