Pineal Gland

Commonly referred as “biological clock”, pineal gland is responsible for circadian rhythm in mammals by secreting melatonin. It is composed of glial cells and neurons known as pinealocytes.

15.4.1 Chemical Structure

Melatonin is derived from an indole ring containing amino acid tryptophan. The hydroxylation of tryptophan produces 5-hydroxytryptophan, followed by carboxylation reaction to yield serotonin (5-hydroxytryptamine). The conversion of serotonin to N-acetyl serotonin (NAS) is catalysed by the enzyme aralkylamine N-acetyltransferase (AANAT), consid­ered as a rate-limiting step in melatonin synthesis. Finally, melatonin will be produced from N-acetyl serotonin by the action N-acetyl serotonin methyl transferase (ASMT).

15.4.2 RegulationofSecretion

Although pineal gland is widely credited as a prime factor in regulating circadian rhythm in mammals, the cellular and molecular mechanisms regulate it reside in the supra- chiasmatic nucleus (SCN) of hypothalamus. The afferent sympathetic innervation to pineal gland is activated by the SCN during darkness. The adrenergic stimulation leads to synthesis of melatonin in pineal gland by activating the transcription and translation of AANAT and ASMT genes. In addition, the rhythmic expression of a certain group of genes known as clock genes (Per1-3, Cry1&2, Bmal1, and clock) especially Per1 stimulates the synthesis of melatonin. The increased synthesis of melatonin corresponds to its high levels observed during night hours. Melatonin acts on the hypothalamus and other peripheral tissues (especially ovary) to activate clock genes, in turn regulating their functioning.

15.4.3 Mechanism of Action

It binds to melatonin receptors, which belong to GPCRs family. MT1 and MT2 are two different types of melatonin receptors present in various tissues. Both of them inhibit the adenylyl cyclase, subsequent production of cAMP and affect various cellular signalling pathways.

15.4.4 Biological Effects

The role of melatonin in regulating circadian rhythm, sleep, and reproduction is very well documented. However, its

Fig. 15.13 Mechanism of synthesis of melatonin and its biological effects. [The supra- chiasmatic nucleus in the hypothalamus stimulates the synthesis and secretion of melatonin during dark period. Melatonin is the major humoral factor implicated in regulating cell cycle, seasonal breeding, and circadian rhythm in animals. [SCN supra-chiasmatic nucleus; AANAT aralkylamine N-acetyltransferase; ASMT N-acetyl serotonin methyl transferase]

other equally important properties are preventing oxidative stress, regulation of cell cycle and apoptosis.

15.4.4.1 Effects on Ovary

Melatonin by binding to its receptors controls some vital physiological processes such as growth of follicles, matura­tion of oocytes, and luteinisation. Much of them are attributed to the anti-apoptotic action of melatonin. In males, the anti­oxidative property of melatonin defends spermatozoa from oxidative damage. Hence, it ensures optimum fertility in animals by effecting steroidogenesis and ameliorating oxida­tive stress on gametes.

15.4.4.2 Effect on Seasonal Breeders

The changes in melatonin levels during different seasons act merely as a transducer in deciding a favourable period to reproduce. In case of short-day breeders like sheep, rise in melatonin levels with decreased duration of day light leads to the onset of oestrous cycle. Whereas in long-day breeders, onset of oestrous cycle corresponds with an increase in day light. This seasonal breeding effect of melatonin is mainly brought about by altering the secretory pattern of pituitary gonadotropins and thyrotropin.

15.4.4.3 Miscellaneous Effects

The stimulation of MAPK pathway and p53 genes by mela­tonin helps in regulating the apoptosis and cell cycle. Ame­lioration of oxidative stress by directly scavenging reactive oxygen species (ROS) or by production of anti-oxidant enzymes is a key property of melatonin (Fig.

Learning Outcomes

• Hormones: Defined as chemical messengers that are secreted into blood in response to an appropriate stimulus, carried and act on a specific target organ or an organ system thereby bringing a well-defined biological response. Being secreted from the duct­less glands, their ability to bind with specific receptors and initiation of signal transducing mechanisms that produce a specific target effect are the major defining properties of a hormone.

• Signal transduction: It involves the initiation of a cascade of enzymatic reactions that initiate signal­ling pathways that result in the production of sec­ondary messengers or activation of enzymes or initiation of transcription and translation of genes.

• Hypothalamus: Situated in the diencephalon, it integrates nervous and endocrine system. Based on their effect on the secretory pattern of pituitary gland hormones, hypothalamic hormones are classified as releasing and inhibiting hormones. The neuroendo­crine cells arranged in distinct nuclei are of two types, i.e. magnocellular and parvocellular neurons.

• Hypophyseal portal system: The hormones secreted from the magnocellular neurons of hypo­thalamus in median eminence are carried to the anterior pituitary gland by hypophyseal portal sys­tem. It is responsible for the hypothalamic regula­tion on pituitary hormones secretion.

• Pituitary gland: Pituitary gland has three distinct regions: anterior lobe, intermediate lobe, and poste­rior lobe. The anterior lobe is functionally contigu­ous with hypothalamus, whereas the posterior lobe is structurally related to hypothalamus. The somatotropes, lactotropes, corticotropes, gonadotropes, and thyrotropes are different neuro­endocrine cell types present in anterior pituitary and are responsible for the secretion of GH, PRL, ACTH, LH/FSH, and TSH. The posterior lobe is mainly composed of the axons arising from hypo­thalamic magnocellular neurons present in PVN and SON. The nerve terminals secrete oxytocin and ADH in to blood on appropriate stimulus.

• Pineal gland: The pineal resides near the third ventricle and regulates circadian rhythm in animals by secreting an effector hormone melatonin. The melatonin is derived from tryptophan with peak synthesis occurring during dark period. Melatonin plays a role in generating sleep-wake cycle, seasonal breeding, and fertility in farm animals. In addition, it mitigate the damage to DNA and other cellular organelles by scavenging ROS directly or indirectly by producing anti-oxidant enzymes.

Exercises

Objective Questions

Q1. What is the higher centre for the integration of endo­crine and nervous systems?

Q2. The term hormone is derived from the Greek word

Q3. Which fatty acid acts as the precursor for the biosyn­thesis of prostaglandins?

Q4. What is the smallest peptide hormone?

Q5. The catecholamines are derived from the amino acid

Q6. The receptors for steroid hormones reside in the

Q7. The large precursor molecules produced by the rough endoplasmic reticulum during the synthesis of a pep- tide/protein hormone are known as_____________.

Q8. What are the secondary messengers produced due to the hormonal stimulation of G_q receptors?

Q9. What is the major neuroendocrine cell type present in the anterior pituitary gland?

Q10. The somatomedin type__________ is responsible for

the post-natal growth of an animal.

Q11. The hormone responsible for the brooding behaviour in birds is.

Q12. What are the glycoprotein hormones released from the anterior pituitary?

Q13. The hormone that has the biological activities of oxy­tocin and ADH found in birds is.

Q14. The precursor molecule produced in the intermediate pituitary lobe for the synthesis of ACTH is

Q15. The specific region of genome to which a steroid hormone-receptor complex bind is known as

Q16. _____________ are the distinct neuroendocrine cells

responsible for the production of posterior pituitary hormones.

Q17. The functional circuit that helps in the transport of hypothalamic hormones to act on the anterior pituitary hormones is called as______________________.

Q18. Which neurotransmitter is also known as the prolactin­inhibiting hormone (PIH)?

Q19. Which hormones is responsible for seasonal breeding in animals?

Q20. The rate-limiting enzyme in the synthesis of melatonin is.

Subjective Questions

Q1. Enlist the different chemical messengers that regulate physiological functions.

Q2. What are the general properties of hormones?

Q3. Describe the different classifications of hormones with examples.

Q4. What are the different types of receptors based on their cellular localisation?

Q5. Describe in detail the steps involved in the synthesis of polypeptide/protein hormones.

Q6. Describe in detail the mechanism of synthesis of ste­roid hormones.

Q7. Why post-translational modifications in protein/poly- peptide hormones is important? Enlist the different types of post-translational modifications.

Q8. Describe in detail the steps in the production of cAMP as a secondary messenger by hormones. Give examples of hormones that act based on this mechanism.

Q9. Explain the downstream signalling pathways due to the activation of phospholipase C (PLC) system by hormone-dependent GPCRs.

Q10. What is the role of receptor tyrosine kinases in peptide signalling?

Q11. What are the different types of neuroendocrine cells in hypothalamus?

Q12. Enlist the different hypothalamic nuclei linked with endocrine activity.

Q13. Explain the structural and functional means by which hypothalamus and pituitary are connected.

Q14. What are the different types of neuroendocrine cells in adenohypophysis? Enlist their respective hormones along with their target effect.

Q15. Why GH is known as a diabetogenic and ketogenic hormone?

Q16. Describe the effects of GH on intermediary metabolism.

Q17. How PRL is responsible for lactogenesis? Describe the factors regulating its secretion.

Q18. Describe the mechanism of synthesis of ACTH and its biological effects.

Q19. Briefly describe the chemical structure of pituitary glycoproteins and explain the role of gonadotropins in regulating animal fertility.

Q20. Describe the steps involved in the synthesis of melato­nin and its effect on seasonal breeding in animals.

