Obesity has been on the rise over the last 30 years, reaching worldwide epidemic proportions. Obesity has been linked to multiple metabolic disorders and co-morbidities such as Type 2 Diabetes Mellitus (T2DM), cardiovascular disease, non-alcoholic steatohepatitis and various cancers. Furthermore, obesity is associated with a chronic state of low-grade inflammation in adipose tissue (AT), and it is thought that insulin resistance (IR) and T2DM is associated with the inflammatory state of AT. Endothelial cells (ECs) mediate the migration of immune cells into underlying tissues during times of inflammation, including obesity- and cardiovascular disease-associated inflammation. Cytokines and chemoattractants released from inflamed tissues promote EC activation. Upon activation, ECs increase the expression of leukocyte adhesion molecules (LCAMs) including intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), E-selectin (E-sel) and P-selectin (P-sel). Increased expression of these LCAMs and increased infiltration of inflammatory cells such as macrophages, have been linked to IR, diabetes and atherosclerosis in obese individuals. Preliminary data from our lab suggests that lipolysis induced by the β-adrenergic receptor agonist CL 316,243 causes an increase in endothelial LCAM gene expression. In addition, histological analyses show increased content of immune cells within AT after the ECs become activated. Here, we demonstrate that CL 316,243-induced lipolysis causes infiltration of neutrophils in wild type (WT) but not E-sel knockout (KO) mice. Following EC activation, there was also a marked increase in cytokine gene expression including IL-1β, MCP-1, and TNF-α in an E-sel-dependent manner. In contrast, fasting-induced lipolysis was associated with increased macrophage infiltration into AT in the absence of EC activation in an E-sel-independent manner. We also examined the role of mitogen activated protein kinase kinase kinase kinase 4 (MAP4K4) as a potential contributor to endothelial activation and atherosclerosis. Here we demonstrate that deletion of MAP4K4 in ECs in vitro diminishes TNF-α-induced EC activation. Additionally, MAP4K4 depletion in primary ECs derived from lungs of mice expressing MAP4K4 shRNA decreases EC activation. Finally, endothelial specific depletion or loss of MAP4K4 reduced atherosclerotic plaque formation in vivo. Taken together, these results highlight the importance of the endothelium in modulating obesity-associated comorbidities. Furthermore, these data implicate endothelial MAP4K4 as a novel regulator of EC activation and consequently AT inflammation and atherosclerosis.

Purpose: This qualitative descriptive study was undertaken to describe Eastern Woodlands Native adult perspectives, health care beliefs and type 2 diabetes management experiences. Specific Aims: The specific aims were to 1) explore and describe perceptions of type 2 diabetes among Eastern Woodland Native adults and how they relate to their understandings about the cause and treatment approaches to the disease, 2) describe how family, friends, and community intersect with type 2 diabetes management, 3) describe relationships with health care providers and 4) determine resources that would help diabetes-self management within their community. Framework: The PEN-3 Model by Airhihenbuwa was the initial framework used for the study. Methods: A qualitative descriptive design with maximum variation and snowball sampling was used and data was analyzed using qualitative content analysis. Results: The overarching theme of Together We Can Return To Balance comprised five sub-themes: Coming to Know Life Paths with T2DM, Negotiating My Way Forward, Making Important Connections, Acknowledging the Imbalance, and Sticking Closer to Mother Earth illustrating physical, spiritual, and environmental health factors influencing DSM capacities. Conclusion: Native perspectives should be viewed as a crucial contextual variation for type 2 diabetes care when developing DSMES and for improving DSM capacities in these populations.

