Awards

The 2023-2024 LAUNCHED Pilot & Feasibility Awardees

Rodrigo Fernandez-Verdejo
Carmen De Miguel
Chirstian Vazquez
Sarah Deemer
Marian Okon
Ifechukwude Biose
Clovis Palmer

Current Projects

Rodrigo Fernandez-Verdejo

Impact of metabolic flexibility on changes in metabolic health

Metabolic flexibility is the capacity to adapt fuel oxidation to fuel availability so that ATP synthesis can match its cellular demands. Enhanced metabolic flexibility has been proposed to protect humans from ectopic lipid accumulation and the subsequent development of insulin resistance and metabolic syndrome. In humans, metabolic flexibility is assessed by measuring changes in glucose and lipid oxidation in response to challenges that increase glucose or lipid availability. The euglycemic-hyperinsulinemic clamp is a widely used challenge to assess metabolic flexibility as it increases glucose availability and thus glucose oxidation. Recently, other methods have been proposed to assess metabolic flexibility, including lipid oxidation during an overnight fast or the changes in 24-hour glucose and lipid oxidation while staying in a metabolic chamber. The influence of metabolic flexibility on metabolic health outcomes remains uncertain. This is partially explained by the cross-sectional nature of the studies and the use of different metabolic challenges. Longitudinal studies using well-controlled methods are required to determine the impact of metabolic flexibility on prospective metabolic health.

In this study, we will use the data from a study conducted 14 years ago in healthy participants without obesity. The study included an euglycemic-hyperinsulinemic clamp, an overnight fasting assessment, a 24-hour stay in a metabolic chamber, and the measurement of metabolic health outcomes. Using the data already collected in that study, we will calculate the metabolic flexibility of each participant in the euglycemic-hyperinsulinemic clamp, the overnight fast, and the metabolic chamber. To test the association between metabolic flexibility(ies) and the change in metabolic health outcomes, we will call back all the participants to reassess several metabolic health outcomes.

Our specific aims are to: [1] Test the association between metabolic flexibility in response to a euglycemic-hyperinsulinemic clamp and the change in metabolic health outcomes after 14 years in humans. [2] Test the association between metabolic flexibility in response to overnight fasting and the change in metabolic health outcomes after 14 years in humans. [3] Test the association between metabolic flexibility in response to a 24-hour stay in a metabolic chamber and the change in metabolic health outcomes after 14 years in humans.

Carmen De Miguel

The Immune ET-1/ETA Axis in Obesity-Induced Kidney Disease

PI: Carmen De Miguel, PhD, MS – Division of Nephrology, Department of Medicine, UAB

Obesity is one of the strongest risk factors for kidney disease. Between 24-33% of kidney disease cases in the United States are associated with obesity. Although the link between obesity and chronic kidney disease has long been known, our understanding of how kidney damage develops and progresses during obesity is critically limited and restricts the available treatments for these patients. Investigating new molecular pathways to target therapeutically is paramount to improve the lives of the many patients living with renal complications of obesity.

Both the innate and adaptive arms of the immune response are altered during obesity and kidney disease; yet, the factors leading to this immune dysregulation are unclear and need urgent investigation. Patients with obesity and kidney disease show elevated levels of the vasoactive peptide endothelin-1 (ET-1) in plasma and kidneys. Actions of ET-1 through its ETA receptor are pro-inflammatory. Importantly, dendritic cells (innate immunity cells) and T cells (adaptive immunity cells) express ETA receptors on their surface, so they are able to respond to changing levels of ET-1. However, there is a significant gap of knowledge regarding whether the ET-1/ETA axis in immune cells drives the kidney disease associated with obesity, or if activation of this immune axis is instrumental for the development of insulin resistance during obesity.

My overall hypothesis is that activation of the ET-1/ETA axis in immune cells is critical for the development of obesity-associated insulin resistance and kidney damage. To clarify the involvement of the ET-1/ETA axis in the innate and adaptive arms of the immune system in these processes, I propose the following 2 aims using two novel KO models:

Aim 1: To determine if activation of the ET-1/ETA axis in dendritic cells is crucial for developing insulin resistance and kidney disease in obesity.

