Maintenance of the thyroid axis during diet-induced obesity in rodents is controlled at the central level

PERELLÓ M; ÇAKIR I; CYR NE; ROMERO A; STUART RC; CHIAPPINI F; HOLLENBERG AN; NILLNI EA

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM

AMER PHYSIOLOGICAL SOC

Año: 2010 p. 976 - 989

0193-1849

The hypothalamic-pituitary-thyroid (HPT) axis is a major contributor in maintainingenergy expenditure and body weight, and the adipocyte hormoneleptin regulates this axis by increasing TRH levels in the fedstate. Leptin stimulates TRH directly in the hypothalamic paraventricularnucleus (PVN; direct pathway) and indirectly by regulatingproopiomelnocortin neurons in the hypothalamic arcuate nucleus(ARC; indirect pathway). Whereas the indirect pathway is fullyfunctional in lean animals, it is inactive during diet-induced obesity(DIO) because of the establishment of leptin resistance. Despite this,the HPT axis activity in obese humans and rodents remains within thenormal levels or slightly higher. Therefore, in this study, we aimed todetermine the mechanism(s) by which the HPT axis is still activedespite leptin resistance. With a combination of using the Sprague-Dawley rat physiological model and the Zuker rat that bears amutation in the leptin receptor, we were able to demonstrate that underDIO conditions the HPT axis is regulated at the central level, but onlythrough the direct pathway of leptin action on TRH neurons. Deiodinaseenzymes, which are present in many tissues and responsible forconverting thyroid hormones, were not statistically different betweenlean and DIO animals. These data suggest that the increase in T4/3seen in obese animals is due mostly to central leptin action. We alsofound that T3 feedback inhibition on the prepro-TRH gene is controlledpartially by leptin-induced pSTAT3 signaling via the TRHpromoter. This interactive relationship between T3 and pSTAT3signaling appears essential to maintain the HPT axis at normal levelsin conditions such as obesity.