Environmental stress profoundly impacts tissue plasticity and metabolism in multicellular organisms. Adipose tissues serve as a unique model for understanding the molecular basis of metabolic adaptation: they are dynamic organs that remodel their cellular size and composition in response to a variety of hormonal cues and stressors, such as nutritional changes (e.g., overeating or fasting) and temperature. 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 cutting-edge technologies and multidisciplinary approaches. Our research paves a path toward new therapeutic interventions for metabolic disorders, aging, cancer, 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). For over four decades, the prevailing dogma has been 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 adipose tissue (Ikeda et al. Nature Medicine 2017; Auger et al. Cell Metabolism 2025). Surprisingly, a large part, if not all, of the anti-obesity and anti-diabetic actions of beige fat are UCP1-independent (Ikeda et al. Nature Medicine 2017; Hasegawa et al. Cell Metabolism 2017; Verkerke et al. Cell 2025). We aim to uncover the molecular basis of UCP1-independent pathways.
The discovery of UCP1-independent thermogenesis also allows us to explore the evolutionary origin of endothermy. Many endothermic or heterothermic animals (e.g., pigs, tuna, swordfish) lack brown fat and functionally thermogenic UCP1 protein. We aim to understand the evolution of UCP1-independent thermogenic pathways in non-mammalian species.
Program 2. Molecular basis of fuel selection and switching via mitochondrial carriers.
A notable metabolic change during chronic cold adaptation is a dynamic shift in fuel utilization from glucose to fatty acids and amino acids in the later phase. How do cells decide what fuels to use, and how do they switch during adaptation?
Our vision is that the key regulatory step lies in mitochondrial metabolite transporters, given the selectively impermeable nature of the mitochondrial inner membrane. We leverage brown fat as a tool, as it contains mitochondria at the highest density among mammalian cells. For instance, we discovered the mitochondrial branched-chain amino acid carrier (SLC25A44 - Yoneshiro et al. Nature 2019), mitochondrial choline carrier (SLC25A48 - Verkerke et al. Cell Metabolism 2024), trimethyl-lysine carrier (SLC25A45 - Auger et al. Science 2026), PEP carrier (SLC25A35 - Yamamuro et al. Cell 2026; SLC25A34 – Oikawa et al. Science Advances 2026), and several others. These discoveries have far-reaching implications beyond brown fat biology, particularly for the mechanisms by which mitochondrial defects lead to metabolic disease.
Program 3. Developing fat targeted “cold mimetics” for improving metabolic health
The metabolic benefits of cold exposure, including elevated energy expenditure and improved glucose/lipid homeostasis, have been well appreciated for the last two decades. However, a major hurdle is that the accompanying sympathetic activation raises blood pressure and cardiovascular risk. We aim to reconstitute the key molecular pathways mediating the metabolic benefits of cold exposure without actual cold exposure, i.e., through molecular cold mimetics.
As an example, the discovery of UCP1-independent futile Ca2+ cycling thermogenesis led to the development of a wireless optogenetic system that stimulates Ca2+ cycling specifically in targeted adipocytes. The light-activated Ca2+ cycling thermogenesis significantly increased whole-body energy expenditure even under thermoneutral conditions and protected against diet-induced obesity (Tajima et al. Nature Comm 2020). The study provides the first proof of concept that fat-specific cold mimetics protect against obesity by activating UCP1-independent thermogenesis. We also elucidated the molecular pathways of the "browning" of white adipose tissue, i.e., beige adipocyte biogenesis (e.g., Chen et al. Nature 2019; Oguri et al. Cell 2020; Shinoda et al. Nature Medicine 2015, etc). These studies led to the development of nutritional approaches that enhance the browning process (e.g., linoleic acid, alpha-lipoic acid).