Aim 2: To assess whether activation of the ET-1/ETA axis in T cells drives insulin resistance and kidney disease during obesity.

Christian Vazquez

Latino Cardiometabolic Health: Does Health System-Affiliation Matter?

Compared to national averages and White adults, Latinos have high rates of obesity and diabetes, often among the highest across all racial/ethnic groups in the U.S. These rates are worse for Spanish-dominant Latinos. Latinos are the second largest racial/ethnic group in the U.S. and Spanish is the second most common language. Research has produced mixed findings on whether healthcare utilization leads to better health, and Spanish-dominant Latinos tend to have low rates of healthcare engagement as they are often met with barriers, such as language and insurance. The proposed project aims to examine possible disparities in CMD risk within Spanish-dominant uninsured Latinos by assessing: 1) within group disparities, 2) if barriers are removed, does this population access healthcare/engage with health programs and what might that do to health longitudinally, and 3) what other types of intervention components can help improve engagement with healthcare to reduce CMD risk. Aim 1 will include assessing if those who engaged a healthcare provider in the past year have better Metabolic Syndrome Severity (MSS) Scores compared to a sample who has not engaged with a provider in past year. In aim 2, the PI will determine if MSS Scores differ between the groups at 6 months after all participants have had 1) education on MSS factors (required), 2) access to health programming (optional), and 3) access to medications (optional). For aim 3, the PI will conduct focus groups to understand what types of interventions are needed, acceptable, and preferred for: a) helping increase regular engagement in healthcare, and b) helping increase action to address/maintain health. This proposal will generate novel data and help determine if this research approach/venue is viable, if the results are in the expected direction, and provide effect size estimates to power an R21 to advance CMD research with underrepresented populations.

Marian Okon

Impact of Comorbidities on Clinical Acute Post-Stroke Hyperglycemia

Hyperglycemia commonly occurs acutely in stroke patients and is an independent determinant of mortality and poor functional outcome. Patients who experience acute post-stroke hyperglycemia (APSH) prior to and / or following clinical treatment for stroke are less likely to experience beneficial outcome. Since intensive glucose control with insulin is not beneficial for APSH, more studies are urgently required to define predicting factors which may lead to APSH with the aim of improved understanding as well as clinical management. Recently, major clinical efforts to characterize the pathophysiology and treatment outcomes in patients with APSH have been intensified but little consideration has been given to the potential factors responsible for hyperglycemia at hospital presentation of stroke and following clinical intervention. Hence, we hypothesize that the presence of multiple morbidity and lifestyle factors are associated with the incidence of APSH. To test the stated hypothesis, we propose the following: Aim 1: To determine the association between multiple comorbidity and incidence of APSH; and Aim 2: To describe the association between lifestyle factors and occurrence of APSH.

Dr Clovis Palmer, Ph.D. (TNRPC)

Controlling Diabetes Via Immune Cell Metabolic Remodelling

Expenditure on diagnosed diabetes mellitus continues to increase globally, accounting for an economic burden of approximately US $412.9 billion dollars in 2022 in the USA alone. Yet, despite significant treatment successes, the personal toll of the disease cannot be overlooked. Many individuals suffer from pill fatigue, are unresponsive to available diabetes therapy, or must manage serious treatment side effects.

Inflammation is a major culprit of diabetes progression, but our fundamental understanding of the link between inflammation and diabetes is limited. Immune cells use nutrients, such as glucose to make inflammatory substances in the body that are known to instigate diabetes. In this study we are subjecting non-human primates (Rhesus Macaques) to high fructose diet, with the goal to understanding how “sugary drinks (cool-aid)”, and “sugar preservatives” affect the way immune cells mobilize nutrients to drive inflammation. We will also test whether using an antibody that removes metabolically abnormal immune cells can temper inflammation and resolve diabetes caused by excessive cool-aid consumption. We also aim to identify plasma metabolite prognostic biomarkers that may identify individuals at greater risk for diabetes. Overall, this work is geared toward discovering more effective and tolerable treatment for Type-2 diabetes.

