Releasing and inhibiting hormones produced by the hypothalamus influence the activities of

Abstract

The hypothalamus is a vital and an integral part of the central nervous system as it regulates a wide range of physiological and psychological processes, including energy homeostasis, reproduction, circadian rhythms, as well as emotional and behavioral patterns. Structurally, the hypothalamus is a complex neuroendocrine tissue composed of an array of unique neuronal cell types that express critical neuromodulators required to mediate hypothalamic function. Until recently, the properties of these hypothalamic neurons were challenging to study, primarily because of the heterogeneity and complex neuronal architecture of the neuroendocrine hypothalamus. However, hypothalamic neuronal cell models have proved to be a useful in vitro tool in understanding hypothalamic function and disorders. This chapter discusses the hypothalamic cell models that have been generated to date primarily to study mechanisms underlying the function of individual hypothalamic neurons in order to gain a more complete understanding of the overall physiology and pathology of the hypothalamus.

Abstract:

The hypothalamus is a centre of convergence and integration of multiple nutrient-related signals. Important short-term signals are conveyed by hormones, cytokines and/or fuel substrates, which are sensed through a variety of cellular mechanisms in order to maintain energy homeostasis. Nevertheless, there are also long-term signals secreted from the adipose tissue [adipokines] that inform the hypothalamus about the size of adipose tissue depots. The present chapter reviews how short- and long-term mechanisms operate in concert to provide an appropriate regulation of satiety, and focuses on emerging knowledge of the metabolic effects of adipokines on energy homeostasis.

E The hypothalamus of reptiles

The reptilian hypothalamus is depicted in Fig. 5.7. In reptiles, there is no longer a PON, but the medial and lateral POAs are present. The PON of anamniotes has separated into the supraoptic nucleus [SON] and paraventricular nucleus [PVN] characteristic of all amniote vertebrates. These paired nuclei consist of peptidergic NS neurons that produce the octapeptide neurohormones AVT and MST. Their axons terminate in the pars nervosa. The hypothalamus is separated into anterior, dorsal, and posterior hypothalamic areas, paraventricular organs, periventricular nucleus, and both ventral and dorsal medial nuclei. The IFN, also called the ARC, is considered homologous to the VH of the amphibian IFN and the ARC nucleus [= IFN] of birds as well as to the major hypophysiotropic area of the mammalian hypothalamus. Aminergic and peptidergic NS fibers originate in this nucleus and terminate in the median eminence.

Hypothalamus

The hypothalamus is located in the ventral diencephalon and below the thalamus. It is part of the limbic system [with the hippocampus, amygdala, thalamic nuclei, mammillary body, limbic cortex, and other structures] and mediates autonomic, endocrine, and behavioral functions. It is the master regulator of numerous physiologic processes.529,530 It generates and receives humoral and neural information; coordinates different levels of autonomic communication between the CNS and central and peripheral organs; and regulates body temperature, hunger, thirst, circadian and circannual rhythmicity, sleep, reproductive drive, sexual dimorphism, growth, behavior, metabolic activity, and other essential functions.529-531 The hypothalamus connects via neural circuits to other structures of the CNS but also sends and receives humoral information. A good example of hypothalamic humoral connection is with the pituitary gland via the portal system in the median eminence.529,530

Histologically, the hypothalamus is arranged in a series of nuclei with magnocellular and parvocellular neurons that secrete releasing [e.g., corticotropin-releasing hormone [CRH], thyrotropin-releasing hormone [TRH], growth hormone–releasing hormone [GHRH], gonadotropin-releasing hormone [GnRH]] and inhibitory [e.g., somatostatin, dopamine] factors into the pituitary portal system to control hormone synthesis and secretion by the adenohypophysis [e.g., adrenocorticotropic hormone [ACTH], growth hormone [GH], thyroid-stimulating hormone [TSH], prolactin].532,533 The hypothalamus also produces peptides that are stored in the neurohypophysis [e.g., oxytocin, vasopressin], as well as factors that modulate melanotrope activity in the pituitary pars intermedia [e.g., dopamine, serotonin, TRH]. The hypothalamus is responsive to peripheral hormones [leptin, ghrelin, insulin, steroids, thyroid hormones], metabolites [glucose], electrolytes [sodium], neural stimuli [light, smell, touch, vascular pressure, pheromones, temperature, input from the thorax, gastrointestinal tract, and reproductive tract], cytokines, and microbial products. The level at which hypothalamic neurons are stimulated or suppressed is dictated by set-points specific to each function [e.g., thermoregulation, thirst, osmolality, blood pressure].532,533

Peptides and large molecules are sensed or gain access to hypothalamic neurons through circumventricular organs, including the subfornical organ and the organum vasculosum of the lamina terminalis. These structures have a fenestrated endothelium and lack an effective blood-brain barrier allowing the hypothalamus to continuously sample systemic circulation and relay information to different parts of the CNS and are essential for feedback regulatory mechanisms that modulate neuroendocrine function.533

