Past Pilots

Malgorzata E. Skaznik-Wikiel, MD

Dates of funding: 2018-2019

Ovulatory dysfunction is responsible for 25% of cases of subfertility and is frequently present in women with excessive body weight. Specifically, a high-fat intake causes excessive storage of lipid in non-adipose tissue, including the ovary, which can affect its physiological function and result in reproductive dysfunction in women. Recommended daily intake of fat is 20-30% of total calories, but most American women consume a diet containing at least 35%. Therefore, it is important to consider the impact of elevated dietary fat in ovarian dysfunction, especially as diets promoting high fat intake are becoming very popular, some resulting in a significant weight loss. There is theoretically a considerable population of women impacted by HFD-induced reproductive dysfunction of which the burden and mechanistic causes of action are undetermined. One potential reason why HFD causes an abnormal ovulatory function includes changes in genes critical to normal ovarian function. Endothelin-2 (Edn2), which is crucial in ovulation, was the most significantly altered gene upon exposure to HFD in my previous studies, regardless of obesity. Endothelin-2 (ET-2) is a recently identified protein that is secreted by ovarian granulosa cells and plays a critical role in ovulation and corpus luteum formation. The mechanisms regulating Edn2 expression in the ovary are not clear and in some cases controversial. Therefore my current research focuses on investigating mechanisms behind abnormal Edn2 expression in HFD exposure. Our central hypothesis is that HFD leads to diminished ovarian estrogen receptor (ER) signaling, with subsequent Edn2 downregulation and impaired ovulation. The knowledge that will be gained from the proposed experiments is critical to understanding the mechanisms behind HFD-induced ovulatory dysfunction. This new knowledge will help me uncover some important clues in previously unexplained ovulatory dysfunction and subfertility and design potential treatment strategies in women in the future.

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Ana Andres-Hernando, DVM, PhD

Dates of funding: 2018-2019
Research Associate, Department of Renal Diseases and Hypertension

Role of fructose in early life predisposition to childhood obesity
Rates of obesity and its co-morbidities are increasing alarmingly throughout the world due to a complex mix of dietary, environmental, and behavioral factors.  Of great concern, 15% of 2-5 year-old children in the U.S. are now obese and more than one third (36,5%) of US adults are obese. Obesity-related conditions include heart disease, stroke, type 2 diabetes and certain types of cancer, some of the leading causes of preventable death. Significantly, emerging evidence indicates that the risk factors associated with obesity and other aspects of metabolic syndrome (MetS) may exert their influence prenatally. Hyper-caloric intake of fat and nutritive sweeteners, such as high-fructose corn syrup, plays perhaps the most crucial detrimental role in this epidemic. However, avoidance of dietary sugar has become increasingly challenging as it is frequently added to all types of food. Our group has focused on the fructose component of sugar in the pathogenesis of metabolic disease and we are actively involved in identifying modifiable biological factors contributing to sugar-induced MetS. Among these potential targets, we have identified the enzyme fructokinase, which catalyzes the first step in conversion of fructose into fat and calories, as a potential candidate to slow the progression of MetS induced by sugar. If the hypothesis tested in this proposal is correct, our findings will lead to new therapeutic approaches to combat the current epidemics of metabolic syndrome and obesity in kids. More specifically, our work will lead to the potential discovery and use of fructokinase inhibitors and fructokinase knockout derived probiotics to be used during pregnancy and lactation to significantly reduce the risk of developing metabolic syndrome during childhood.

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Jayne Martin-Carli, PhD

Dates of funding: 2018-2019
Postdoctoral Fellow at University of Colorado Anschutz Medical Campus

While breastfeeding is known to improve neonatal and long-term health outcomes in humans, many mothers, especially those with obesity or insulin resistance, have difficulty initiating and/or maintaining sufficient milk production to sustain breastfeeding. Exclusive and extended lactation protects against subsequent metabolic impairments in these mothers, who are at increased risk of developing type 2 diabetes, and in their offspring, who are at elevated risk for prediabetes during youth. However, basic biological mechanisms and physiological processes regulating lactation initiation and adequate milk production remain poorly understood. The focus of this proposal is to evaluate insulin signaling in mammary epithelial cells in women with insulin resistance during pregnancy with regard to their lactation outcomes. The results from this study will lay a foundation upon which to develop rational interventions and/or therapeutic strategies to improve breastfeeding outcomes.

