Thyrotropin-releasing hormone (TRH) has an important role in the regulation of energy
homeostasis not only through effects on thyroid function orchestrated through hypophysiotropic
neurons in the hypothalamic paraventricular nucleus (PVN), but also through central
effects on feeding behavior, thermogenesis, locomotor activation and autonomic regulation.
Hypophysiotropic TRH neurons are located in the medial and periventricular parvocellular
subdivisions of the PVN and receive direct monosynaptic projections from two, separate,
populations of leptin-responsive neurons in the hypothalamic arcuate nucleus containing
either alpha-melanocyte-stimulating hormone (alpha-MSH) and cocaine- and amphetamine-regulated
transcript (CART), peptides that promote weight loss and increase energy expenditure,
or neuropeptide Y (NPY) and agouti-related protein (AGRP), peptides that promote weight
gain and reduce energy expenditure. During fasting, the reduction in TRH mRNA in hypophysiotropic
neurons mediated by suppression of alpha-MSH/CART simultaneously with an increase
in NPY/AGRP gene expression in arcuate nucleus neurons contributes to the fall in
circulating thyroid hormone levels, presumably by increasing the sensitivity of the
TRH gene to negative feedback inhibition by thyroid hormone. Endotoxin administration,
however, has the paradoxical effect of increasing circulating levels of leptin and
melanocortin signaling and CART gene expression in arcuate nucleus neurons, but inhibiting
TRH gene expression in hypophysiotropic neurons. This may be explained by an overriding
inhibitory effect of endotoxin to increase type 2 iodothyroine deiodinase (D2) in
a population of specialized glial cells, tanycytes, located in the base and infralateral
walls of the third ventricle. By increasing the conversion of T4 into T3, tanycytes
may increase local tissue concenetrations of thyroid hormone, and thereby induce a
state of local tissue hyperthyroidism in the region of hypophysisotrophic TRH neurons.
Other regions of the brain may also serve as metabolic sensors for hypophysiostropic
TRH neurons including the ventrolateral medulla and dorsomedial nucleus of the hypothalamus
that have direct monosynaptic projections to the PVN. TRH also exerts a number of
effects within the central nervous system that may contribute to the regulation of
energy homeostasis. Included are an increase in core body temperature mediated through
neurons in the anterior hypothalamic-preoptic area that coordinate a variety of autonomic
responses; arousal and locomotor activation through cholinergic and dopaminergic mechanisms
on the septum and nucleus accumbens, respectively; and regulation of the cephalic
phase of digestion. While the latter responses are largely mediated through cholinergic
mechanisms via TRH neurons in the brainstem medullary raphe and dorsal motor nucleus
of the vagus, effects of TRH on autonomic loci in the hypothalamic PVN may also be
important. Contrary to the actions of T3 to increase appetite, TRH has central effects
to reduce food intake in normal, fasting and stressed animals. The precise locus where
TRH mediates this response is unknown. However, evidence that an anatomically separate
population of nonhypophysiotropic TRH neurons in the anterior parvocellular subdivision
of the PVN is integrated into the leptin regulatory control system by the same arcuate
nucleus neuronal populations that innervate hypophysiotropic TRH neurons, raises the
possibility that anterior parvocellular TRH neurons may be involved, possibly through
interactions with the limbic nervous system.
