| 溝上 顕子（みぞかみ あきこ） | データ更新日：2023.12.06 |
准教授 ／
歯学研究院
歯学部門
口腔常態制御学
| 1. | 溝上顕子、安河内（川久保）友世、＠大谷崇仁、＠平田雅人, オステオカルシンのホルモン作用, 糖尿病・内分泌代謝科, 2022.03. |
| 2. | Takahito Otani, Akiko Mizokami, Tomoyo Kawakubo-Yasukochi, Hiroshi Takeuchi, Tetsuichiro Inai, Masato Hirata, The roles of osteocalcin in lipid metabolism in adipose tissue and liver., Elsevier BV, 10.1016/j.jbior.2020.100752, 2020.12, Bone provides skeletal support and functions as an endocrine organ by producing osteocalcin, whose uncarboxylated form (GluOC) increases the metabolism of glucose and lipid by activating its putative G protein-coupled receptor (family C group 6 subtype A). Low doses (≤10 ng/ml) of GluOC induce the expression of adiponectin, adipose triglyceride lipase and peroxisome proliferator-activated receptor γ, and promote active phosphorylation of lipolytic enzymes such as perilipin and hormone-sensitive lipase via the cAMP-PKA-Src-Rap1-ERK-CREB signaling axis in 3T3-L1 adipocytes. Administration of high-dose (≥20 ng/ml) GluOC induces programmed necrosis (necroptosis) through a juxtacrine mechanism triggered by the binding of Fas ligand, whose expression is induced by forkhead box O1, to Fas that is expressed in adjacent adipocytes. Furthermore, expression of adiponectin and adipose triglyceride lipase in adipocytes is triggered in the same manner as following low-dose GluOC stimulation; these effects protect mice from diet-induced accumulation of triglycerides in hepatocytes and consequent liver injury through the upregulation of nuclear translocation of nuclear factor-E2-related factor-2, expression of antioxidant enzymes, and inhibition of the c-Jun N-terminal kinase pathway. Evaluation of these molecular mechanisms leads us to consider that GluOC might have potential as a treatment for lipid metabolism disorders. Indeed, there have been many reports demonstrating the negative correlation between serum osteocalcin levels and obesity or non-alcoholic fatty liver disease, a common risk factor for which is dyslipidemia in humans. The present review summarizes the effects of GluOC on lipid metabolism as well as its possible therapeutic application for metabolic diseases including obesity and dyslipidemia.. |
| 3. | Takashi Kanematsu, Kana Oue, Toshiya Okumura, Kae Harada, Yosuke Yamawaki, Satoshi Asano, Akiko Mizokami, Masahiro Irifune, Masato Hirata, Phospholipase C-related catalytically inactive protein A novel signaling molecule for modulating fat metabolism and energy expenditure, journal of oral biosciences, 10.1016/j.job.2019.04.002, 2019.06, [URL], Background: Overweight and obesity are defined as excessive or abnormal fat accumulation in adipose tissues, and increase the risk of morbidity in many diseases, including hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, and stroke, through pathophysiological mechanisms. There is strong evidence that weight loss reduces the risk of metabolic syndrome by limiting blood pressure and improving the levels of serum triglycerides, total cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. To date, several attempts have been made to develop effective anti-obesity medication or weight-loss drugs; however, satisfactory drugs for clinical use have not yet been developed. Therefore, elucidation of the molecular mechanisms driving fat metabolism (adipogenesis and lipolysis) represents the first step in developing clinically useful drugs and/or therapeutic treatments to control obesity. Highlight: In our previous study on intracellular signaling of phospholipase C-related catalytically inactive protein (PRIP), we generated and analyzed Prip-double knockout (Prip-DKO) mice. Prip-DKO mice showed tolerance against insulin resistance and a lean phenotype with low fat mass. Here, we therefore reviewed the involvement of PRIP in fat metabolism and energy expenditure. We conclude that PRIP, a protein phosphatase-binding protein, can modulate fat metabolism via phosphoregulation of adipose lipolysis-related molecules, and regulates non-shivering heat generation in brown adipocytes. Conclusion: We propose PRIP as a new therapeutic target for controlling obesity or developing novel anti-obesity drugs.. |
| 4. | 溝上顕子、＠平田雅人, 骨による全身の糖・エネルギー代謝調節機構, FOOD Style 21, 2018.03. |
| 5. | 安河内友世、溝上顕子、平田雅人, 次世代肥満を制御する妊娠期オステオカルシンの有用性, BIO Clinica, 2017.11. |
| 6. | 安河内友世、溝上 顕子、平田雅人, 次世代生活習慣病の予防を目指して, メディカルサイエンス・ダイジェスト, 2017.06. |
| 7. | Akiko Mizokami, Tomoyo Kawakubo-Yasukochi, Masato Hirata, Osteocalcin and its endocrine functions, Biochemical Pharmacology, 10.1016/j.bcp.2017.02.001, 2017.05, [URL], Bone has traditionally been regarded as a static structural organ that supports movement of the body and protects the internal organs. However, evidence has been accumulated in the past decade showing that bone also functions as an endocrine organ that regulates systemic glucose and energy metabolism. Osteocalcin, an osteoblast-specific secreted protein, acts as a hormone by stimulating insulin production and increasing energy expenditure and insulin sensitivity in target organs. Animal studies have shown that an increase in the circulating concentration of osteocalcin, including via exogenous application of the protein, prevents obesity and glucose intolerance. Moreover, a number of epidemiological analyses support the role of osteocalcin in the regulation of glucose and energy homeostasis in humans. Therefore, it has been suggested that osteocalcin could be a feasible preventive or therapeutic agent for metabolic disorders. In this review, we summarize the current knowledge regarding the endocrine functions of osteocalcin and its various modes of action.. |
| 8. | 溝上顕子、安河内友世、平田雅人, オステオカルシンとエネルギー代謝, 骨粗鬆症治療, 2017.03. |
| 9. | 溝上顕子、安河内友世、竹内弘、平田雅人, オステオカルシンとインスリン分泌, 2015.03. |
| 10. | Akiko Mizokami, Tomoyo Kawakubo-Yasuchochi, Hiroshi Takeuchi, Masato Hirata, Organ network for preventing metabolic syndromes with a reference to the roles of osteocalcin, Folia Pharmacologica Japonica, 10.1254/fpj.145.201, 2015.01, [URL]. |
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