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Laura Hudish, PhD

Dates of funding: 2018-2019

Diabetes affects more than 20 million people in the United States, or roughly 1 of out 11 individuals and obesity-induced diabetes incidence is steadily increasing. Despite great efforts, there is unfortunately still no cure. The best treatments for the disease require constant and diligent patient management and even when managed appropriately, the disease can still lead to serious complications like heart disease, blindness, and amputation. We have long known that obesity is a great risk factor for diabetes, however, many of the disrupted genetic pathways that contribute to the disease are still unknown. My proposal seeks to identify novel molecules involved in the onset and/or progression of diabetes with the ultimate goal of discovering effective therapeutics for the many patients affected by diabetes. In particular, I am focusing on a novel class of molecules called long non-coding RNAs (lncRNAs), which were previously unknown to be important in biology, but contain properties that facilitate therapeutic targeting. In this study, I have identified a new lncRNA that becomes highly upregulated in the β cells of several obese-diabetic mouse models and islets from obese diabetic patients. We hypothesize that this lncRNA is important for the onset and/or progression of diabetes and we propose a set of studies to determine its specific role during disease development and assess whether targeted disruption of its expression can improve β cell function and patient outcomes.

Josiane Broussard, PhD

Dates of Funding: 2017-2019
Assistant Professor, Department of Health and Exercise Science, Colorado State University Assistant Professor, Division of Endocrinology, Metabolism and Diabetes, University of Colorado, Anschutz Medical Campus

The Impact of Insufficient Sleep on Peripheral Metabolic Tissues

Short nightly sleep duration and untreated sleep disorders are now recognized as risk factors for metabolic diseases with more than 35%of Americans sleeping less than the recommended 7 hours/night. Acute, experimental sleep restriction studies have demonstrated inadequate sleep alters glucose homeostasis, primarily by decreasing whole-body insulin sensitivity. However, the mechanisms responsible for the adverse effect of sleep restriction on insulin sensitivity are not known and understanding the effects of sleep restriction on other metabolic tissues is in its infancy. Our long-term goal is to demonstrate the importance of adequate sleep duration and to establish sleep as a third pillar of health—in addition to diet and exercise—in the maintenance of cellular, tissue and whole-body metabolic homeostasis. The overall objective for this project is to determine how insufficient sleep impairs insulin sensitivity in peripheral metabolic tissues biopsied from healthy young lean men and women after normal and insufficient sleep.

Sarah Wherry, PhD

Dates of Funding to: 2016-2019

PTH and Calcium responses to Exercise in Older Adults (PACE Sr.)

Age-related increases in osteoporotic fracture are associated with a large healthcare burden. Weight-bearing exercise is recommended to prevent osteoporosis, but emerging evidence indicates exercise may not always result in osteogenic benefit. Preliminary work suggests calcium losses during exercise triggers increases in bone resorption and are attenuated by calcium supplementation. Therefore, the global aim is to investigate nutritional contributions to calcium homeostasis, including calcium needs during exercise. SA1 will determine if preventing serum ionized calcium (iCa) declines during exercise prevents increases in bone resorption. Participants will complete walking bouts under conditions of 1) intravenous calcium infusion (prevent iCa decline) and 2) volume-matched saline infusion. We hypothesize that exercise will stimulate resorption to stabilize iCa concentration more under the saline condition. Additionally, SA1 will measure calcium infusion amounts needed to prevent iCa declines. SA2 will determine how bisphosphonate medication impacts this relationship. Bisphosphonates diminish osteoclast activity, which is believed the be the cell primarily responsible for bone resorption during exercise. However, if bone resorption still increases during exercise, this would suggest that the osteocyte contributes to calcium homeostasis. To our knowledge, this will be the first study investigating osteocytic osteolysis in vivo in humans. Combined, these experiments will inform future supplementation trials to determine calcium recommendations. Long-term, this may lead to improved bone adaptations and reduced osteoporosis-related incidents.

Tanya Halliday, PhD

Assistant Professor at the University of Utah

Influence of Acute Exercise Modality on Hormonal and Behavioral Appetite Regulation and Energy Intake

Lifestyle interventions are often successful in promoting weight loss, but maintenance of weight loss  is often unsuccessful due to biological and behavioral adaptations that favor weight regain. The efficacy of exercise for weight loss and weight loss maintenance is often attributed to its effect on increasing energy expenditure, but exercise may assist in weight management by improving    appetite regulation and helping individuals control energy intake (EI). While promising, research is limited, findings are inconclusive, and mechanisms by which exercise influences appetite regulation remain unknown. Furthermore, most studies have focused on aerobic exercise (AEx), and the few involving resistance exercise (REx) have primarily studied normal weight adults. Therefore, it is unknown how different exercise modalities, and specifically REx, may uniquely influence appetite regulation and EI in overweight/obese (OW/OB) adults. The primary goal of the proposed study is to compare the acute effects of REx and AEx in OW/OB adults on appetite regulation and EI. To   achieve this goal, appetite ratings, appetite-related hormones, eating-related behaviors, and EI will   be compared following acute bouts of Rex, AEx, and a sedentary control condition. Results of this study will provide insight on how exercise modality deferentially influences acute appetite and EI.

