Timothy F. Osborne, Ph.D.

Research Interests

Dr. Osborne’s research is focused on the regulation of lipid metabolism and how it is integrated into more global aspects of physiology and cell biology. A major focus has been on the sterol regulatory element binding proteins (SREBPs) and over the past three decades his lab has revealed fundamental principles in how metabolism regulates physiology and in doing so his lab has made and validated several molecular reagents and assay systems for studying SREBPs using in vitro, cell culture and whole animal model systems.

His team was among the first to demonstrate that nutrient (cholesterol) regulation is associated with chromatin modification changes in promoters for genes regulated by cholesterol. His more recent studies combine animal knockout and genome-wide approaches that indicate SREBPs are at the intersection of nutrient sensing and many other cell-environment interactions including responses to chemical and biological threats. This is particularly important in immune cells, which participate as a first line of defense against external threats and his lab has uncovered a role for SREBPs in regulating inflammatory response in innate and adaptive programs.

His team also is also interested in additional mechanisms that influence hepatic lipid metabolism and has identified a novel lysine methyl transferase—SETDB2—that is increased during fasting in the liver, a time when SREBPs are shut off. They have shown SETDB2 influences chromatin dynamics to specifically suppress SREBP activity. SETDB2 is also activated by inflammatory signals in innate immune cells and his lab has recently uncovered a role for SETDB2 in a form of innate immune memory.

Dr. Osborne has established a collaboration with Dr. Steven Smith from AdventHealth from the Advent Health Translational Research to explore epigenetic regulation of human adipocyte gene expression. When women gain weight, they deposit excess subcutaneous adipose tissue in one of two patterns: around the abdominal mid-section (“apple” shape) or in the gluteal/femoral region or hips and thighs (“pear” shape). As men gain weight, they tend to gain more weight around their midsection, similar to apple-shaped women. This pattern of weight deposition has been in the clinical literature for decades and more recent studies have shown that “pears” are protected from developing the obesity-related metabolic disease whereas “apples” are more susceptible. The molecular basis for this distinction and what role the different subcutaneous adipose tissues have in regulating metabolic disease progression. In a series of recent publications, this team has shown that differentially expressed genes in adipose derived stem cells (ADSCs) from apples vs pears are decorated with differential histone modification patterns and altered 3D chromatin features that contribute to their unique gene expression profiles.