Laboratory of Molecular Pathology & Metabolic Disease,
Faculty of Pharmaceutical Sciences
Tokyo University of Science
Research background
Adipose tissue is roughly classified into two types, white adipose tissue and brown adipose tissue. White adipose tissue is mainly distributed under the skin and internal organs and functions as a tissue for energy storage. White adipocytes contain few mitochondria. On the other hand, brown adipose tissue is mainly distributed around the clavicle and spine, contains a large amount of mitochondrion, and plays a role of consuming energy and producing heat. From about 20 years ago, it has been recognized as "white adipose tissue is the largest endocrine organ in the body". Thereafter, its function and secreted bioactive molecules (adipokines) are still being actively researched.
It is widely accepted that long-term caloric restriction (CR) improves metabolism, suppresses age-associated patho-physiological changes, and extends lifespan. It is known that suppression of growth hormone (GH) / insulin-like growth factor 1 (IGF-1) signaling is important as the molecular mechanism of CR. Since both GH and IGF-1 are involved in maintaining skeletal muscle and bone in aged persons, interventions that suppress GH and IGF-1 are not appropriate for middle-aged and elderly people. Therefore, we are researching the GH / IGF-1 signal-independent mechanism of CR. As a result, we found that activation of mitochondrial biogenesis mediated by a transcriptional cofactor called peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) by a fatty acid synthesis-related transcription factor called sterol regulatory element-binding protein 1c (SREBP-1c) in white adipose tissue is important for the beneficial effects of CR. This discovery is the basis of our current research.
Research on calorie restriction, aging, and mitochondrial function
As described above, CR improves whole body metabolism, suppresses age-related patho-physiological changes and extends lifespan probably via activation of mitochondrial biogenesis in white adipose tissue in a SREBP-1c-dependent manner. Mitochondria, which have DNA in itself, are organelles that have various kinds of function, including energy metabolism. SIRT3, a deacetylase, enhances enzymatic activity of various mitochondrial matrix proteins. We found that one of the mitochondrial signal peptidases, mitochondrial intermediate peptidase (MIPEP), is involved in the maturation of SIRT3 in a SREBP-1c-dependent manner. Mitochondrial quality is thought to be controlled by proteostasis (protein homeostasis), biogenesis, mitophagy (selective autophagy of mitochondria), and dynamics (division / fusion). MIPEP controls mitochondrial proteostasis. Currently, we are promoting research on these mitochondrial quality control mechanisms.
Research on obesity and autophagy
In obese adipose tissue, enlarged and hypertrophic adipocytes increase. Hypertrophic adipocytes secrete bioactive molecules (cytokines) that induce inflammation and aggregate inflammatory cells. We found that WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is induced in a tumor suppressor TP53-dependent manner and acts as a defense against adipocyte dysfunction in obese adipose tissue. Currently, we are analyzing the molecular defensive mechanisms of WWP1 in adipocytes. In addition, it was clarified that autophagosome formation is activated in the initial pathological condition of obese adipose tissue, but autophagosomes are accumulated due to the impaired lysosomal function by imbalance of cathepsin family, which are lysosomal hydrolases. Recently, we are investigating the relationship among mitochondrial function, autophagosome accumulation, and mitophagy. Moreover, we also clarified the molecular function of trehalose and taurine, which are known to be autophagy inducer.