3. Hypothalamus

The hypothalamus is thought to regulate both the development and continuation of the estrus cycle in female rats and we have studied the role of 3H-estradiol binding in relation to these functions [45, 46]. Both the anterior and posterior hypothalamus contain nuclear and cytoplasmic receptors[Fig. 12] and more binding occurs in the anterior than posterior part of the hypothalamus. It is not known if this is due to more receptor sites per cell or to a greater number of receptive cells per unit weight of tissue. The neonatal administration of androgen to female rats alters the function of the preoptic region of the hypothalamus producing permanent alteration in ovarian, uterine and vaginal function [4] and we wondered if this was mediated via the 3H-estradiol binding mechanism. At 28 days of age, the anterior hypothalamus from androgenised female rats had a lower nuclear and higher cytoplasmic uptake of 3H-estradiol in vivo, an effect that was not obtained with posterior hypothalamus or cortex. By 60 days of age, androgenisation had decreased binding in both these subcellular fractions [Fig. 13]. Because of the 26 day gap between androgen and 3H-estradiol injection these effects cannot be due to competition between the two steroids for receptor sites. In any case, testosterone does not compete with 3H-estradiol in either the anterior or posterior hypothalamus. The exact mechanism whereby androgen produces this effect on the anterior hypothalamus is not known but it could be explained by a primary defect in either the transport or nuclear acceptor mechanism giving the results seen in the 28 day old animals; by 60 days this might lead to an overall drop in receptor sites. Such an hypothesis would require proof that prolonged lack of nuclear retention leads to an overall decrease in binding. Such evidence is not available. How does androgen exert this effect? Kato [18] has shown that the hypothalamic estradiol binding mechanism is not functional in neonatal rats so androgenisation may affect the development of the receptor mechanism rather than blocking an existing function. We would also like to know if the androgenisation effect is similar to the mechanism whereby the cycling activity of the preoptic nucleus in males is switched off on day 4/5 of life. Could this be explained by the presence of androgen receptors in both neonatal male and female hypothalamus which are switched off by androgen in the female?

Incoming signals

The hypothalamus secretes thyrotropin-releasing hormone [TRH] that in turn induces the secretion of thyroid-stimulating hormone [TSH] from the anterior pituitary gland.

TSH stimulates the thyroid gland to produce the thyrotrophic hormones thyroxine [T4] and to a lesser extent triiodothyronine [T3]. T4 synthesis relies on the availability of sufficient levels of iodine. T4 has low biological activity, and it is converted into the more active T3 by the selenium-dependent deiodinase in peripheral tissues. Therefore, iodine and selenium are essential for the production of thyroid hormones.

Circulating levels of T3 and T4 provide negative feedback regulation of TRH and TSH production. Both thyroid hormones, through their nuclear receptors [THRB and THRA], directly inhibit the synthesis and release of TSH in pituitary cells. Also, T3 inhibits the preprocessing of the TRH protein in the hypothalamus.

The destruction of thyroid follicles by autoreactive CD4 T cells in Hashimoto’s thyroiditis is considered the most common cause of dysfunctional secretion of thyroid hormones. Overall the molecular mechanisms leading to decreased thyroid hormone production are not well understood.

Genetic Factors in Mouse Obesity

Several strains of mice have been discovered that are naturally genetically obese. The genetic defects have been traced to specific genes and to changes in the corresponding polypeptides. These polypeptides occur in various tissues in the body, but one thing they have in common is that they all act in the hypothalamus.

Thus, an appreciation of the genetic factors of mouse obesity requires some background in the physiology of the hypothalamus.

Endocrine system

The hypothalamus, which functions as an interface between the nervous and endocrine systems, resides ventrally to the thalamus in the lower portion of the brain [Fig. 2.25]. The hypothalamus produces several hormones [Ogawa and Parhar, 2013; Biran et al., 2015], and is connected to another endocrine structure, the pituitary gland. The pituitary is parted into neurohypophysis and adenohypophysis, the last one comprising the rostral pars distalis, proximal pars distalis, and pars intermedia. Some neurosecretory cells of the hypothalamus have their axons ending at the neurohypophysis, which stores and releases the hormones produced by these cells [Table 2.2] to the rest of the body. Teleosts do not have the hypothalamic-pituitary-portal vascular system, which carries the blood passing through the hypothalamus directly to the adeno-hypophysis. However, hypothalamic neurosecretory cells release hormones that influence the production and release of adenohypophysial hormones [Table 2.2].

Table 2.2. Main endocrine organs of Teleosts, hormones and their main functions

The adenohypophysis produces several hormones that act directly in some organs, but others regulate the production and release of hormones from endocrine glands [Whittington and Wilson, 2013; Martos-Sitcha et al., 2014. Prado-Lima and Val, 2015; Ah and Khairnar, 2018]. These endocrine glands and other organs that release hormones are in Table 2.2 and Fig. 2.25.

