Melatonin and Fat Mass Regulation
Chapter One
Preamble of the Study
Melatonin (N‐acetyl‐5‐methoxytryptamine or, according to IUPAC, N‐[2‐(5‐methoxy‐1H‐indol‐3‐yl) ethyl] acetamide) is an ancient molecule ubiquitously present in nature including both plant and animals. It is well known that in mammals, melatonin is synthesized in several cells, tissues, and organs mainly for local utilization (autocrine and paracrine actions) and that circulating melatonin is largely provided by the pineal gland where it is produced and directly released to the blood and cerebrospinal fluid.
CHAPTER TWO
REVIEW OF RELATED LITERATURE
Introduction
Melatonin and energy metabolism
All physiological and behavioral processes of the body are organized to balance energy intake, storage, and expenditure. The energy balance guarantees the individual’s survival, growth and reproduction, and, consequently, species perpetuation. Through the adequate circadian distribution and organization of the metabolic processes, most animals optimize energy balance by concentrating energy harvesting and intake during the active phase of the day and mobilizing body energy stores during the resting phase in order to produce the energy necessary to sustain the living processes. Melatonin is the key mediator molecule for the integration between the cyclic environment and the circadian distribution of physiological and behavioral processes and for the optimization of energy balance and body weight regulation, events that are crucial for a healthy metabolism. In this scenario, to fully understand the role played by melatonin in the control of energy metabolism, it is necessary to address the subject from following the perspectives: i), from the perspective of the classical endocrinology, examining the role played by melatonin in the regulation of metabolic processes; ii), from the perspective of the chronobiology, considering the role played by melatonin in the regulation of the circadian internal temporal order of the physiological processes involved in energy metabolism; iii), and finally, understanding the role played by melatonin in the regulation of energy balance and its final outcome, that is, body weight, as a way to sum up its regulatory role on energy metabolism
Melatonin and the regulation of metabolic processes
The relation between pineal gland, melatonin, and energy metabolism was initially hinted at in both humans and rodents many years ago. The very first experiments demonstrated that infusion of pineal extracts led to hypoglycemia, increased glucose tolerance, and hepatic and muscular glycogenesis after glucose loading, while pinealectomy induced a diminished glucose tolerance and a reduced hepatic and muscular glycogenesis. More recently, the metabolic disruption caused by the absence of melatonin in the pinealectomized animal was characterized as a diabetogenic syndrome that includes glucose intolerance and peripheral (hepatic, adipose, and skeletal muscle) and central (hypothalamus) insulin resistance. This dramatic pathological picture can be reverted by melatonin replacement therapy or restricted feeding, but not by physical training. Moreover, insulin resistance, glucose intolerance, and several alterations in other metabolic parameters can be seen in some physiological or pathophysiological states associated with reductions in blood melatonin levels, as aging, diabetes, shift work, and environmental high level of illumination during the night. It is emphasized that adequate melatonin replacement therapy alleviates most of the mentioned metabolic alterations in these situations. Furthermore, a similar metabolic syndrome is seen in MT1‐knockout animals.
The genesis of the pinealectomy‐induced insulin resistance and glucose intolerance is related to the cellular consequences of the absence of melatonin, such as a deficiency in the insulin‐signaling pathway and reduction in GLUT4 gene expression and protein content. The insulin‐sensitive tissues (white and brown adipose tissue and skeletal and cardiac muscles) of the pinealectomized animal exhibit a greater reduction in GLUT4 mRNA and microsomal and membrane protein contents that reverts to the level of the intact animal following adequate melatonin replacement therapy. Moreover and emphasizing the functional synergism between melatonin and insulin, it was shown that melatonin by itself, acting through MT1 membrane receptors, induces rapid tyrosine phosphorylation and activation of the tyrosine kinase β‐subunit of the insulin receptor, and mobilizing several intracellular transduction steps of the insulin‐signaling pathway (tyrosine phosphorylation of IRS‐1; IRS‐1/PI(3)‐kinase and IRS‐1/SHP‐2 associations; and downstream AKT serine, MAP‐kinase, and STAT3 phosphorylation).
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