Original Research: Metabolic alterations from early life thyroxine replacement therapy in male Ames dwarf mice are transient

Abstract

Ames dwarf mice are exceptionally long-lived due to a Prop1 loss of function mutation resulting in deficiency of growth hormone, thyroid-stimulating hormone and prolactin. Deficiency in thyroid-stimulating hormone and growth hormone leads to greatly reduced levels of circulating thyroid hormones and insulin-like growth factor 1, as well as a reduction in insulin secretion. Early life growth hormone replacement therapy in Ames dwarf mice significantly shortens their longevity, while early life thyroxine (T4) replacement therapy does not. Possible mechanisms by which early life growth hormone replacement therapy shortens longevity include deleterious effects on glucose homeostasis and energy metabolism, which are long lasting. A mechanism explaining why early life T4 replacement therapy does not shorten longevity remains elusive. Here, we look for a possible explanation as to why early life T4 replacement therapy does not impact longevity of Ames dwarf mice. We found that early life T4 replacement therapy increased body weight and advanced the age of sexual maturation. We also find that early life T4 replacement therapy does not impact glucose tolerance or insulin sensitivity, and any deleterious effects on oxygen consumption, respiratory quotient and heat production are transient. Lastly, we find that early life T4 replacement therapy has long-lasting effects on bone mineral density and bone mineral content. We suggest that the transient effects on energy metabolism and lack of effects on glucose homeostasis are the reasons why there is no shortening of longevity after early life T4 replacement therapy in Ames dwarf mice.

Keywords: Ames dwarf; T4; aging; longevity; thyroid hormone; thyroxine.

Figure 1

T4 replacement therapy accelerates growth and sexual maturation. (a) Male Ames dwarf mice (df/df) body weight was monitored after treatment with T4 (n = 7) or saline (n = 10). Their normal littermates (N) were also monitored after treatment with T4 (n = 10) or saline (n = 9). (b) Sexual maturation in df/df and N mice was determined by balanopreputial separation (n = 9 for all groups)

Figure 2

T4 replacement therapy has lasting effects on bone, but not body composition. Eight months after the last injection with T4, (a) body weight, (b) percent body fat, (c) bone mineral density (BMD) and (d) bone mineral content (BMC) of male Ames dwarf mice (df/df) treated with T4 or saline, along with their normal littermates (N) treated with T4 or saline, was measured (n = 7 for all groups)

Figure 3

T4 replacement therapy does not impact glucose homeostasis. (a) Male Ames dwarf mice (df/df) treated with T4 (n = 4) or saline (n = 6), along with their normal littermates (N) treated with T4 (n = 10) or saline (n = 9), underwent a glucose tolerance test (GTT) one week following treatment. (b) df/df mice treated with T4 (n = 5) or saline (n = 6), along with N mice treated with T4 (n = 10) or saline (n = 9), underwent an insulin tolerance test (ITT) two weeks following treatment

Figure 4

T4 replacement therapy transiently impairs energy metabolism. The day after the last T4 injection, (a) spontaneous locomotor activity, (b) oxygen consumption, (c) respiratory quotient and (d) heat production of male Ames dwarf mice (df/df) treated with T4 or saline (n = 4), along with their normal littermates (N) treated with T4 or saline (n = 5), was measured. Four weeks later, (e) spontaneous locomotor activity, (f) oxygen consumption, (g) respiratory quotient and (h) heat production was measured in the same mice

Figure 5

T4 replacement therapy does not impact body temperature. Body temperature of male Ames dwarf mice (df/df) treated with T4 or saline (n = 5), along with their normal littermates (N) treated with T4 or saline (n = 5), was measured one week following treatment