Metabolism and adipocytes
Metabolism depends on the cooperation of many tissues throughout the body to sense nutrient levels, to take up nutrients from circulation, and to regulate how these nutrients are stored or converted to energy. We are particularly interested in adipose tissue because it plays a far reaching role in whole-body nutrient homeostasis, and excess adiposity is closely associated with insulin resistance and metabolic disease. Beyond its role as a lipid reserve, adipose tissue secretes proteins and lipids that regulate metabolic processes throughout the body. Specific kinds of adipocytes like brown or beige adipocytes contribute to whole-body energy expenditure due to their unique capacity to produce heat from glucose and fat via mitochondrial oxidation. Our goal is to dissect the relationship between metabolism and insulin sensitivity, using various biological models, omics technologies, and a combination of metabolic and molecular techniques.
Identifying mechanisms by which FGF21 regulates adipocyte metabolism
Adipocyte metabolism can be rewired to stimulate weight loss during obesity. A hormone, FGF21 was recently discovered to do this. One of the projects in the lab examines the signals that underlie this process.
Video: Watch Annabel talking about our research into FGF21 for a 3 Minute Thesis Competition
Studying the interaction between cellular signaling and metabolism
As cells pursue their lifelong desire for homeostasis, they respond to their ever-changing environment using a diverse range of regulatory mechanisms. I am particularly interested in the interplay between cellular signalling and metabolism, and how this breaks down in metabolic disease. Studying adipocytes (fat cells) as a model system, I am using a combination of reductionist molecular biology and various omics technologies to explore two broad questions:
1) How does insulin signalling regulate glucose metabolism? Recent work from our laboratory (Humphrey et al, Cell Metab 2013) has shown that insulin regulates thousands of phosphorylation events in a precise fashion over time. What part does metabolism play in this orchestra? I am studying how the insulin-stimulated phosphorylation of numerous metabolic proteins coordinates the glucose flux down different pathways over time.
2) How does cellular metabolism influence signalling? Cells use signal transduction to manipulate intracellular metabolism, matching energy supply with demand for cellular processes such as growth. However, we recently showed that glucose metabolism can alter the cell’s responsiveness to insulin (Trefely et al, J Biol Chem in press). This suggests that metabolism itself can fine-tune signalling pathways according to cellular demands. I am exploring the mechanisms by which this occurs and how this contributes to insulin resistance.
Investigating adipose tissue lipid metabolism as a key regulator of whole-body glucose tolerance
Adipose tissue balances lipid synthesis and lipid oxidation to modulate adipose tissue expansion itself or metabolism in other tissues of the body. The enzyme Acetyl-CoA Carboxylase (ACC) is situated at the intersection of lipid metabolism by stimulating fat synthesis from glucose and blocking fat oxidation, causing a net accumulation of fat. Adipose fat accumulation is strongly associated with insulin resistance and glucose intolerance; conditions which are characteristic of type 2 diabetes. The purpose of this project is to explore the adipose-specific functions of ACC, and how adipose tissue lipid metabolism affects adiposity, insulin sensitivity and whole-body glucose homeostasis.
Figure 2. Acetyl-CoA Carboxylase is a central regulator of lipid synthesis from glucose and mitochondrial fat oxidation in adipocytes.