Tetrahydrobiopterin activates brown adipose tissue and regulates systemic energy metabolism
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
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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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 9

BH4 directly activates brown adipocytes NO-dependently.

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BH4 directly activates brown adipocytes NO-dependently. (A and B) mRNA l...
(A and B) mRNA levels of brown adipose tissue–related (BAT-related) genes by quantitative RT-PCR (A; n = 4–5) and protein expression levels of UCP1 (B; n = 3) in differentiated brown adipocytes on day 7 after incubated with or without 10 or 100 μM tetrahydrobiopterin (BH4) for 24 hours. (C–E) Changes of oxygen consumption rate (OCR) (C); values of OCR related to basal respiration, ATP production, proton leak, and maximum respiration (D); and coupling and uncoupling rate (E) in the differentiated brown adipocytes on day 7 incubated with or without 100 μM BH4 for 24 hours (n = 7–8). (F) NO production in the differentiated brown adipocytes on day 7 incubated with or without 10 or 100 μM BH4 for 24 hours (n = 5). (G) mRNA level of Ucp1 in the presence of the 100 μM nitric oxide synthase (NOS) inhibitor (L-NAME) in the differentiated brown adipocytes on day 7 incubated with or without 100 μM BH4 for 24 hours (n = 5–6). Values are mean ± SEM. Statistical analysis was performed by Student’s t test (C–E and G). *P < 0.05, **P < 0.01, NS vs. control group (C–E) or vs. values without BH4 (G). In addition, statistical analysis was performed by 2-way ANOVA (C) or 1-way ANOVA with Tukey post-hoc test (A, B, and F). *P < 0.05, **P < 0.01 vs. control group.