IMPORTANCE OF IRON HOMEOSTASIS IN BEIGE AND BROWN ADIPOCYTES

Beige/brown adipocytes are specialized for non-shivering thermogenesis, dissipating mitochondrial energy into heat via uncoupling protein 1 (UCP1), thereby contributing to whole-body energy expenditure. The development of beige/brown adipocytes is an iron-demanding process for mitochondrial biogenesis, implicating that modulation of iron metabolism is involved in activating beige/brown adipocytes. Iron homeostasis is tightly regulated at the dual levels, intracellular regulation by the iron regulatory protein (IRP)/IRE system and systemic regulation by iron regulatory hormone hepcidin. However, little information is available on iron regulation within thermogenic adipocytes and systemic iron redistribution from the iron storage site to thermogenic adipocytes. This dissertation aims to investigate the role of adipocyte iron homeostasis and systemic iron modulation on the development of thermogenic adipocytes. Firstly, iron regulation during beige adipocyte formation was examined. IRP/IRE interaction was proportional to the thermogenic capacity of adipose tissue depots (i.e., Brown \u3e beige \u3e white adipose tissue), which was associated with mitochondrial biogenesis. The iron requirement was higher in HIB1B brown adipocytes than 3T3-L1 white adipocytes during adipocyte differentiation. Depletion of labile iron pool attenuated the formation of beige/brown adipocytes. Consistently, adipocyte browning induced IRP-mediated iron import into adipocytes and relocation to mitochondria in response to thermogenic cues during beige adipogenesis. Next, systemic iron mobilization during thermogenic fat development was identified. Adipocyte browning upon β3-adrenoceptor activation-induced hypoxia in the kidneys, subsequent erythropoietin production in the spleen, and stress erythropoiesis, thereby suppressing hepcidin transcription for iron liberation. The genetic ablation of IRPs or blockage of systemic iron mobilization, either by inhibiting hypoxia or exogenous hepcidin injection, impaired beige fat development. Lastly, dietary iron deficiency was induced in C57BL/6 mice to confirm the contribution of iron to beige fat development. Chronic low iron intake (3 ppm) decreased fatty acid oxidation and blunted adaptive thermogenesis upon thermogenic cue, resulting in increased adiposity and insulin resistance. Taken together, research in this dissertation identified that both intracellular and systemic iron homeostasis is critical for thermogenic activation and systemic energy homeostasis. Also, this work provides a novel insight into adipocyte iron regulation as a therapeutic target to circumvent obesity by augmenting thermogenic energy expenditure