BLRD Merit Review Research Career Scientist (RCS) Award (IK6)

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The prevalence of obesity and associated co-morbidities, including type 2 diabetes and cardiovascular disease, has increased dramatically in the past several decades. It is well-established that an immune component contributes to the etiology of metabolic diseases – especially when driven by obesity. For example, nearly all of the immune cells in existence have been shown to reside in adipose tissue (AT). Resident macrophages in AT are thought to contribute to development and proper function of the AT by various homeostatic functions. During weight gain, the numbers and phenotypes of all of the immune cells in AT change such that the overall milieu becomes pro-inflammatory, promoting insulin resistance at the tissue and systemic levels. The Hasty laboratory currently has 2 main areas of investigation in this burgeoning area of immunometabolism: Immunologic memory to weight loss and weight cycling: While weight loss is the ideal approach to reduce the negative metabolic consequences of obesity, it is clear that sustained weight loss is difficult to achieve. Bouts of weight loss followed by subsequent weight-gain lead to “weight-cycling”. Interestingly, several studies in humans demonstrate that weight-cycling increases the risk of developing metabolic diseases. Dr. Hasty and others have published data showing antigenic responses in AT during weight gain. Thus, she has developed the hypothesis that weight-cycling results in a T cell-driven secondary immune response that heightens inflammation in AT, leading to local and systemic insulin resistance (IR). In addition, she has begun to study whether macrophages also “remember” the obesogenic environment in a process called trained innate immunity. This work is funded by her VA Merit Award and by a new Innovation award from the American Heart Association. Macrophage iron handling: Dr. Hasty’s group discovered a novel population of macrophages in AT that are critical for control of local iron concentrations, thereby contributing to adipogenesis and to protection from oxidative stress. Her laboratory’s recent advances offer an excellent opportunity to define a role for resident AT macrophages in iron-related control of AT homeostasis. The intrinsic immunometabolism, i.e. fuel utilization and bioenergetics of the cell, and extrinsic immunometabolism, i.e. secreted products that affect the surrounding tissue environment, are manipulable properties that influence how macrophages contribute to tissue homeostasis. We will determine how iron cycling influences both arms of the immunometabolic role of AT macrophages, thereby influencing systemic insulin action. This work is funded by a new R01. Dr. Hasty has published over 100 peer-reviewed manuscripts in this area in high impact journals including Diabetes, Nature Medicine, Am. J. Physiol. and Mol. Metab. She has always maintained a strong cohort of young scientists within her group, and is keen on training the next generation of immunometabolism experts. Dr. Hasty’s research is highly relevant to Veterans as rates of obesity and metabolic disease are even higher in Veteran’s than in the general civilian population. The work performed by Dr. Hasty and her team are critical for us to better understand immune-mediated mechanisms of obesity-accelerated metabolic disease.