Inhibition of angiotensin II increases hypothalamic thyroid hormone and stimulates orexigenic NPY/AgRP neurons (LB437)

We have demonstrated that mice lacking renin ( Ren1c ‐/‐) are lean and resistant to diet‐induced obesity, which is associated with increased energy expenditure and uncoupling proteins (UCPs) expression. Surprisingly, plasma catecholamine levels of Ren1c‐/‐ mice were similar to wild type (WT) mice, and their plasma total T3 and T4 were lower than those of WT, although they showed no obvious signs of hypothyroidism. We here investigate whether mice lacking renin display true hypothyroidism, and if so, the specific mechanism by which they develop it. The Ren1c ‐/‐ mice have approximately 50% levels of free T3, freeT4 and TSH in the plasma, as well as reduced TRH expression in the hypothalamus compared to WT. Administration of TRH or angiotensin II (Ang II) both restored plasma TSH and thyroid hormones in the Ren1c‐/‐ mice, while these hormones were not affected by human renin, which stimulates mouse MAP kinases but does not cleave mouse angiotensinogen to Ang I. Moreover, the Ang II receptor blocker losartan decreased TRH, TSH, and thyroid hormones of WT mice to the levels similar to those in mice lacking renin. Furthermore, mice lacking renin and WT mice treated with losartan have significantly increased hypothalamic expression of type 2 deiodinase (Dio2), which converts T4 to the more potent T3, and have increased thyroid hormones in the hypothalamus, which likely inhibits TRH through feedback. Both mice lacking renin and WT mice treated with losartan have 3‐fold higher uncoupling protein‐2 (UCP2), orexigenic neuropeptide Y (NPY) and agouti‐related protein (AgRP), as well as 5‐fold lower anorexigenic proopiomelanocortin (POMC) gene expression in the hypothalamus relative to untreated WT mice. In contrast, Ren1c‐/‐ mice treated with human renin had similar expression levels of these genes. These results suggest that the inhibition of Ang II not of Ang‐independent effects of renin causes hypothyroidism and enhances food intake, which likely decrease energy expenditure. We hypothesize that changes in gene expression of the hypothalamus do not contribute to increased energy expenditure of the Ren1c‐/‐ mice, and that hypothalamic hyperthyroidism feedback inhibits TRH, leading to systemic hypothyroidism. Caution should be paid to hypothyroidism when using high dose of inhibitors of the renin angiotensin system. Grant Funding Source : National Science Council: 102‐2320‐B‐009 ‐002 ‐MY3