Ifechukwude Biose

Understanding the Neural Basis of Obesity in a Novel Mouse Model

Obesity impacts more than 40% of young adults in the United States, and it is associated with neuroinflammation. We hypothesize that our novel model of polygenic obesity -i.e., the transgenic mouse line with Floxed-stop Expression of IF1 (FEI) have early onset mitochondria dysfunction-induced hypothalamic inflammation which may impair leptin signaling, leading to hyperphagia and obesity. In Aim 1, we will determine if leptin signaling is impaired in the brain at various stages of obesity development in the FEI mice as well as determine whether early treatment with Quercetin, a potent antioxidant flavonoid known to improve mitochondria function, before overt obesity phenotype is sufficient to mitigate the development of obesity. In Aim 2, in addition to quantifying mitochondria dysfunction and hypothalamic inflammation, we expect to characterize the mechanisms underlying spontaneous obesity in our FEI mice by evaluating any changes in the central regulation of feeding as well as early feeding and drinking patterns. The result from the successful completion of this study will uncover the specific mechanism underlying the obese phenotype in among the FEI mice and serve as a pilot study for forming a multi-PI R01 application to NIDDK.

Sarah Deemer

New Insights into Inflammation, Obesity, and Metabolic Health: Identifying Relationships Between
Specialized Pro-Resolving Lipid Mediators (SPMs) and Epigenetic Markers of Obesity

Obesity is recognized as a chronic state of low-grade inflammation suggesting that individuals with obesity may have an impaired ability to resolve inflammation. Inflammation resolution is an active process that is driven by the recruitment of specialized pro-resolving mediators (SPMs) which are derived from omega-3 fatty acids (ω-3 FAs). Omega-3 fatty acids have long shown to have beneficial effects on cardiometabolic health in epidemiological studies, and this could be through their effect on the epigenome, particularly in the regulation of inflammation. However, there is a paucity of information surrounding the association of epigenetics and inflammation resolution. It is the overall objective of this study to 1) identify the relationship between circulating SPMs and ω-3/ω-6 FA concentrations, obesity, and metabolic health; and 2) to investigate the circulating expression of SPMs and the epigenetic regulation of targeted genes previously identified as central to the inflammatory profile. For this pilot study, we aim to recruit adults that are lean and classified as metabolically healthy (n=10), or that have obesity and are classified as metabolically healthy (n=10) or metabolically unhealthy (n=10). Each participant will undergo body composition measurements, dietary analysis, and a 75g oral glucose tolerance test. Blood samples will be drawn and analyzed for glucose, insulin, lipid profile, fatty acid profile, SPMs, and DNA methylation of target genes. It is hypothesized that there will be a direct positive relationship between metabolic health, ω-3 intake, and expression of SPMs. Individuals who are classified as metabolically healthy will have greater expression of SPMs and a greater concentration of ω-3 FAs incorporated into the red blood cell membrane. As an exploratory aim, we will examine the DNA methylation pattern of targeted genes (TNF, NF-κΒ1, PPARG, FADS1/FADS2, CMKLR1, and PTGS2) and relate that to ω-3/ω-6 concentrations, SPM expression, and metabolic health profile. The results from this study may help to further understanding in the biological ‘drivers’ for conversion of metabolically healthy to unhealthy obesity which may help inform future interventions or treatments.

The 2022-2023 LAUNCHED Pilot & Feasibility Awardees

Aline Zaparte
Bruna Visniauskas
Maria Sanchez-Pino

Current Projects

Bruna Visniauskas

A novel link between nocturnal blood pressure and circadian clocks in adipose tissue during menopause

Inadequate sleep disrupts the precise orchestration of circadian clocks, dysregulates glucose metabolism in adipose tissue, and increases the risk for obesity, hypertension, and cardiovascular diseases. Sleep disruption is one of the most common symptoms during the menopausal transition and post menopause, but whether it exacerbates the detrimental impact of menopause on cardiovascular and metabolic function is not known. To fill this knowledge gap, we propose to study the impact of sleep restriction on the cardiometabolic phenotype using a mouse model that mimics menopause. Specific Aim 1: elucidate the direct consequences of estrogen loss and sleep restriction on blood pressure rhythms, and cardiometabolic responses in females fed a high fat diet, and Specific Aim 2: will assess the impact of sleep restriction on blood pressure rhythms and characterize changes in the metabolic profile in a cohort of obese postmenopausal women.

