Impaired metabolic effects of a thyroid hormone receptor beta-selective agonist in a mouse model of diet-induced obesity

Abstract

Background: The use of selective agonists of the thyroid hormone receptor isoform beta (TRbeta) has been linked to metabolic improvement in animal models of diet-induced obesity, nonalcoholic liver disease, and genetic hypercholesterolemia.

Methods: To identify potential target tissues of such compounds, we exposed primary murine brown adipocytes and skeletal myocytes for 24 hours to 50 nM GC-24, a highly selective TRbeta agonist. GC-24 (17 ng/[g BW.day] for 36 days) was also tested in a mouse model of diet-induced obesity.

Results: While the brown adipocytes responded to GC-24, with 17%-400% increases in the expression of 12 metabolically relevant genes, the myocytes remained largely unresponsive to GC-24 treatment. In control mice kept on chow diet, GC-24 treatment accelerated energy expenditure by about 15% and limited body weight gain by about 50%. However, in the obese animals the GC-24-mediated reduction in body weight gain dropped to only 20%, while energy expenditure remained unaffected. In addition, an analysis of gene expression in the skeletal muscle, brown adipose tissue, and liver of these obese animals failed to identify a conclusive GC-24 transcriptome footprint.

Conclusion: Feeding a high-fat diet impairs most of the beneficial metabolic effects associated with treatment with TRbeta-selective agonists.

FIG. 1.

Experimental design. (A) Group of mice kept on Chow diet; (B) Group of mice kept on high-fat diet (HFD).

FIG. 2.

Gene expression profile of primary brown adipocytes (A) and skeletal myocytes (B) exposed to vehicle, 50 nM T3 or 50 nM GC-24, for 24 hours. Results are expressed as ratios of test mRNA/cyclophilin mRNA and normalized to the levels observed in the vehicle-treated cells. The genes analyzed are grouped in different sets as indicated. Values are the mean ± SEM of three independent samples; gene abbreviations are as indicated in the Materials and Methods section; *p < 0.01 versus vehicle-treated cells; **p < 0.01 versus T3-treated cells. T3, triiodothyronine; SEM, standard error of the mean.

FIG. 3.

Metabolic profile of animals kept on a chow diet and treated with GC-24. (A) Animals were weighed daily and differences in body weight (ΔBW) are shown. (B) Caloric intake. Food intake was measured during a 48-hour period. (C) Energy expenditure in vehicle-treated mice before (day 20) and after treatment (day 56). (D) Same as (C), except that animals were treated with GC-24. (E) Energy expenditure shown as an average of the data in (C) and (D). Each entry is the mean ± SEM of three to four animals. NS, not significant.

FIG. 3.

Metabolic profile of animals kept on a chow diet and treated with GC-24. (A) Animals were weighed daily and differences in body weight (ΔBW) are shown. (B) Caloric intake. Food intake was measured during a 48-hour period. (C) Energy expenditure in vehicle-treated mice before (day 20) and after treatment (day 56). (D) Same as (C), except that animals were treated with GC-24. (E) Energy expenditure shown as an average of the data in (C) and (D). Each entry is the mean ± SEM of three to four animals. NS, not significant.

FIG. 4.

Metabolic profile of animals kept on HFD and treated with GC-24. (A) Caloric intake. Food intake was measure daily. During the first 3 weeks of the experiment, animals were fed with either chow or HFD; *p < 0.001 versus chow diet. (B) HFD mice in (A) were split into three different groups and treated with GC-24 or T3 as indicated. Shown is the average of daily caloric intake for each animal group during the treatment period. Each entry is the mean ± SEM of eight animals; *p < 0.001 versus chow; **p < 0.001 versus HFD. (C) Body weight gain during the experimental period. Animals were weighed daily and body weight gain (ΔBW) is shown. Each entry is the mean ± SEM of eight animals; *p < 0.01 versus chow; **p < 0.001 versus HFD. (D) Energy expenditure of HFD animals treated with vehicle or GC-24.

FIG. 5.

Gene expression profile in skeletal muscle (gastrocnemius), heart, liver, and BAT of mice placed on chow or HFD and treated with GC-24 or T3 as indicated. Each entry is the mean ± SEM of eight animals; gene abbreviations are as indicated in the Materials and Methods section; *p < 0.01 versus chow; ^#p < 0.01 versus HFD; ⁺p < 0.01 versus T3-treated animals. BAT, brown adipose tissue.