Environmental stress profoundly affects cellular plasticity and metabolism in multicellular organisms. Adipose tissues serve as a unique model to understand the molecular basis of metabolic adaptation: it comprises a dynamic organ that remodels its cellular size and composition in response to a variety of hormonal cues and stress, such as nutritional changes (e.g., overeating or fasting) and temperatures. Such metabolic adaptation, involving lipolysis, lipogenesis, adipogenesis, mitochondrial biogenesis/clearance, and thermogenesis, plays a central role in the regulation of energy homeostasis.
We apply the most cutting-edge technologies and multidisciplinary approaches to generate a blueprint for engineering regulatory circuits of adaptive responses and restoring metabolic health by defined factors. This approach will have a profound impact on the prevention and treatment of metabolic disorders, cancer, aging, and beyond.
1. Mechanisms of fuel switch via mitochondrial transporters.
A notable metabolic change during cold adaptation is fuel utilization from glucose to fatty acids and amino acids. We recently found that, besides glucose and fatty acids, brown/beige fat cells actively uptake branched-chain amino acids (BCAA) in the mitochondria, thereby enhancing systemic BCAA clearance. This is highly significant because increased BCAA levels – due to impaired BCAA oxidation in metabolic organs – are tightly associated with human diabetes. By studying the fuel switch mechanisms, we identified SLC25A44 as the first mitochondrial transporter for BCAA (Yoneshiro et al. Nature 2019). We aim to explore the biological roles of this newly identified mitochondrial BCAA transporter as well as other uncharacterized transporters in health and disease.
A proposed model of BCAA catabolism in thermogenic adipose cells. Cold stimuli activate BCAA uptake and oxidation in the mitochondria of thermogenic adipocytes. Mitochondrial BCAA oxidation promotes BAT thermogenesis. This process requires SLC25A44, the mitochondrial BCAA transporter (Yoneshiro et al. Nature 2019).
2. Cellular plasticity and heterogeneity in adipose tissues.
Historically, it has been considered that mammals possess “two types” of adipose cells – brown and white fat cells. However, emerging evidence suggests that adipose cell origins and composition are far more complicated than merely two types. In fact, we and others showed that beige adipocytes- an inducible form of thermogenic fat cells – exist in mice and humans (e.g., Shinoda et al. Nature Med 2015). More recently, we identified Myod+ myogenic progenitors and CD81+ progenitors that give rise to a subtype of beige fat (termed “g-beige” fat) and cold-induced beige fat, respectively (Chen et al. Nature 2019; Oguri et al. Cell 2020). It is conceivable that adipose tissues contain diverse subtypes of progenitors that differentially respond to external and hormonal stimuli, and each of them gives rise to developmentally and functionally distinct mitochondria-enriched adipocytes. We aim to generate a complete lineage map of adipose cells.
3. Metabolic engineering to improve metabolic health.
The browning of white fat is accompanied by a substantial improvement in metabolic health, including improved glucose tolerance, insulin sensitivity, lipid profile, and cardiovascular health. The conventional dogma was that these metabolic effects are through UCP1-mediated thermogenesis; however, surprisingly, we demonstrated that a large part, if not all, of the anti-diabetic actions of beige fat is UCP1-independent (Ikeda et al. Nature Medicine 2017; Haseawa et al. Cell Metabolism 2017). We aim to explore this unexpected observation by 1) uncovering the mechanisms of UCP1-independent anti-diabetic actions, 2) reconstituting such anti-diabetic effects in adipose tissues.