 In NTIS, the concentrations of these deiodinases are altered, although it is unclear whether NTIS is the cause or effect of this in peripheral tissues; in some studies, the alterations in thyroid hormone concentrations occurred before the changes in deiodinase activity.Typically, peripheral D1 and D2 are downregulated, while peripheral D3 is upregulated; this is associated with lower T4 and increased rT3.Thyrotropin releasing hormone (TRH) neurons in the hypothalamus integrate global signals about the body's energy state.