Responsiveness to Thyroid Hormone and to Ambient Temperature Underlies Differences Between Brown Adipose Tissue and Skeletal Muscle Thermogenesis in a Mouse Model of Diet-Induced Obesity

Abstract

Thyroid hormone accelerates energy expenditure (EE) and is critical for cold-induced thermogenesis. To define the metabolic role played by thyroid hormone in the dissipation of calories from diet, hypothyroid mice were studied for 60 d in a comprehensive lab animal monitoring system. Hypothyroidism decreased caloric intake and body fat while down-regulating genes in the skeletal muscle but not brown adipose tissue thermogenic programs, without affecting daily EE. Only at thermoneutrality (30 C) did hypothyroid mice exhibit slower rate of EE, indicating a metabolic response to hypothyroidism that depends on ambient temperature. A byproduct of this mechanism is that at room temperature (22 C), hypothyroid mice are protected against diet-induced obesity, i.e. only at thermoneutrality did hypothyroid mice become obese when placed on a high-fat diet (HFD). This is in contrast to euthyroid controls, which on a HFD gained more body weight and fat at any temperature while activating the brown adipose tissue and accelerating daily EE but not the skeletal muscle thermogenic program. In the liver of euthyroid controls, HFD caused an approximately 5-fold increase in triglyceride content and expression of key metabolic genes, whereas acclimatization to 30 C cut triglyceride content by half and normalized gene expression. However, in hypothyroid mice, HFD-induced changes in liver persisted at 30 C, resulting in marked liver steatosis. Acclimatization to thermoneutrality dramatically improves glucose homeostasis, but this was not affected by hypothyroidism. In conclusion, hypothyroid mice are metabolically sensitive to environmental temperature, constituting a mechanism that defines resistance to diet-induced obesity and hepatic lipid metabolism.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Thus, substantial differences exist between mice and rats with respect to their metabolic responsiveness to thyroid hormone. Hypothyroid mice do not exhibit a decrease in VO 2 at room temperature, only after acclimatization at thermoneutrality (211). However, the total daily energy expenditure is decreased in the hypothyroid mouse acclimatized at room temperature, a parameter that takes into account the VO 2 and the RQ.…”

“…However, these differences were no longer observed after 3 weeks of treatment (209). A state of hypothyroidism can be achieved faster if PTU or MMI are combined with 1% KClO 4 in the drinking water, a potent NIS inhibitor (210,211). However, their combination will also magnify the effect that these drugs have on water consumption.…”

“…Both basal metabolic rate (i.e., energy spent to sustain life in a resting state) and adaptive energy expenditure (e.g., cold-induced) are up-regulated by thyroid hormone. Direct activation of the UCP1 gene transcription in BAT is the underlying mechanism by which thyroid hormone accelerates cold-induced thermogenesis (267,269,592); it is less clear that thyroid hormone plays a role in diet-induced adaptive energy expenditure (211,593). In addition to these direct actions in energy homeostasis, thyroid hormone also acts in the CNS (e.g., hypothalamus) influencing major homeostatic pathways; for example, sympathetic activity, appetite, and food intake (594,595).…”

“…However, the total daily energy expenditure is decreased in the hypothyroid mouse acclimatized at room temperature, a parameter that takes into account the VO 2 and the RQ. The sustained total daily energy expenditure in the hypothyroid mouse is due to enhanced sympathetic stimulation of BAT (211,602). This indicates that the reduction in thyroid hormone signaling is compensated for by an increase in sympathetic activity, sustaining VO 2 at room temperature (211).…”

“…Hypothyroid rats or mice are not obese when kept on a chow diet (211,593), but when they are placed on a high-fat diet, the response is different between rats and mice and depends on the environmental temperature (211,593). At room temperature, hypothyroid rats placed on a high-fat diet become just as obese as euthyroid control rats (593), whereas mice are protected against diet-induced obesity (211). Only at thermoneutrality do hypothyroid mice become obese when placed on a high-fat diet (211).…”