Studies in humans and in animal models show negative correlations between thyroid hormone (TH) levels and longevity. TH signaling is implicated in maintaining and integrating metabolic homeostasis at multiple levels, notably centrally in the hypothalamus but also in peripheral tissues. The question is thus raised of how TH signaling is modulated during aging in different tissues. Classically, TH actions on mitochondria and heat production are obvious candidates to link negative effects of TH to aging. Mitochondrial effects of excess TH include reactive oxygen species and DNA damage, 2 factors often considered as aging accelerators. Inversely, caloric restriction, which can retard aging from nematodes to primates, causes a rapid reduction of circulating TH, reducing metabolism in birds and mammals. However, many other factors could link TH to aging, and it is these potentially subtler and less explored areas that are highlighted here. For example, effects of TH on membrane composition, inflammatory responses, stem cell renewal and synchronization of physiological responses to light could each contribute to TH regulation of maintenance of homeostasis during aging. We propose the hypothesis that constraints on TH signaling at certain life stages, notably during maturity, are advantageous for optimal aging.

Thyroid hormone (TH) is essential for vertebrate brain development. Most research on TH and neuronal development focuses on late development, mainly the perinatal period in mammals. However, in human infants neuromotor development correlates best with maternal TH levels in the first trimester of pregnancy, suggesting that TH signaling could affect early brain development. Studying TH signaling in early embryogenesis in mammals is experimentally challenging. In contrast, free-living embryos, such as Xenopus laevis, permit physiological experimentation independent of maternal factors. We detailed key elements of TH signaling: ligands, receptors (TR), and deiodinases during early X. laevis development, before embryonic thyroid gland formation. Dynamic profiles for all components were found. Between developmental stages 37 and 41 (~48 h after hatching, coincident with a phase of continuing neurogenesis) significant increases in T(3) levels as well as in mRNA encoding deiodinases and TR occurred. Exposure of embryos at this developmental stage for 24 h to either a TH antagonist, NH-3, or to tetrabromobisphenol A, a flame retardant and known TH disruptor, differentially modulated the expression of a number of TH target genes implicated in neural stem cell function or neural differentiation. Moreover, 24-h exposure to either NH-3 or tetrabromobisphenol A diminished cell proliferation in the brain. Thus, these data show first, that TH signaling exerts regulatory roles in early X. laevis neurogenesis and second, that this period represents a potential window for endocrine disruption.

The type 4 melanocortin receptor MC4R, a key relay in leptin signaling, links central energy control to peripheral reserve status. MC4R activation in different brain areas reduces food intake and increases energy expenditure. Mice lacking Mc4r are obese. Mc4r is expressed by hypothalamic paraventricular Thyrotropin-releasing hormone (TRH) neurons and increases energy usage through activation of Trh and production of the thyroid hormone tri-iodothyronine (T 3 ). These facts led us to test the hypothesis that energy homeostasis should require negative feedback by T 3 on Mc4r expression. Quantitative PCR and in situ hybridization showed hyperthyroidism reduces Mc4r mRNA levels in the paraventricular nucleus. Comparative in silico analysis of Mc4r regulatory regions revealed two evolutionarily conserved potential negative thyroid hormone-response elements (nTREs). In vivo ChIP assays on mouse hypothalamus demonstrated association of thyroid hormone receptors (TRs) with a region spanning one nTRE. Understanding how central genes involved in endocrine and metabolic axes are regulated is crucial to these problems.Thyroid hormones (THs) regulate metabolism and appetite (1, 2). THs, particularly the biologically active form tri-iodothyronine, T 3 , stimulate the basal metabolic rate. Hyperthyroidism leads to increased catabolism and weight loss; hypothyroidism causes weight gain (3). TH levels are kept within physiological ranges through hypothalamo-pituitary neuroendocrine feedback loops. Increased T 3 represses transcription of hypothalamic Thyrotropinreleasing hormone, Trh (4), the master regulator of the hypothalamo-pituitary-thyroid (HPT) axis (5). In turn, decreased T 3 output reduces metabolism and energy usage (6).Hypothalamic TRH neurons integrate numerous metabolic, endocrine, and neuronal signals (7). T 3 -responsive TRH neurons in the paraventricular nucleus (PVN) express all the functional TH nuclear receptors (TRs) and a key membrane receptor involved in energy homeostasis, namely the type 4 melanocortin receptor (MC4R). In situ hybridization studies show that nearly all TRH neurons in the caudal-medial parvocellular PVN express MC4R (8).MC4R, a membrane α-melanocyte stimulating hormone (αMSH) receptor, is integral to central leptin/melanocortin signaling (9). Leptin, a major satiety hormone, regulates energy homeostasis through food intake, energy partition, and thermogenesis (9). Centrally, leptin signaling is relayed mainly through the hypothalamic melanocortin system and MC4R-expressing neurons. Mc4r expression is widespread in the brain (10, 11), with high levels in the hypothalamus and brainstem, areas involved in energy homeostasis (12). The hypothalamus governs metabolism through complex neuroendocrine regulations. The brainstem also integrates metabolic signaling, notably regulating thermogenesis via the autonomic nervous system (13).In the PVN, leptin stimulates TRH production by coordinating pathways that culminate in MC4R activation and increased intracellular cAMP levels. A cAMP response bindin...