Role of tetrahydrobiopterin in differentiation and proliferation of brown adipose tissue and application of transplantation therapy

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09826
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kyoto University
• Principal Investigator: Fujita Yoshihito 京都大学, 医学研究科, 助教 (50547809)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 褐色脂肪組織 / 一酸化窒素 / 先制医療 / 肥満症 / 糖尿病

Outline of Final Research Achievements

Tetrahydrobiopterin (BH4) is an essential co-factor of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis including norepinephrine, and nitric oxide synthase. We investigated the role of BH4 in the differentiation of BAT using a mouse model of BH4 deficiency. Hph-1 neonatal mice exhibited dysplasia of BAT as well as attenuated thermogenesis-related gene expressions.
We next evaluated the direct effect of BH4 in brown adipocyte differentiation using brown pre-adipocytes isolated from control and Hph-1 mice. Brown pre-adipocytes from Hph-1 mice reduced differentiation capacity, and BH4 supplementation in brown pre-adipocytes from Hph-1 mice ameliorated differentiation capacity.Maternal BH4 supplementation ameliorated dysplasia of neonatal BAT and thermogenesis-related genes. Intriguingly, offsprings of maternal BH4 supplementation groups had less weight gain, improved glucose intolerance, and sustained cold tolerance after growth under high fat chow diet.

Free Research Field

糖尿病学

Academic Significance and Societal Importance of the Research Achievements

BH4は胎児期のBATの分化に関与し、母体への補充療法は、子の糖・エネルギー代謝に有益な持続的効果をもたらす可能性が示された。本研究の結果は、BH4が、BATの成熟・分化のピークを迎える妊娠後期から出生時におけるBATの分化を制御するだけでなく、成獣期の過栄養環境におけるエネルギー代謝の適応機構にも影響を及ぼすことを示している。胎児期の種々の子宮内の環境要因は将来の生活習慣病の発症と関連するとされるが、現在までに、有効な介入手法は見出されていない。BH4投与によるBATの制御は肥満症及び糖尿病の発症を予防する、先制医療の標的となる可能性がある。