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Scott Ferguson, PhD

Dates of funding 2017-2019

Impact of dietary nitrate supplementation via beetroot juice on skeletal muscle metabolic control and exercise tolerance in sickle cell anemia

Sickle Cell Disease results in severely compromised exercise capacity, and thus the quality of life, for those afflicted. This is due to both central cardiopulmonary and peripheral vascular factors which conspire to reduce maximal oxygen uptake (VO2max) and instill premature fatigue during exercise. SCD results in high rates of hemolysis and the resulting release of free-hemoglobin (HB) rapidly scavenges nitric oxide (NO) resulting in impaired cardiovascular control. Our work focuses on the impact of Hb on skeletal muscle vascular and metabolic control as this is likely a primary mechanism of peripheral vasculopathy and exercise decrement in SCD.

Over the past decade, a plethora of investigations have demonstrated the robust efficacy of dietary nitrate supplementation in the treatment of many prevalent diseases related to loss of NO bioavailability; accordingly, it has been hailed as an “unrecognized nutrient.” Previous investigations in humans and animals have demonstrated that NO3, when consumed, serves as a powerful controller of muscle O2perfusion, presumably following its reduction to nitrite (NO2) and NO in vivo. Collectively, these results strongly support the premise that dietary NO3 as a nutritional therapeutic will ameliorate Hb-mediated NO depletion for patients with SCD, and therefore evoke improved exercise tolerance and quality of life. Thus, this project is aimed at uncovering the mechanistic basis for skeletal muscle dysfunction in SCD and the therapeutic potential of dietary NO3 in preclinical models of this disease. Results from these investigations will directly impact the design of future clinical studies at the University of Colorado, Denver in the coming years.

Veronica Ferchaud Roucher, PhD

Dates of funding: 2018-2019

University of Colorado, Anschutz Medical Campus · Obstetrics and Gynecology Department, Division of Reproductive Sciences

Jacinda Nicklas, M.D., MPH/MSPH
Dates of funding: 2014-2018
Assistant Professor, Medicine-Internal Medicine

“My research focuses on women's health, obesity, weight loss, and disease prevention. Her main project during fellowship was the TEAM GDM (Taking Early Action for Mothers with Gestational Diabetes Mellitus) study, where she and a team of researchers at Brigham and Women's Hospital developed and tested Balance after Baby, a web-based lifestyle intervention program for women with recent gestational diabetes. She is currently developing a mobile health lifestyle intervention program called Fit After Baby for postpartum women at high risk for cardiometabolic disease.”
Amy Keller, P.h.D.
Dates of funding: 2014-2017
Assistant Professor, Division of Endocrinology, Metabolism, & Diabetes, University of Colorado School of Medicine

In people with diabetes (DM), cardiovascular disease, (CVD) is a major cause of death; this is not alleviated by CVD management or standard treatments for DM. Vascular contractility and mitochondria dysfunction are not only associated with hyperglycemia, decreased antioxidant defense, and insulin resistance, but precede vascular inflammation, vascular stiffness, and smooth muscle cell (SMC) apoptosis. As we and others have shown that nitric oxide synthase (NOS) enzymes regulate contractility and mitochondrial function, targeting NOS recoupling is a potential strategy for novel vasculature therapeutics in DM. Sepiapterin, a NOS coupler, has been shown to restore NOS function both in vivo and in vitro. Our findings in vivo with sepiapterin supplementation include an unexpected beneficial effect on blood glucose. This compound also significantly normalized both vascular contractility and mitochondrial function. This proof-of-concept study provided a platform for the research of other potentially bioactive and multifactorial compounds, sourced from medicinal plants, as homeostasis regulators in the diabetic vasculature. To date, we have continued our in vivo and in vitro studies begun in our pilot award, and broadened our investigation of other in vivo function and cellular mechanisms of action. (-)-epicatechin (EPICAT), a compound found in food and known to modulate NOS activity is central to our current work, and we and others have shown that it restores vascular relaxation and modulates mitochondrial activity. Overall, our research continues to investigate whether disrupted cellular homeostasis intrinsic to the DM vasculature can be restored by reestablishing physiological NOS regulation and mitochondrial fuel metabolism.