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.
Our long-term goal is to use the insights we gain to restore metabolic health. To achieve this goal, we apply the most cutting-edge technologies and multidisciplinary approaches. Our research leads to new therapeutic interventions for the treatment of metabolic disorders and beyond.
Program 1. How do cells make heat? - UCP1-independent thermogenesis.
The best-characterized mechanism of heat production is mitochondrial proton uncoupling via UCP1 (uncoupling protein 1). The long-standing dogma for over 30 years is that UCP1 is the only protein responsible for non-shivering thermogenesis in mammals. However, we and others discovered UCP1-independent mechanisms of thermogenesis, such as Ca2+ cycling thermogenesis in beige fat (Ikeda et al. Nature Medicine 2017). Surprisingly, a large part, if not all, of the anti-obesity and anti-diabetic actions of beige fat is UCP1-independent (Ikeda et al. Nature Medicine 2017; Haseawa et al. Cell Metabolism 2017). We aim to uncover the molecular basis of UCP1-independent pathways.
Program 2. Molecular basis of fuel choice via mitochondrial carriers.
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 (Yoneshiro et al. Nature 2019). 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 carrier for BCAA (MBC). We aim to explore the biological roles of this newly identified mitochondrial BCAA carrier, as well as other uncharacterized transporters, in health and disease.
Program 3. 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. We and others demonstrated 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 progenitors that give rise to distinct subtypes of beige fat (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 functionally distinct adipocytes. We aim to generate a complete lineage map of adipose cells.