Dawn K. Coletta

Development of ectodermal tissues in humans is a complex process regulated by interacting signaling pathways. This review adopts an evolutionary medicine framework to examine how genetic variation in components of the ectodysplasin A (EDA) signaling pathway may have conferred human evolutionary fitness during the last ice age, but today may present an evolutionary mismatch, contributing to modern chronic diseases. A missense substitution at amino acid 370 in the human EDA receptor (EDAR) gene (EDARV370A), which is very common in East Asian, Native American, and Latino populations, produces pleiotropic effects in ectodermal tissues such as hair, teeth, mammary glands, and skin appendages. Several hypotheses have been offered to explain the high frequency of EDARV370A, proposing selective advantages related to thermal regulation, mother-infant vitamin D transmission, and/or tooth shape. However, new insight suggests that the selective advantage could have involved EDAR’s systemic and epithelial immune effects rather than embryonic effects alone. We explore the possibility that inflammatory effects associated with EDARV370A were the target of selection approximately 20 000 years ago, but that this selective advantage could now represent an evolutionary mismatch in the context of abundant caloric supply, resulting in chronic inflammation and a higher risk of metabolic syndrome. Finally, we outline directions for future research.

VWA8 is a mitochondrial protein expressed at high levels in mitochondria-enriched organs such as the liver, kidney, and heart. Deletion of VWA8 (VWA8-KO) in AML12 mouse hepatocytes leads to oxidative stress characterized by elevated production of reactive oxygen species (ROS) and, subsequently, higher oxidative capacity. Concurrently, there is a substantial rise in the expression of the transcription factor HNF4α in VWA8-KO hepatocytes. Thus, exploring the potential significance of HNF4α in the observed effects warrants investigation. In this study, we deleted the HNF4α gene using CRISPR/Cas9 in VWA8-KO AML12 mouse hepatocytes. Measurements of ROS production rates, MitoStress Assays in permeabilized cells, and MitoStress Assays in intact cells were performed. Our results show that Deleting HNF4α in VWA8-KO AML12 mouse hepatocytes (V&H-KO) rescued the increased rate of ROS production observed in VWA8-KO cells, returning ROS to levels comparable to wild-type cells, thereby reversing the oxidative stress associated with VWA8-KO. Furthermore, V&H-KO recovered the elevated respiration rates observed in VWA8-KO intact cells and permeabilized cells when fueled by palmitate, lowering them to wild-type levels. However, the increased respiration rate in VWA8-KO intact cells when using glucose as the fuel source remained unaltered by V&H-KO. This suggests that HNF4α plays an important role but is not the sole factor contributing to the phenotypic changes resulting from VWA8-KO. We conclude that deleting HNF4α in VWA8-KO AML12 mouse hepatocytes rescues the oxidative stress and partially rescues the higher oxidative capacity observed in VWA8-KO cells.

Obesity is a persistent public health issue, often resulting in metabolic complications such as insulin resistance (IR). The secretion of pro-inflammatory cytokines from adipose tissue (AT) is increased during obesity, contributing to the impairment of systemic insulin sensitivity. While interventions in animal models have shown that reducing inflammation restores insulin sensitivity, human studies reducing systemic inflammation have produced inconsistent results. We recently demonstrated that three months of high-dose (4 g/daily) ω-3PUFA (fish oil, FO) supplementation improved insulin sensitivity, and decreased systemic and AT inflammation in individuals with obesity (BMI ≥ 30 kg/m²). Given recent studies highlighting the involvement of microRNA (miRNA) in inflammatory cytokine production, we investigated the effect of ω-3PUFA supplementation on AT miRNA expression in this cohort. AT biopsies were collected before and after ω-3PUFA supplementation. miRNA was processed on the Affymetrix miRNA 4.0 GeneChip and analyzed using existing inflammatory gene sets sourced from MSigDB. Unbiased, differentially expressed miRNA analysis identified miR-4498 and miR-5689 as significantly increased after three months of ω-3PUFA supplementation. Real-time PCR confirmed bioinformatic analysis findings. Our study reports the modulation of miRNA in AT, reductions in systemic and AT markers of inflammation, and the improvement of IR post ω-3PUFA supplementation. Further research is needed to elucidate the link between miR-4498, miR-5689, and whole-body insulin sensitivity.