Obesity accounts for $168 billion in annual medical expenses and increases the risk of cardiovascular disease, cancer, and type-2 diabetes, three diseases responsible for over 50% of deaths in the United States. It is well established that the pattern of adiposity is an important factor in the relationship with disease risk and that visceral adiposity, which favors hypertrophy (characterized by enlarged cells) is more dangerous than subcutaneous adiposity, which tends to be hyperplastic (characterized by an increase in cell number). Hypertrophy is associated with inflammation and insulin resistance, and hyperplasia (adipogenesis, i.e., the formation of new adipocytes), is associated with improved insulin sensitivity. Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine that activates a nuclear factor-kappa B (NFKB) intracellular pathway that is an important mediator of obesity-associated insulin resistance and increased risk of type-2 diabetes. Interestingly, obesity has been positively associated with both low vitamin D status and elevated levels of TNF-alpha. Our studies focused on examining the influence of the active vitamin D hormone, 1,25-dihydroxyvitamin D, and TNF-alpha on adipogenesis and inflammation in human primary adipocytes and determining whether the balance of these two factors influences the extent to which adipocytes accumulate lipid or express pro-inflammatory cytokines. We found no effect of 1,25-dihydroxyvitamin D on adipogenesis or pro-adipogenic gene expression despite a clear upregulation of a vitamin D responsive gene, 24-hydroxylase, in response to treatment with 1,25-dihydroxyvitamin D. TNF-alpha clearly inhibited adipogenesis and expression of PPAR-gamma and C/EBP-alpha and enhanced expression of the pro-inflammatory cytokines IL-6 and MCP-1, but not IL-8. There was a trend towards a dose-dependent downregulation of MCP-1 by 1,25-dihydroxyvitamin D in three individuals; however, this effect was not statistically significant. While we found no interaction between TNF-alpha and 1,25-dihydroxyvitamin D on adipogenesis, there is a potential anti-inflammatory action of 1,25-dihydroxyvitamin D in human primary adipocytes. Future studies into this potential are warranted in light of the growing obesity epidemic and the interest in finding nutritionally modifiable treatment or prevention strategies to mitigate the negative consequences of obesity.

37.3 million Americans (11.2% of the US population) currently have Type 2 diabetes mellitus (T2DM) with over 1.5 million new cases being diagnosed each year. The multifactorial etiology of the patient having neuropathy, overweight/obesity, foot deformities, ischemia, and infection leads to a condition called diabetic foot ulcer (DFU). One in six patients with a DFU will require amputation with infected DFUs have a 155-fold increased risk of amputation. Staphylococcus aureus is the most common bacteria isolated from severe DFU infections that require amputation. Interestingly, diabetics are more heavily colonized with S. aureus compared to non-diabetics suggesting a unique advantageous adaptation to diabetes. The specifics of the underlying molecular mechanisms and triggers by which S. aureus adapts and thrives in the T2DM patient that increase its pathogenicity and colonization compared to non-diabetics with skin ulcer infections are not fully elucidated. Thus, our studies aimed to identify the key virulence components in the pathogenesis of S. aureus infected DFUs and using that information to develop therapeutics aimed at disrupting these components to increase the success rate of conservative treatment and prevent non-traumatic lower extremity amputations in T2DM patients. Our studies found that several different elevated sugars in T2DM patients can trigger virulence factor production in S. aureus. We also found by comparing several different clinical DFU S. aureus isolates that there are clear differences in the ability of each isolate to cause necrotic infections. And lastly, we identified a possible therapeutic, the amino acid L-arginine, that can help prevent/treat S. aureus infections in the Tallyho diabetic mouse model. In conclusion, we have increased the understanding of the pathogenesis of S. aureus infected DFU and have proposed a possible therapeutic to add to the conservative treatment regimen.

