Tetrahydrobiopterin activates brown adipose tissue and regulates systemic energy metabolism
Yasuo Oguri, … , Hiroyuki Hasegawa, Nobuya Inagaki
Yasuo Oguri, … , Hiroyuki Hasegawa, Nobuya Inagaki
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e91981. https://doi.org/10.1172/jci.insight.91981.
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Research Article Metabolism

Tetrahydrobiopterin activates brown adipose tissue and regulates systemic energy metabolism

Abstract

Brown adipose tissue (BAT) is a central organ that acts to increase energy expenditure; its regulatory factors could be clinically useful in the treatment of obesity. Tetrahydrobiopterin (BH4) is an essential cofactor of tyrosine hydroxylase and nitric oxide synthase (NOS). Although BH4 regulates the known regulatory factors of BAT, such as noradrenaline (NA) and NO, participation of BH4 in BAT function remains unclear. In the present study, we investigate the role of BH4 in the regulation of BAT. Hph-1 mice, a mouse model of BH4 deficiency, exhibit obesity, adiposity, glucose intolerance, insulin resistance, and impaired BAT function. Impaired BAT function was ameliorated together with systemic metabolic disturbances by BAT transplantation from BH4-sufficient mice (control mice) into BH4-deficient mice, strongly suggesting that BH4-induced BAT has a critical role in the regulation of systemic energy metabolism. Both NA derived from the sympathetic nerve and NO derived from endothelial NOS in the blood vessels participate in the regulation of BH4. In addition, a direct effect of BH4 in the stimulation of brown adipocytes via NO is implicated. Taken together, BH4 activates BAT and regulates systemic energy metabolism; this suggests an approach for metabolic disorders, such as obesity and diabetes.

Authors

Yasuo Oguri, Yoshihito Fujita, Abulizi Abudukadier, Akiko Ohashi, Tsuyoshi Goto, Futoshi Furuya, Akio Obara, Toru Fukushima, Naomi Matsuo, Minji Kim, Masaya Hosokawa, Teruo Kawada, Hiroyuki Hasegawa, Nobuya Inagaki

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Figure 4

Supplementation of BH4 to BH4-deficient mice ameliorates BAT dysfunction as well as metabolic disturbance.

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Supplementation of BH4 to BH4-deficient mice ameliorates BAT dysfunction...
Rectal temperature (A; n = 8), H&E staining and white adipose cell size of brown adipose tissue (BAT) (B; n = 3) (original magnification, ×15), mRNA levels in BAT by quantitative RT-PCR (C; n = 4–6), fasting blood glucose levels after 16 hours fasting (D; n = 8), fed blood glucose levels (E; n = 8), and intraperitoneal glucose tolerance test (IPGTT; 2 g/kg glucose) after 16 hours fasting (F; n = 5) in hph-1 mice after the treatment with or without 20 mg tetrahydrobiopterin (BH4)/kg body weight for 10 days from the age of 5 weeks. Values are mean ± SEM. Statistical analysis was performed by 2-way ANOVA with Bonferroni post-hoc test (F) or Student’s t test (A–F). *P < 0.05, **P < 0.01 vs. saline group.