Thyroid hormone-stimulated increases in PGC-1α and UCP2 promote life history-specific endocrine changes and maintain a lipid-based metabolism

Abstract

Thyroid hormones (THs) regulate metabolism, but are typically suppressed during times of stressful physiological conditions, including fasting. Interestingly, prolonged fasting in northern elephant seal pups is associated with reliance on a lipid-based metabolism and increased levels of circulating THs that are partially attributed to active secretion as opposed to reduced clearance. This apparent paradox is coupled with complementary increases in cellular TH-mediated activity, suggesting that in mammals naturally adapted to prolonged fasting, THs are necessary to support metabolism. However, the functional relevance of this physiological paradox has remained largely unexplored, especially as it relates to the regulation of lipids. To address the hypothesis that TSH-mediated increase in THs contributes to lipid metabolism, we infused early and late-fasted pups with TSH and measured several key genes in adipose and muscle, and plasma hormones associated with regulation of lipid metabolism. TSH infusion increased the mRNA expressions of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) more than 6.5-fold at 60 min in muscle, and expression of uncoupling protein 2 (UCP2) more than 27-fold during the early fast at 60 min, in adipose. Additionally, during the late fast period, the protein content of adipose CD36 increased 1.1-fold, and plasma nonesterified fatty acid (NEFA) concentrations increased 25% at 120 min, with NEFA levels returning to baseline after 24 h. We show that the TSH-induced increases in THs in fasting pups are functional and likely contribute to the maintenance of a lipid-based metabolism.

Keywords: fasting; lipids; metabolism; thyroid; uncoupling protein.

Fig. 1.

Protocol diagram representing the sampling period for both TSH- and saline-treated animals. The pups were sampled during either the early fasting period (1–2 wk after weaning) or the late fasting period (6–8 wk after weaning).

Fig. 2.

Messenger RNA expressions (means ± SE) of adipose peroxisome proliferator activated receptor gamma coactivator α (PGC-1α) (A), adipose uncoupling protein 2 (UCP2) (B), muscle peroxisome proliferator activated receptor gamma coactivator α (PGC-1α) (C), and muscle uncoupling protein 2 (UCP2) (D) from northern elephant seal pups before (0) and 60 and 120 min and 24 h after TSH infusion in early fasted (n = 6; 2–3 wk after weaning) and late fasted (n = 6; 6–8 wk after weaning) elephant seal pups. #Significant (P < 0.05) difference from 2 to 3 wk after weaning. *Significant (P < 0.05) difference from T0 within a group.

Fig. 3.

Relative protein expressions (means ± SE) of fatty acid translocase/CD36 (CD36) (A) and plasma circulating levels of nonesterified fatty acids (NEFAs) (B) from northern elephant seal pups before (0) and 60 and 120 min and 24 h after TSH infusion in early fasted (n = 6; 2–3-wk after weaning) and late fasted (n = 6; 6–8 wk after weaning) elephant seal pups. #Significant (P < 0.05) difference from 2 to 3 wk after weaning. *Significant (P < 0.05) difference from T0 within a group.

Fig. 4.

Plasma circulating levels (means ± SE) of glucose (A) and insulin (B) from northern elephant seal pups before (0) and 60 and 120 min and 24 h after TSH infusion in early fasted (n = 6; 2–3 wk after weaning) and late fasted (n = 6; 6–8 wk after weaning) elephant seal pups. #Significant (P < 0.05) difference from 2 to 3 wk after weaning. *Significant (P < 0.05) difference from T0 within a group.

Fig. 5.

Plasma circulating levels (means ± SE) of lactate (A) and triglycerides (B) from northern elephant seal pups before (0) and 60 and 120 min and 24 h after TSH infusion in early fasted (n = 6; 2–3 wk after weaning) and late fasted (n = 6; 6–8 wk after weaning) elephant seal pups. #Significant (P < 0.05) difference from 2 to 3 wk after weaning. *Significant (P < 0.05) difference from T0 within a group.

Fig. 6.

Plasma circulating levels (means ± SE) of IGF-1 from northern elephant seal pups before (0) and 60 and 120 min and 24 h after TSH infusion in early fasted (n = 6; 2–3 wk after weaning) and late fasted (n = 6; 6–8 wk after weaning) elephant seal pups. #Significant (P < 0.05) difference from 2 to 3 wk after weaning. *Significant (P < 0.05) difference from T0 within a group.