Background: A diet rich in vegetables, fruits, grains, fat-free or low-fat dairy, and proteins is known to have multiple beneficial health effects. However, a very limited number of studies have characterized food group intake and its association with cardiometabolic risk factors in Hispanic children. Objectives: The objectives of this study were to 1) assess food group intake in a sample of Hispanic children; and 2) examine the association between food group intake and overweight and elevated blood pressure in the same population. Methods: Data came from a pilot study of metabolic syndrome in Hispanic children. The study sample consisted of 116 2-to-10-year-old children receiving well-child care at a community health center in Johnson City, TN, from June 2015 to June 2016. Blood pressure, height and weight were measured using standard protocols. Food group intake was ascertained using the Block Kids Food Screener, a validated instrument. Child’s age, sex, and mother’s educational attainment were included as covariates. Binomial test of proportions was used to compare the study sample with the National Health and Nutrition Examination Survey (NHANES) gender-age group proportions not meeting recommended daily food group intake. Two sample t-test was used to examine differences in mean food intake by outcome variables of elevated blood pressure (>=90th percentile for age and sex) and being overweight (>85th percentile of the 2000 CDC growth charts). Multiple logistic regression was used to examine the association between food group intake and elevated blood pressure and being overweight while accounting for child's sex, age, and mother's educational attainment. Results: Hispanic children exceeded minimum fruit and legume national recommendations. Compared with the corresponding NHANES gender-age groups, a larger proportion of the sample met legume recommendations. However, similar proportions met fruit, vegetable, wholegrain, fiber and dairy recommendations. Children with elevated blood pressure ate less fruits, vegetables, and legumes than children with normal blood pressure. Legume intake (OR: 0.052, 95% CI: 0.04-0.64), dairy intake (OR: 0.61, 95% CI: 0.37-0.99), and fiber intake (OR: 0.88, 95% CI: 0.81-0.96) were protective against elevated blood pressure. In contrast, only fruit intake was protective against overweight (OR: 0.93, 95% CI: 0.87-0.99). Conclusion: Public health nutrition programs aimed at reducing the prevalence of overweight and elevated blood pressure in Hispanic children should consider supporting the intake of legumes, dairy, and fiber (for decreasing elevated blood pressure), and fruits (for reducing overweight).

Maternal obesity, physical inactivity, and negative perceptions of neighborhoods have been identified as obesogenic factors in older children; however, no study has explored this relationship in young Hispanic children. Furthermore, the relation between obesogenic maternal factors and blood pressure in Hispanic children has not been examined. Objectives: This study aimed to assess the association between Hispanic mother’s physical activity (PA) levels, body mass index (BMI), and PA-related perceptions of neighborhoods and their children’s PA, TV screen time, blood pressure (BP), and BMI. Methods: Data of 118 mother-child dyads enrolled in a cross-sectional study of metabolic syndrome in Hispanic children at a community health center in Johnson City, TN were used. Parent and child questionnaires were used to ascertain mother’s BMI, PA, perception of the safety and availability of PA amenities in their children’s neighborhoods, satisfaction with their children’s neighborhoods as a place to bring up children, and children’s PA and TV screen time. Children’s height, weight, and BP were measured. Multiple logistic regression was used to examine the association between child and maternal variables, adjusting for mother’s education and the child’s sex and age. Results: Children of obese mothers were more likely than children of mothers with normal BMI to engage in less than three days of at least 60 minutes of vigorous PA per week (OR: 6.47: 95% CI: 1.61-26.0). Children whose mothers did not engage in moderate PA were more likely to engage in less than three days of at least 60 minutes of vigorous PA per week (OR: 2.92, CI: 1.18-7.24); and have elevated BP (OR: 2.50, 95% CI: 1.02-4.53) than children whose mothers engaged in moderate PA. Conclusion: Our results suggest the need for interventions to help Hispanic mothers model physical activity and achieve and maintain healthy weight; if successful, these strategies could potentially influence their children’s blood pressure and physical activity levels.

As the prevalence of vitamin D deficiency continues to grow, mounting evidence supporting its link with chronic disease strengthens suggesting vitamin D’s candidacy in the prevention and treatment of multiple disease states and their complications. Dietary guidelines, however, do not take sun exposure into account. The present study sought to explore the impact of sun exposure on vitamin D status (serum 25(OH)D), and identify other significant determinants of serum levels which may have the greatest effects on overall health. Participants (n = 34) were pre-menopausal women aged 18 to 50 years (mean age 39 ± 6 years), who had their blood drawn at a local pathology lab and a follow-up appointment at a health assessment lab for the collection of other measurements. Mean serum 25(OH)D level was 64 ± 18 nmol/L, and mean dietary vitamin D intake was approximately 327 ± 229 IU/day. Although 82% of participants were below the RDA guidelines (600 IU/day for females ages 9-50 years) for dietary vitamin D intake, only 32% had serum 25(OH)D levels < 50 nmol/L (the recommended level of sufficiency for bone health) reflecting deficiency. While serum 25(OH)D levels were significantly correlated to dietary vitamin D intake (r = 0.42, p = 0.0139), it is reasonable to assume that participants obtained adequate vitamin D from sun exposure. Fasting serum insulin levels were significantly, positively correlated with BMI (r = 0.83, p < 0.0001), and sun exposure index (Body Surface Area x Minutes of Direct Sunlight) was significantly, positively correlated with serum 25(OH)D levels (fall weekend SEI: r = 0.47, p = 0.0059; spring weekend SEI: r = 0.43, p = 0.0135; average weekend SEI: r = 0.43, p = 0.013; and average overall SEI: r = 0.39, p = 0.0247). Reported sun exposure appeared to be least during winter weekdays and the most during summer weekends. Regression analysis was used to determine the strongest predictors of serum 25(OH)D levels, which were found to be sun exposure, dietary vitamin D intake, skin reflectance, age, BMI, and ethnicity (R2 = 0.58 , p = 0.0031), demonstrating that simple questionnaires, such as those employed in this study, can help to predict serum 25(OH)D status and thus be considered in the future treatment of vitamin D deficiency.

