Metabolic disorders, such as obesity and type 2 diabetes, are one of the leading causes of morbidity and mortality worldwide, with prevalence reaching epidemic levels. Over the last decade, preclinical studies have shown that the hypothalamus, a brain region that exerts control over peripheral glucose, fat and energy metabolism, activate immune and inflammatory pathways in response to shifts in peripheral nutrient availability. This inflammation in the hypothalamus is characterized by the accumulation of resident and infiltrating immune cells of the hypothalamus, such as microglia and proinflammatory myeloid cells, respectively. Further, dietary-related immune activation of the hypothalamus precedes metabolic disturbances in peripheral tissues and overt weight gain, implicating early onset of hypothalamic inflammation in the pathophysiology of metabolic dysfunction. More recent work has shown that environmental perturbations, such as maternal malnutrition and stress, influence hypothalamic development to produce lasting alterations in the hypothalamic control of metabolism. While it is well-established that these maternal factors influence hypothalamic circuits that control appetite, feeding and metabolism, the role of immune cells in hypothalamic programming during this critical period of development is less understood. Thus, the objective of this K01 application is to determine the role of maternal gut microbiota- derived metabolites on immune development within the hypothalamus, determine how these reprogrammatic events influence hypothalamic control over metabolism, and increased lifelong risk for metabolic disorders. I will test my hypothesis in three Specific Aims, 1) demonstrate stress-induced immune programming by maternal gut- microbiota derived short chain fatty acids (SCFAs), 2) determine lasting impact of maternal SCFAs on hypothalamic dysregulation of glucose, fat, and energy metabolism, 3) identify the molecular mechanisms by which maternal SCFAs regulate microglia development and disruption of hypothalamic control of metabolism. As the maternal gut microbiome is readily accessible and can be manipulated in a non-invasive manner, completing this work may reveal novel strategies and biomarkers of maternal adversity and lasting health outcomes in offspring. The candidate, Dr. Eldin Jasarevic, is training in the lab of Dr. Tracy Bale at the University of Maryland School of Medicine. The career development goal of this K01 application is to provide protected time for Dr. Jasarevic to cultivate his emerging research program and forge a path towards academic independence. Accordingly, this K01 application has been designed to (1) gain technical and didactic training in immunology and metabolism using our mouse model of hypothalamic dysregulation; (2) leverage cutting-edge techniques, such as fluorescence activated cell sorting, cell-type specific transgenics and next generation sequencing, to expand our knowledge on early-life immunity in the developing hypothalamus within the field of central regulation of metabolism; and (3) enhance grantsmanship and mentorship.
Maternal adversity during pregnancy, such as stress or diet, is a key player in offspring brain development and contributes to metabolic disease risk across the lifespan. Using our well-established mouse model of maternal stress, we demonstrated that lasting hypothalamic dysregulation is associated with alterations to the changes to the maternal gut microbiome and metabolites produced by the maternal gut microbiome necessary for offspring brain development. We hypothesize that there is an important interaction between maternal gut microbiome- derived metabolites and programming of immunocompetent cells in the developing brain. The early-in-life events increase susceptibility to hypothalamic inflammation and metabolic dysfunction in adulthood. Therefore, we will use our model of hypothalamic dysregulation to examine mechanistic changes to maternal gut derived metabolites and programmatic effects of microglia on hypothalamic control of metabolism.
