My laboratory explores research focused on harnessing the potential of brown and beige adipose tissues as therapeutic targets for combating human obesity and associated metabolic disorders. In response to cold exposure, brown and beige adipocytes undergo metabolic activation, expending stored energy in glucose and lipids to generate heat—a process known as non-shivering thermogenesis. Activated brown/beige adipose tissue has the potential to prevent obesity through increased energy expenditure and offers protection against diet-induced insulin resistance and hepatic steatosis.

iPSC-Based Therapeutic Strategies to Increase Energy Expenditure

Traditional drug-based methods to increase energy expenditure in human adipose tissue for obesity and diabetes have faced significant challenges and cardiovascular risks. As an alternative, we are exploring cell-based therapies that could supplement obese patients with additional brown or beige adipose tissue, their precursor cells, or the secreted factors derived from these cells. However, obtaining these progenitor cells from humans involves invasive procedures, and their potential for expansion and differentiation diminishes with age and weight gain. To overcome these hurdles, our laboratory has leveraged induced pluripotent stem cell (iPSC) technology, successfully reprogramming somatic cells from both normal and diabetic patients into renewable, metabolically active human beige adipocytes. These cells show promise, secreting anti-diabetic factors and serving as a potential model for developing anti-obesity and anti-diabetic therapies. Additionally, we are actively developing 3-D adipose tissue models for testing in obese/diabetic mice to assess their effectiveness in promoting weight loss and combating obesity-related diabetes.

Optogenetic control of energy expenditure

A significant hurdle in implementing adipocyte cell-based therapies is the need to maintain cell activation post-transplantation. To address this challenge, we utilize optogenetic techniques to engineer adipocytes expressing a blue light-inducible bacterial adenylyl cyclase, capable of increasing intracellular cAMP and activating thermogenesis. This cutting-edge optogenetic tool enables precise temporal, spatial, dosage, and bidirectional control of thermogenesis. Our ongoing objective involves integrating 3-D iPSC-derived beige adipocytes with miniaturized, remote-controlled, blue light wireless transmitters for transplantation testing and the development of metabolic syndrome therapies.

MicroRNA Regulation in Thermogenesis

Recent models propose that exosomes released from brown/beige fat carry diverse signaling molecules, including microRNAs, RNAs, proteins, and lipids, with potential therapeutic impacts on metabolic disorders. An intriguing and underexplored concept is that exosome secretion might offer a swift mechanism for gene expression control within the secreting cell, particularly in microRNA disposal. Supporting this idea, our research highlights a rapid release of exosomes enriched in miR-27—known for its anti-thermogenic properties—during beige adipocyte activation. To delve deeper into miR-27 and its role in thermogenesis, we have developed miR-27 null and conditional mice. Ongoing research aims to identify miR-27 target genes and assess the impact of miR-27 deletion on beige and brown adipose tissue responses to temperature shifts and high-fat diets. This exploration holds the potential for uncovering novel therapies for metabolic diseases associated with miR-27 and its target genes.

Selected Publications: