All ETDs from UAB

Advisory Committee Chair

Chad S Hunter

Advisory Committee Members

Martin Young

Ronadip R Banerjee

Kirk M Habegger

Glenn C Rowe

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Metabolic disease encompasses various disorders, including obesity and diabetes, that negatively impact glucose and lipid homeostasis and increase the risk of co-morbidities. Adipose tissue, which regulates whole-body energy balance and acts as a specialized endocrine tissue, is negatively affected by obesity and diabetes. Brown adipose tissue (BAT) functions to dissipate excess energy as heat and therefore is an attractive target against metabolic disease. To develop more effective therapeutic strategies, BAT physiology and genetic regulatory mechanisms need to be better understood. This dissertation highlights studies seeking to illuminate novel transcriptional regulation and islet transplantation applications of BAT. We investigated the requirement of the transcriptional co-regulator LDB1 for BAT function. We hypothesized that LDB1 has direct roles in regulating BAT thermogenesis and substrate metabolism. Using models of BAT-specific LDB1 loss, we found that LDB1 regulates brown adipocyte genes involved in thermogenesis and lipid oxidation, possibly via direct occupation of gene regulatory regions. Additionally, LDB1 governs brown adipocyte substrate utilization and maintains whole-body glucose and insulin tolerance, energy expenditure, and thermogenesis. To explore novel applications of the BAT microenvironment, we investigated the efficacy of BAT as a site for pancreatic islet transplantation. Given BAT has a highly vascularized and anti-inflammatory microenvironment, we hypothesized that murine islets engrafted into BAT could restore euglycemia and protect islets from immune-mediated destruction. To test this, we conducted a series of transplant experiments using the NOD mouse, a model system for Type 1 Diabetes. We found that islet engraftment into BAT could maintain islet function without negatively impacting BAT thermogenesis and energy expenditure. Subsequent analysis in the context of autoimmune and allogeneic immune rejection demonstrated that BAT as an engraftment site could significantly delay graft rejection possibly due to an enrichment of anti-inflammatory cells, including M2 macrophages and T regulatory cells. In summary, these studies highlight novel transcriptional co-regulation required for BAT function and the advantages of BAT as an islet transplantation site. Detailed characterization of BAT physiology and genetic regulation may have future implications for the development of targeted therapies for metabolic disease.

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