The prevalence of non-alcoholic fatty liver disease (NAFLD) in children has increased over the past decades, creating a need for animal models that recapitulate the features of the pediatric disease. Iberian pigs have a leptin-resistant phenotype characterized by hyperleptinemia, hyperphagia, and extreme adipogenesis. We hypothesized that neonatal Iberian pigs fed a high fat high-fructose (HFF) diet will develop a pattern of liver injury resembling pediatric NAFLD. In addition, we sought to determine if a mixture of probiotics would prevent the disease. Animals were fed 1 of 4 diets containing (g/kg body weight × d) 0 g fructose, 11 g fat and 199 kcal (CON-N; n=8), 22 g fructose, 16 g fat and 300 kcal (HFF2-N; n=8), CON + probiotic (CON-P; n=6), or HFF2 + probiotic (HFF2-P; n=6) every 6 h for 70 d. The probiotic mixture (6.2 × 104 cfu/mL) contained Pediococcus acidilactici, Pediococcus pentosaceus, Lactobacillus plantarum and Bacillus amyloliquefaciens. Body weight was recorded every 3 d. Serum markers of liver injury and dyslipidemia were measured on d 40 and 65 at 2 h post feeding. Fasting leptin, insulin, glucose and homeostatic model assessment (HOMA) values were assessed on d 70. Liver and skeletal muscle (longissimus dorsi) were collected on d 70 for histology, triacylglyceride (TAG) quantification, relative gene expression, and Western blot analysis. Metabolomic analysis was performed on liver tissue and plasma. Body weight was not significantly greater in HFF fed pigs compared to CON. Leptin, alanine and aspartate aminotransferases, alkaline phosphatase, lactate dehydrogenase and total bilirubin were increased (P ≤ 0.001), and high and low density lipoproteins decreased (P ≤ 0.05) in HFF2-N and HFF2-P. Livers in HFF2-P and HFF2-N had higher relative weight and TAG (P ≤ 0.001), micro and macrovesicular steatosis, ballooning degeneration, Mallory-denk bodies, inflammation and necrosis, increased gene expression of TNFα, TGFβ, IL1α and PPARγ (P ≤ 0.001), and decreased ChREBP (P ≤ 0.001). A probiotic affect was seen as pigs fed CON-P and HFF2-P had higher insulin and HOMA values were increased (P ≤ 0.05). Western blot analysis showed dysregulation of autophagy in liver of pigs fed CON-P and HFF2-P, and in skeletal muscle of pigs fed CON-N and HFF2-N. Metabolomic analysis demonstrated dysregulation of one-carbon metabolism, the tricarboxylic acid cycle (TCA), the urea cycle, and amino acid metabolism of pigs fed HFF2 diets compared to CON diets. In conclusion, Iberian pigs fed a HFF diet recapitulate many pediatric NAFLD-associated features, in the absence of obesity and independently of probiotic supplementation, suggesting a potentially suitable model for pediatric NAFLD research. Furthermore, probiotic supplementation did not ameliorate the onset of NAFLD when fed in conjunction with a HFF diet.

