Hypothalamic mTOR pathway mediates thyroid hormone-induced hyperphagia in hyperthyroidism
N Martinez Sanchez1,2, L. Varela1,2, L. Martins1,2, P Martinez de Morentin1,2, R. Gallego1, M. Vazquez1,2, J. Roa2,3,4, M. Gandara1, E. Schoenmakers5, R. Nogueiras1,2, K. Chatterjee5, M. Tena Sempere2,3,4, C. Dieguez1,2 & M. Lopez1,2
Hyperthyroid rats and humans exhibit increased energy expenditure and marked hyperphagia. Recent evidence has pointed that alterations of thermogenesis linked to hyperthyroidism are associated to dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear.
Objective: The aim of our study was to assess if alterations in feeding in hyperthyroidism are associated with impairment of hypothalamic mammalian target of rapamycin (mTOR) signalling.
Methods: We used adult male SpragueDawley rats. Hyperthyroidism was induced by chronic subcutaneous administration of L-thyroxine. Intracerebroventricular treatments and stereotaxic microinjection of T3 and adenoviral expression vectors. Analysis by blood biochemistry, in situ hybridization, Real-time quantitative PCR, Immunohistochemistry and western blotting.
Results: Here, we demonstrate that hyperthyroid rats exhibit marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR colocalizes with thyroid hormone receptor alpha (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism-effects on feeding and mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss.
Conclusion: Overall, these data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced upregulation of mTOR signalling. Furthermore our finding that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rationale design of specific and selective therapeutic compounds aimed at reversing the metabolic consequence of this disease.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.