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. 2011 Feb 4;585(3):539-44.
doi: 10.1016/j.febslet.2010.12.044. Epub 2011 Jan 14.

The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure

Wagner S da-Silva  1 , Scott Ribich, Rafael Arrojo e Drigo, Melany Castillo, Mary-Elizabeth Patti, Antonio C Bianco
Affiliations

The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure

Wagner S da-Silva et al. FEBS Lett. .

Abstract

Exposure of cell lines endogenously expressing the thyroid hormone activating enzyme type 2 deiodinase (D2) to the chemical chaperones tauroursodeoxycholic acid (TUDCA) or 4-phenylbutiric acid (4-PBA) increases D2 expression, activity and T3 production. In brown adipocytes, TUDCA or 4-PBA induced T3-dependent genes and oxygen consumption (∼2-fold), an effect partially lost in D2 knockout cells. In wild type, but not in D2 knockout mice, administration of TUDCA lowered the respiratory quotient, doubled brown adipose tissue D2 activity and normalized the glucose intolerance associated with high fat feeding. Thus, D2 plays a critical role in the metabolic effects of chemical chaperones.

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Figures

Figure 1
Figure 1. Tauroursodeoxycholic acid and 4-phenylbutyric acid stimulate D2 message, activity and T3 production in intact cells
(A) D2 activity in MSTO-211H cells exposed to 500 μM TUDCA or 1000 μM 4-PBA for the indicated times. (B) Dose-response curve of D2 activity in MSTO-211H cells treated for 24h with the indicated amounts of 4-PBA or TUDCA. (C) T3 production in MSTO-211H cells treated for 48h with TUDCA or 4-PBA at indicated doses. (D) D2 activity in MSTO-211H cells treated with 4-PBA and/or cyclohexamide for the indicated times. (E) Dio2 gene expression in MSTO-211H cells treated for 24h with 500μM TUDCA or 1mM 4-PBA. Values are the mean ± SEM of 3–6 experiments. # P<0.05, * P< 0.01, ** P< 0.001, *** P< 0.0001 vs. vehicle treated cells.
Figure 2
Figure 2. TUDCA and 4-PBA increase energy expenditure and modify gene expression in brown adipocytes
(A) D2 activity in differentiated wild type primary brown adipocytes exposed to increasing amounts of 4-PBA or 500μM TUDCA for 24h. (B) and (C), oxygen consumption in wild type or Dio2−/− primary brown adipocytes treated with 1mM 4-PBA for 48h or 500μM TUDCA for 24 or 72h. (D) Relative mRNA levels in TUDCA or 4-PBA-treated wild type or Dio2−/− primary brown adipocytes at indicated doses. Values are the mean ± SEM of 6–10 samples of at least 2 experiments. # P<0.05, * P< 0.01 or *** P< 0.0001 vs. vehicle-treated cells.
Figure 3
Figure 3. Impact of tauroursodeoxycholic acid on indirect calorimetry of wild type or Dio2−/− animals
Oxygen consumption (A−B) and respiratory quotient (RQ) (C–D) in mice on chow diet before and after treatment with 0.5mg/g BW TUDCA for 7 days. For (A–D) all values were calculated as the area under the curve of measurements made on the first or last 24h of treatment, and are presented as the mean ± SEM of 3 animals. In (D), P<0.05 vs. Dio2−/− by two-tail Students' t-test.
Figure 4
Figure 4. Tauroursodeoxycholic acid improves glucose tolerance in wild type but not in Dio2−/−mice
Glucose tolerance test in WT (A) and Dio2−/− (B) placed on a chow or high fat diet. All values are the mean ± SEM of 4 animals, where * P< 0.01, ** P< 0.001 and # P<0.05 vs. high fat diet group. These experiments were repeated at least 2 times.
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