Maria Sanchez-Pino

The Effect of Weight Loss by Pharmacotherapy on Chronic Pro-tumor Inflammatory Cells

Obesity is a progressive disease of excess adiposity that increases the risk of developing many types of cancer. Louisiana has the fifth-highest all-cancer mortality rate in the nation and has the highest rate of severe obesity in the US. Observational studies report that bariatric surgery, an anti-obesity intervention, is associated with a decreased cancer incidence. However, only 1-2% of people get access to bariatric surgery. Therefore, it is essential to understand the anti-neoplastic mechanism underlying bariatric surgery to determine if more accessible treatments, such as medication, could also provide the same clinical benefit operating under the same mechanism. Bariatric surgery reduces body weight, facilitates improvement in metabolic changes, and attenuates inflammation. Evidence indicates that an increased number of myeloid-derived immunosuppressive cells (MDSC) are critical for the long-lasting inflammatory condition that facilitates malignancy. We have found that bariatric surgery significantly reduces the number of circulating low-density neutrophils (LDNs), a subset of inflammatory granulocytic cells that may act as precursors of MDSC. This finding suggests that bariatric surgery could interrupt obesity-induced malignancy by diminishing LDN/MDSC. Whether different modalities of weight management impede LDN/MDSC accumulation, and therefore, mitigate the malignancy risk in obesity, could foster a new treatment paradigm in cancer prevention. Consequently, the overall objective of this application is to determine the ability of weight management with glucagon-like peptide-1 receptor agonists and phentermine/topiramate medications to influence the numbers and functional phenotype of LDN/MDSC in blood. We hypothesize that patients undergoing pharmacological treatment as part of their standard-of-care for obesity, achieving clinically significant weight loss at 6 months (defined as > 5% of total body weight), and metabolic improvement have reduced the number of and altered the inflammatory phenotype of LDN/MDSC in blood. Two specific aims are proposed to test our hypothesis: Specific Aim 1: To determine changes in circulating LDN/MDSC numbers, BMI, and inflammatory and metabolic markers after weight loss medication compared to baseline; and Specific Aim 2: To determine the contribution of medication on LDN/MDSC phenotype.

Aline Zaparte

Broccoli extract supplementation and gastrointestinal health in older adults with active alcohol use and low diet quality

Aging confers an increased susceptibility to multimorbidity, in part due to dysregulated immunity and oxidative stress. Alcohol use disorder (AUD) in older adults is increasingly prevalent, as is poor nutritional status. Drinking is the 3rd most prevalent health behavior associated with adverse health outcomes in the United States and emerging data suggest an interaction with diet. Our group has reported that higher lifetime alcohol consumption is associated with geriatric frailty syndrome. Further, in both preclinical models and in humans, we have reported that alcohol impairs the gastrointestinal barrier and promotes mucosal inflammation, which contributes to distal end-organ disfunction, in part mediated by intestinal dysbiosis. In preliminary studies to support this pilot project in humans, we tested generally recognized as safe (GRAS) compounds in rodent model of alcohol use as a strategy to mitigate detrimental effects of gut leak and inflammation. Broccoli is considered a health-promoting food, and its efficacy has been tested with diseases closely related with geriatric comorbidities, such as neurodegenerative diseases, cancer, and osteoporosis. Our preclinical experiments using broccoli sprouts extract (BSE) showed significant reductions in alcohol-induced gut barrier leak, inflammation, and oxidative stress. My hypothesis is that BSE will reduce gut leak and systemic biomarkers of inflammation and oxidative stress. My hypothesis will be tested in a pilot clinical trial testing in effect of 4 weeks BSE diet supplementation in older adults that consume alcohol and a nutritionally poor diet. Specific Aim 1: To test the effect of BSE on gut leak using PEG400 translocation. Specific Aim 2: To test the effect of BSE on peripheral blood pro-inflammatory mediators and immune cells. Specific Aim 3: To test the effect of BSE on oxidative stress and antioxidant capacity in peripheral blood.