Hypothalamus

The hypothalamus produces thyrotropin-releasing hormone [TRH], corticotrophin hormone [CRH], gonadotropin-releasing hormone [GnRH], growth hormone-releasing hormone [GRH], and somatostatin [growth hormone inhibitory hormone]. These hormones act on the anterior pituitary resulting in release of various other hormones, including thyroid-stimulating hormone [TSH], adrenocorticotropin [ACTH], FSH, LH, and GH. Somatostatin inhibits the release of GH. Dopamine [also known as prolactin inhibitory hormone], a neurotransmitter, is also produced by the hypothalamus. Dopamine can inhibit GH secretion.

The supra optic and paraventricular nuclei of the hypothalamus produce antidiuretic hormone [ADH; also known as vasopressin] and oxytocin. These hormones are stored in the posterior pituitary and act on certain body parts rather than acting on pituitary like other tropic hormones. ADH acts on the collecting ducts of the renal tubules and causes absorption of water. ADH secretion is linked to serum osmolality, and increased serum osmolality results in increased secretion of ADH. Lesions of the hypothalamus may result in inadequate ADH secretion, also known as cranial diabetes insipidus. Failure of ADH to act on the collecting ducts results in nephrogenic diabetes insipidus. Causes of nephrogenic diabetes insipidus include hypercalcemia, hypokalemia, and lithium therapy. In both types of diabetes insipidus, polyuria with low osmolality is common symptoms. Please see Chapter 5 for more detail.

Oxytocin is a nonapeptide hormone [nine amino acids] primarily synthesized in the magnocellular neurons of paraventricular and supraoptic nuclei of hypothalamus, and most of oxytocin produced is transported to the posterior pituitary where it is released to regulate parturition and lactation. In addition, oxytocin plays an important role in the development of the capacity to form social bonds, the mediation of the positive aspects of early-life nurturing on adult bonding capacity, and the maintenance of social bonding [2]. Hormones released by hypothalamus and their characteristics are listed in Table 2.

Table 2. Characteristics of hormones released by hypothalamus.

A brief discussion of the hypothalamus and pituitary glands

The hypothalamus contains the master regulating hormones of the endocrine system. In the classical endocrine consideration, hypothalamic hormones stimulate pituitary hormones in a vertical feed forward action and are inhibited in turn by these hormones through feedback. While this is certainly true, the role of the hypothalamus is more complex. It is itself subjected to regulation by the pineal gland.1 It is the origin of classical hormones which are in turn neurotransmitters [TRH, histamine],2 regulators of the global energy economy [pro-opiomelanocortin, αMSH],3 consolidators of dreams and memory [growth hormone releasing hormone],4, 5 and many other divergent tasks. Thus, we find that a more complete consideration of hypothalamic hormones must include these various activities.

The pituitary gland consists of three lobes: anterior, intermediate, and posterior. The anterior lobe contains the majority of pituitary hormones and includes all those that regulate the four endocrine axes: corticotropic [POMC, ATCH, β-lipotropin], gonadotropic [FSH, LH], thyrotropic [TSH], and somatotropic [GH].6 The intermediate lobe is exclusively dedicated to POMC derivatives of the corticotropic axis [MSH family, endorphins, γ-lipotropin, ACTH].7 The posterior pituitary contains two key and unique hormones: vasopressin and oxytocin.8 According to the theory of Endobiogeny, pituitary hormones have direct inter- and intra-axial peripheral activities that complement the activity of its peripheral glands. This is where the notion of the axial arrangement of hormones in alternating catabolic and anabolic functions [Chapter 4] reveals a logic that allows us to develop a coherence theory of complex systems regulation. For example, catabolic ACTH stimulates the “adjacent” axial hormone anabolic FSH, and anabolic FSH stimulates its “adjacent” axial hormone TSH, etc. [Chapter 10]. What is more, pituitary hormones have extra-axial activity on other endocrine glands and nonendocrine glands. In the assessment of clinical disorders of adaptation, it is important to evaluate the role of central factors, peripheral factors, and central-peripheral interactions, both within each axis and across axes as they relate to one another in a coherent and logical manner.

The relationship of the hypothalamus to the pituitary is functional in nature. The hypothalamus is not adjoining the pituitary. Its hormones are discharged by nerve terminals into the hypophyseal portal drainage system that baths the anterior pituitary cells. Thus, all hypothalamic hormones are neurohormones. An overview of the general relationship reveals a few interesting observations:6 [1] prolactin is the only pituitary hormone not regulated by a hypothalamic hormone within its own axis. It is regulated by the hormone TRH9 and the neurotransmitter dopamine,10 [2] the cells that produce growth hormone take up about 50% of the anterior pituitary,11 and [3] approximately two-thirds of the total volume of the anterior pituitary is dedicated exclusively to somatotropic hormones, indicating their crucial role in global functioning [Table 6.1].11

Table 6.1. Pituitary volume by cell type

[+]: stimulates, [−]: inhibits. GH: growth hormone.

Modified from Nussey S, Whitehead S. The pituitary gland. In: Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001 [chapter 7]; Copyright © 2001.