Background/Objectives: Latinos, particularly those of Mexican ancestry, experience high rates of type 2 diabetes and sleep disturbances, exacerbating adverse health outcomes. This study aimed to examine the prevalence of excessive daytime sleepiness and its associations with diet, cardiometabolic risk factors, and glycemic control in this population. Methods: This cross-sectional study utilized data from the El Banco por Salud biobank, including 1685 participants (aged 52.6 ± 14.5 years, BMI: 32.4 ± 7.0 kg/m²) recruited from Federally Qualified Community Health Centers. Excessive daytime sleepiness was assessed using the Epworth Sleepiness Scale, while dietary information was obtained via the Brief Dietary Assessment Tool for Hispanics. Primary outcomes included cardiometabolic risk factors and glycated hemoglobin (HbA1c) levels. Results: Excessive daytime sleepiness (Epworth Sleepiness Scale > 10) was present in 22.0% of participants and was associated with higher BMI (p < 0.001), larger waist circumference (p = 0.002), poorer diet quality, increased dyslipidemia (p = 0.036), and elevated HbA1c (p = 0.007). Linear regression analyses confirmed that excessive daytime sleepiness was significantly associated with higher HbA1c levels, both in unadjusted (R² = 0.011; p < 0.001) and adjusted for demographic, anthropometric, and socioeconomic factors (R² = 0.107; p = 0.004) models. Conclusions: Excessive daytime sleepiness among Latinos of Mexican ancestry is associated with unhealthy dietary patterns and poor glycemic control, highlighting the need for targeted interventions addressing sleep and dietary habits in this vulnerable population.

Obesity and type 2 diabetes mellitus (T2DM) are metabolic diseases at epidemic proportions. The economic burden for these diseases is at an all-time high, and as such, there is an urgent need for advancements in identifying targets for treating these complex disorders. The extracellular matrix (ECM), comprising collagen, fibronectin, laminin, elastin, and proteoglycan, surrounds skeletal muscles and plays a critical role in maintaining tissue homeostasis by providing structural support and facilitating cell-to-cell communication. Disruption of the ECM signaling results in changes to its micro/macroenvironment, thereby modifying tissue homeostasis. Skeletal muscle ECM remodeling has been shown to be associated with insulin resistance, an underlying feature of obesity and T2DM. This narrative review explores the critical components of skeletal muscle ECM and its accumulation and remodeling in metabolic diseases. In addition, we discuss potential treatments to mitigate the effects of ECM remodeling in skeletal muscle. We conclude that targeting ECM remodeling in skeletal muscle represents a promising yet underexplored therapeutic avenue in the management of metabolic disorders.

Physical activity (PA), including sedentary behavior, is associated with many diseases, including Alzheimer’s disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. To address this knowledge gap, we first assessed the conventional observational associations of three self-reported and three device-based PA measures with circulating levels of 2,911 plasma proteins measured in the UK Biobank (n _max =39,160) and assessed functional enrichment of identified proteins. We then used bi-directional Mendelian randomization (MR) to further evaluate the evidence for causal relationships of PA with protein levels. Finally, we performed mediation analyses to identify proteins that may mediate the relationship of PA with incident all-cause dementia. Our findings revealed 41 proteins consistently associated with all PA measures and 1,027 proteins associated with at least one PA measure. Both conventional observational and MR study designs converged on proteins that appear to increase as a result of PA, including integrin proteins such as ITGAV and ITGAM, as well as MXRA8, CLEC4A, CLEC4M, GFRA1, and ADGRG2; and on proteins that appear to decrease as a result of PA such as LEP, LPL, INHBC, CLMP, PTGDS, ADM, OGN, and PI3. Functional enrichment analyses revealed several relevant processes, including cell-matrix adhesion, integrin-mediated signaling, and collagen binding. Finally, several proteins, including GDF15, ITGAV, HPGDS, BCAN, and MENT, were found to mediate the relationship of PA with all-cause dementia, implicating processes such as synaptic plasticity, neurogenesis and inflammation, through which PA protects against dementia. Our results provide insights into how PA may affect biological processes and protect from all-cause dementia, and provide avenues for future research into the health-promoting effects of PA.

Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic disease that carries with it a high prevalence of comorbid conditions, making T2DM one of the leading causes of death in the U.S. Traditional lifestyle interventions (e.g., diet, exercise) can counter some adverse effects of T2DM, however, participation in these activities is low with reasons ranging from physical discomfort to lack of time. Thus, there is a critical need to develop novel management strategies that effectively reduce cardiometabolic disease risk and address barriers to adherence. High-resistance inspiratory muscle strength training (IMST) is a time-efficient and simple breathing exercise that significantly reduces systolic and diastolic BP and improves vascular endothelial function in adults with above-normal blood pressure. Herein we describe the study protocol for a randomized clinical trial to determine the effects of a 6-week IMST regimen on glycemic control and insulin sensitivity in adults with T2DM. Our primary outcome measures include fasting plasma glucose, fasting serum insulin, and insulin resistance utilizing homeostatic model assessment for insulin resistance (HOMA-IR). Secondary outcome measures include resting systolic BP and endothelium-dependent dilation. Further, we will collect plasma for exploratory proteomic analyses. This trial seeks to establish the cardiometabolic effects of 6 weeks of high-resistance IMST in patients with T2DM.

Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic disease that carries with it a high prevalence of comorbid conditions, making T2DM one of the leading causes of death in the U.S. Traditional lifestyle interventions (e.g., diet, exercise) can counter some adverse effects of T2DM; however, participation in these activities is low with reasons ranging from physical discomfort to lack of time. Thus, there is a critical need to develop novel management strategies that effectively reduce cardiometabolic disease risk and address barriers to adherence. High-resistance inspiratory muscle strength training (IMST) is a time-efficient and simple breathing exercise that significantly reduces systolic and diastolic BP and improves vascular endothelial function in adults with above-normal blood pressure. Herein, we describe the study protocol for a randomized clinical trial to determine the effects of a 6 week IMST regimen on glycemic control and insulin sensitivity in adults with T2DM. Our primary outcome measures include fasting plasma glucose, fasting serum insulin, and insulin sensitivity utilizing homeostatic model assessment for insulin resistance (HOMA-IR). Secondary outcome measures include casual (resting) systolic BP and endothelial-dependent dilation. Further, we will collect plasma for exploratory proteomic analyses. This trial seeks to establish the cardiometabolic effects of 6 weeks of high-resistance IMST in patients with T2DM.

The vitamin D receptor (VDR) is vital for maintaining calcium and phosphate balance and regulating bone metabolism. Recent research has suggested that VDR also plays an essential role in metabolic diseases. Previous studies on non-Hispanic whites have shown that VDR single nucleotide polymorphisms (SNP) are associated with cardiometabolic phenotypes. However, the association between VDR SNPs and cardiometabolic traits in Hispanics remains unclear. This study investigated the association between VDR SNPs and cardiometabolic phenotypic data in self-reported Hispanics (n = 1610) from the Arizona Insulin Resistance registry and Sangre Por Salud Biobank. The study population was predominantly female (66.4%) with a mean age of 40 ± 14 years (n = 121 2. We performed a genotyping association analysis of VDR SNPs (Taq1-rs731236, Fok1-rs2228570 and Apa1-rs7975232) with cardiometabolic traits using linear regression models. The results showed that Taq1 and Apa1 were strongly associated with systolic blood pressure (SBP) in children (<18 years), while Fok1 was associated with measures of adiposity, including fat mass, waist circumference, and BMI. In age-stratified adult (≥18 years) models, Taq1 was strongly associated with hemoglobin A1c, while Apa1 was associated with BMI and fasting glucose. Fok1 had no significant associations in the adult models. In conclusion, the VDR SNPs were associated with several cardiometabolic phenotypes in this Hispanic sample, but the type and strength of the associations varied by age group.