Answer to Objective Questions

A1. Hypothalamus

A2. Ormao

A3. Arachidonic acid

A4. TRH

A5. Tyrosine

A6. Cytoplasm

A7. Preprohormones

A8. DAG, IP₃

A9. Somatotropes

A10. Somatomedin-C (IGF1)

A11. Prolactin

A12. LH, FSH, TSH

A13. Vasotocin

A14. Pro-opiomelanocortin (POMC)

A15. Hormone response element (HRE)/Steroid response element (SRE)

A16. Magnocellular neurons

A17. Hypothalamic-hypophyseal portal system

A18. Dopamine

A19. Melatonin

A20. Aralkylamine N-acetyltransferase (AANAT)

A7. Biological activity, half-life, glycosylation, acetylation, sulfation, and amidation

A8. GPCRs, adenylyl cyclase, cAMP, and protein Kinase A

A9. GPCRs, phospholipase C, DAG, and IP₃

A10. Tyrosine kinase receptors, tyrosine kinase-associated receptors, insulin, GH, and PRL

A11. Magnocellular neurons and parvocellular neurons

A12. PVN, POA, DMN, ACN and SON

A13. Hypophyseal portal system, pituitary stalk

A14. Somatotropes-GH, lactotropes-PRL, Corticotropes (ACTH), gonadotropes (LH/FSH), and thyrotropes- TSH

A15. Peripheral utilisation of glucose, insulin resistance, gluconeogenesis in liver, and lipolysis

A16. Shift of metabolism from carbohydrates to fats, protein accumulation, and lipolysis

A17. Lobulo-alveolar growth, lactose, and casein synthesis

A18. Pre-POMC, POMC, and adrenal cortex

A19. α and β sub-units of TSH, LH and FSH, folliculogenesis, CL formation, spermatogenesis, and steroidogenesis,

A20. Tryptophan, serotonin, AANAT, ASMT, effect on thy­rotropin and gonadotropin secretion

Further Reading

Textbooks

McDonald LE, Pineda MH, Dooley MP (2003) McDonald’s veterinary endocrinology and reproduction. 5th ed./edited by M.H. Pineda, with the editorial assistance of Michael P. Dooley. Ames, Iowa: Iowa State Press. Print

Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (2017) Williams textbook of endocrinology, 13th edn. Elsevier Inc., pp 1855-1916. https://doi.org/10.1016/C2013-0-15980-6

Nussey SS, Whitehead SA (2001) Endocrinology: an integrated approach. https://www.ncbi.nlm.nih.gov/books/NBK22

Keywords for the Answer to Subjective Questions

A1. Neurotransmitters, Hormones, Neurohormones, Paracrines, Autocrines, Cytokines

A2. High-affinity receptors, onset of action, signal trans­duction, and feedback mechanisms

A3. Based on the source of secretion, chemical nature, physiological action, and solubility

A4. Transmembrane, cytosolic, and nuclear receptors

A5. Pre-pro hormone, prohormone, and hormone

A6. Cholesterol, StAR, p450scc, pregnenolone, and tissue specific hydroxylase

Articles

Bousfield GR (2019) Biosynthesis and posttranslational processing of peptide hormones. https://doi.org/10.1016/B978-0-12-801238-3. 92822-8

Clarke IJ (2011) Hypothalamus as an endocrine organ. Compr Physiol 5(1):217-253. https://doi.org/10.1002/cphy.c140019

Devesa J, Almenglo C, Devesa P (2016) Multiple effects of growth hormone in the body: is it really the hormone for growth? Clin Med Insights Endocrinol Diabetes 9:47-71. https://doi.org/10.4137/ CMED.S38201

Hu J, Zhang Z, Shen WJ, Azhar S (2010) Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metabol 7(1):1-25. https://doi.org/10.1186/1743- 7075-7-47

Kim KH, Seong BL (2001) Peptide amidation: Production of peptide hormones in vivo and in vitro. Biotechnol Bioprocess Eng 6(4):244-251. https://doi.org/10.1007/BF02931985

Levin ER, Hammes SR (2016) Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nat Rev. Mol Cell Biol 17(12):783-797. https://doi.org/10.1038/nrm.2016.122

M0llerN, Jprgensen JOL (2009) Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev 30(2):152-177. https://doi.org/10.1210/er.2008-0027

Posner BI, Laporte SA (2010) Cellular signalling: peptide hormones and growth factors. Prog Brain Res 181:1-16. https://doi.org/10.1016/ S0079-6123(08)81001-1

Psarra AM, Solakidi S, Sekeris CE (2006) The mitochondrion as a primary site of action of steroid and thyroid hormones: presence and action of steroid and thyroid hormone receptors in mitochondria of animal cells. Molecular and cellular endocrinology 246(1-2):21-33. https://doi.org/10.1016Zj.mce.2005.11.025

Scanes CG, Jeftinija S, Glavaski-Joksimovic A, Proudman J, Aramburo C, Anderson LL (2005) The anterior pituitary gland: lessons from livestock. Domest Anim Endocrinol 29(1):23-33. https://doi.org/10.10167j.domaniend.2005.04.002

Talpur HS, Chandio IB, Brohi RD, Worku T, Rehman Z, Bhattarai D, Yang L (2018) Research progress on the role of melatonin and its receptors in animal reproduction: a comprehensive review. Repro­duction in Domestic Animals 53(4):831-849. https://doi.org/10. 1111/rda.13188

Weigel NL, Moore NL (2007) Kinases and protein phosphorylation as regulators of steroid hormone action. Nucl Recept Signal 5(1):nrs- 05005. https://doi.org/10.1621/nrs.05005