Childhood obesity is a foremost concern throughout the health care community. Approximately 17.6% of the pediatric population meet the criteria for obesity, which can lead to health disparities later in life, such as hypertension, type 2 diabetes mellitus, and metabolic syndrome. Emerging mobile and wearable lifestyle tracking devices can be a viable solution to the challenging problem of childhood obesity through behavior changes, feasibility, and adherence. The purpose of this literature review was to determine the effect that mobile and wearable activity tracking devices have on the obese pediatric population. A centralized review of the literature was conducted using various data basesand resulted in 19 articles. 5 articles were chosen to review in more detail. 13 other articles were hand searched through credible resource citations, rendering 14 articles that met all criteria. The three general themes found in this literature review suggest that wearable activity tracking devices can be designed and effectively used by the pediatric population. Also, wearable activity tracking devices are accurate in conveying information on physical activity, calories, and heart rate. Lastly, wearable activity tracking devices can initiate behavioral changes in children leading to an increase in physical activity, resulting in the prevention and treatment of pediatric obesity.While in a majority of the studies analyzed trails were short. The research suggests wearable activity tracking devices will produce the desired results of increased activity in pediatric populations when they are worn correctly, are adequately engaging, and when they are designed in a feasible manner that is appealing to children.

Arterial blood pressure (BP) undergoes a 24-hour oscillation that peaks in the active day and reaches a nadir at night during sleep in humans. Reduced nocturnal BP fall (also known as non-dipper) is the most common disruption of BP circadian rhythm and is associated with increased risk of untoward cardiovascular events and target organ injury. Up to 75% of diabetic patients are non-dippers. However, the mechanisms underlying diabetes associated non-dipping BP are largely unknown. To address this important question, we generated a novel diabetic db/db-mPer2Luc mouse model (db/db-mPer2Luc) that allows quantitatively measuring of mPER2 protein oscillation by real-time mPer2Luc bioluminescence monitoring in vitro and in vivo. Using this model, we demonstrated that the db/db-mPer2Luc mice have a diminished BP daily rhythm. The phase of the mPER2 daily oscillation is advanced to different extents in explanted peripheral tissues from the db/db-mPer2Luc mice relative to that in the control mice. However, no phase shift is found in the central oscillator, the suprachiasmatic nucleus (SCN). The results indicate that the desynchrony of mPER2 daily oscillation in the peripheral tissues contributes to the loss of BP daily oscillation in diabetes. Extensive research over the past decades has been focused on how the components of food (what we eat) and the amount of food (how much we eat) affect metabolic diseases. Only recently has it become appreciated that the timing of food intake (when we eat), independent of total caloric and macronutrient quality, is also critical for metabolic health. To investigate the potential effect of the timing of food intake on the BP circadian rhythm, we simultaneously monitored the BP and food intake profiles in the diabetic db/db and control mice using radiotelemetry and BioDAQ systems. We found the loss of BP daily rhythm is associated with disrupted food intake rhythm in the db/db mice. In addition, the normal BP daily rhythm is altered in the healthy mice with abnormal feeding pattern, in which the food is available only during the inactive-phase. To explore whether imposing a normal food intake pattern is able to prevent and restore the disruption of BP circadian rhythm, we conducted active-time restricted feeding (ATRF) in the db/db mice. Strikingly, ATRF completely prevents and restorers the disrupted BP daily rhythm in the db/db mice. While multiple mechanisms likely contribute to the protection of ATRF on the BP daily rhythm, we found that ATRF improves the rhythms of energy metabolism, sleep-wake cycle, BP-regulatory hormones and autonomic nervous system (ANS) in the db/db mice. To further investigate the molecular mechanism by which ATRF regulates BP circadian rhythm, we determined the effect of ATRF on the mRNA expressions of core clock genes and clock target genes in the db/db mice. Of particular interest is that we found among all the genes we examined, the mRNA oscillation of Bmal1, a key core clock gene, is disrupted by diabetes and selectively restored by the ATRF in multiple peripheral tissues in the db/db mice. More importantly, we demonstrated that Bmal1 is partially required for ATRF to protect the BP circadian rhythm. In summary, our findings indicate that the desynchrony of peripheral clocks contributes to the abnormal BP circadian pattern in diabetes. Moreover, our studies suggest ATRF as a novel and effective chronotherapy against the disruption of BP circadian rhythm in diabetes.