Disruption of thyroid hormone activation in type 2 deiodinase knockout mice causes obesity with glucose intolerance and liver steatosis only at thermoneutrality

Abstract

Objective: Thyroid hormone accelerates energy expenditure; thus, hypothyroidism is intuitively associated with obesity. However, studies failed to establish such a connection. In brown adipose tissue (BAT), thyroid hormone activation via type 2 deiodinase (D2) is necessary for adaptive thermogenesis, such that mice lacking D2 (D2KO) exhibit an impaired thermogenic response to cold. Here we investigate whether the impaired thermogenesis of D2KO mice increases their susceptibility to obesity when placed on a high-fat diet.

Research design and methods: To test this, D2KO mice were admitted to a comprehensive monitoring system acclimatized to room temperature (22°C) or thermoneutrality (30°C) and kept either on chow or high-fat diet for 60 days.

Results: At 22°C, D2KO mice preferentially oxidize fat, have a similar sensitivity to diet-induced obesity, and are supertolerant to glucose. However, when thermal stress is eliminated at thermoneutrality (30°C), an opposite phenotype is encountered, one that includes obesity, glucose intolerance, and exacerbated hepatic steatosis. We suggest that a compensatory increase in BAT sympathetic activation of the D2KO mice masks metabolic repercussions that they would otherwise exhibit.

Conclusions: Thus, upon minimization of thermal stress, high-fat feeding reveals the defective capacity of D2KO mice for diet-induced thermogenesis, provoking a paradigm shift in the understanding of the role of the thyroid hormone in metabolism.

Figures

FIG. 1.

Effect of ambient temperature on body composition, indirect calorimetry, and NE turnover of D2KO mice. A: Body composition as measured by DEXA in WT and D2KO mice acclimatized at the indicated ambient temperatures; body weights were as follows: D2KO, 21.55 ± 0.46 and WT, 25.4 ± 0.6 g at 22°C; D2KO, 22.4 ± 0.45 and WT, 23.9 ± 0.6 g at 30°C. B: Same as in A, except that what is shown is Vo2. C: Same as in B, except that what is shown is RQ. D: Interscapular BAT NE turnover at the indicated time points. All animals were kept on chow diet. Measurements were made during the light cycle. Entries are means ± SE of four to five animals; a is P < 0.01 vs. animals of the same genotype. NS, not significant.

FIG. 2.

Effect of high-fat feeding at room temperature on body composition and indirect calorimetry. D2KO and WT mice were fed with high-fat diet for 8 weeks and kept at 22°C (A–D). A: Body composition as measured by DEXA in WT and D2KO mice at the end of the experiment; body weights were D2KO, 26.9 ± 2.68 and WT, 36.3 ± 2.5 g. B: Vo2 was measured at day 1 and day 60 in WT and D2KO, after the animals started on the high-fat feeding. C: Same as B, except that what is shown is RQ. D: Body weight gain in WT and D2KO mice. Entries are means ± SE of four to five animals; a is P < 0.05 vs. animals of the same genotype.

FIG. 3.

Effect of high-fat feeding at thermoneutrality on body composition and indirect calorimetry. D2KO and WT mice were acclimatized at 30°C for 2 weeks and subsequently fed with high-fat diet for 8 weeks while at 30°C (A–F). A: Body composition as measured by DEXA in WT and D2KO mice at the end of the experiment; body weights were D2KO, 41.6 ± 1.23 and WT, 39.45 ± 1.8 g. B: Vo2 was measured at day 1 and day 60 in WT and D2KO. C: Same as B, except that what is shown is RQ. D: Body weight gain in WT and D2KO mice. At day 1 body weights were D2KO, 25.5 ± 0.57 and WT, 28.43 ± 1.12 g. E: Image of representative WT and D2KO mice at the end of the experiment. F: UCP1/Cyclophilin A mRNA levels in the BAT at the end of the experiment. Entries are means ± SE of four to five animals; *P < 0.01 vs. WT. (A high-quality color representation of this figure is available in the online issue.)

FIG. 4.

Effect of acclimatization temperature and/or diet on lipid deposition in the liver. Oil Red O staining of liver sections obtained from D2KO and WT fed with chow or high-fat diet (HFD) for 8 weeks, acclimatized to 22°C or 30°C, as indicated (A–H) is shown. A and B: D2KO and WT fed with chow diet, acclimatized to 22°C. C and D: Same as A and B, except acclimatization was at 30°C. E and F: D2KO and WT fed with high-fat diet for 8 weeks, acclimatized to 22°C. G and H: Same as E and F, except acclimatization was at 30°C. Scale bar is 50 μm. (A high-quality digital representation of this figure is available in the online issue.)

FIG. 5.

Effect of temperature and/or diet on glucose tolerance. Blood glucose concentrations at the indicated time points following intraperitoneal injection of 1 g/kg glucose in D2KO and WT animals fed with chow or high-fat diet, acclimatized to 22°C or 30°C, as indicated are shown. A: D2KO and WT fed with chow diet, acclimatized to 22°C. B: Same as A, except acclimatization was at 30°C. C: D2KO and WT fed with high-fat diet for 8 weeks, acclimatized to 22°C. D: Same as C, except acclimatization was at 30°C. Entries are means ± SE of four to five animals; *P < 0.01 vs. WT.