Central Regulation of Energy Metabolism With Special Reference To Circadian Rhythm

Katsuya Nagai

• Publisher: Routledge
• Year: 2022
• ISBN:
  9781351461955
• Edition: 1
• Topic: Médecine
• Subtopic: Biochimie en médecine

This excellent book describes the roles of the suprachiasmatic nucleus (SCN) of the hypothalamus as a regulatory center of homeostatic mechanism and a circadian oscillator in mammals, including humans. The authors emphasize two important points based on their findings: 1) SCN plays a critical role in central regulation of energy metabolism through which a constant supply of glucose to the central nervous system (CNS) is well maintained; and 2) neurons responsible for the regulation of energy metabolism are located in the ventrolateral part of the SCN and receive retinal neural inputs through both the retinohypothalamic tract and the geniculohypothalamic tract. The authors then discuss the evolutionary importance of these points to the survival of mammals on earth. Other topics examined include the involvement of light in the regulation of neural activity of the autonomic nervous system through the retina and SCN, in addition to the relation of the SCN with regulations of other autonomic nerve functions, such as blood pressure and body temperature. Central Regulation of Energy Metabolism with Special Reference to Circadian Rhythm is important reading for researchers and students in neuroendocrinologists, neurobiologists, biochemists, endocrinologists, physiologists, chronobiologists, psychologists, pharmacologists, and others interested in the topic.

Chapter 1 HOMEOSTATIC CONTROL OF ENERGY METABOLISM

DOI: 10.1201/9781315138985-1

I. HISTORICAL BACKGROUND OF "HOMEOSTASIS"

In 1849 Bernard¹ found that stimulation of the floor of the fourth cerebral ventricle in dog caused glycosuria. This phenomenon is now known as “piqure diabétique” and became the first evidence for central regulation of blood glucose level. Besides this finding Bernard made a number of essential discoveries in the field of physiology, including glycogen and gluconeogenesis. The term “internal secretion”, which is now preferentially used for endocrinology, was also created by him; it originally meant a phenomenon such as a glucose release into the bloodstream from the liver. Based on these findings, Bernard established a notion of “constancy of the internal environment (milieu interieur)” of the body by which animals could cope with severe environmental changes and still survive.

Almost a century later, Bernard’s concept was followed by that of Cannon² which was based on endocrinological and neurological aspects. His experimental results led to the realization that the autonomic nervous system was involved. On the basis of these findings, Cannon extended Bernard’s concept to “homeostasis”, in which the internal environment would remain relatively constant even though it might vary. Since then, much additional attention has been directed to the contributions of the central and autonomic nervous systems to homeostatic controls of blood glucose.

II. HOMEOSTATIC CONTROL OF ENERGY METABOLISM

A. WHY SHOULD HOMEOSTASIS OF THE LEVEL OF BLOOD GLUCOSE BE MAINTAINED?

The central nervous system (CNS) of human beings or other mammals requires glucose as a sole energy source. Neuronal cells are so sensitive that they cannot survive in culture even in the presence of adequate oxygen if glucose is not supplied, immediately after the cells are isolated from brains of embryonic or infantile animals. Moreover, the CNS needs a large quantity of energy. The human adult brain, for example, utilizes about 20% of the total energy consumption of the body in a resting state. This corresponds to 120 g of glucose per day. In newborn humans, the energy consumption of the brain is almost 50% of the body. In the brain, glucose is converted to water and carbon dioxide, but glycogen is not stored (less than 0.2% of brain weight) and gluconeogenesis does not occur. Accordingly, glucose must be supplemented by peripheral organs.

Blood glucose is the immediate source of brain energy. Thus, maintenance of its homeostasis is essential in coping with the urgent need of energy supply to the brain. In line with this situation, slight disturbances of brain function such as irritability and extreme sensitivity to noise occur when blood glucose falls to 60 to 70 mg/dl. More severe disturbances such as a hyperkinesia with tremor and an obvious aggressiveness happen when it falls to 50 to 60 mg/dl.

B. GLYCOGEN STORAGE IN THE LIVER AS A SOURCE OF ENERGY TO THE BRAIN

Our body is endowed with three means of maintaining homeostasis of the level of blood glucose: (1) glycogen storage, (2) food intake, and (3) gluconeogenesis. Glycogen is converted to glucose which is released into the bloodstream. This is useful for a constant or an emergency supply of energy to the brain. Glycogen is mainly stored in the liver and muscle. However, muscle lacks glucose 6-phosphatase, a terminal enzyme catalyzing the degradation of glycogen to glucose. Consequently, muscle cannot respond to an urgent need of the brain for glucose, since lactate is its main product of glycogenolysis. Liver glycogen is the main source of energy for the brain. Much evidence has been accumulated that glycogen metabolism is regulated by hormones such as adrenaline and glucagon (main factors in the liver). However, regulation of the secretion of these hormones is done by the autonomic nervous system. This seems to imply that the autonomic nervous system plays a key role in regulating energy supply to the brain.

C. FOOD INTAKE

In the human adult, about 60 g of glycogen can be stored in the liver (0.4% of its weight), which is equivalent to about half of the daily energy requirements of the brain. Gluconeogenesis meets a part of this requirement, but the rest must be supplied exogenously. Consequently, we must take food several times per day, and food intake is regulated in close harmony with the internal conditions of energy metabolism. Thus, attention has been directed to known feeding centers in the hypothalamus as candidates for the sites of central regulation of energy metabolism.

D. GLUCONEOGENESIS

Diurnal animals such as human beings and monkeys eat mainly in the light period (day), while nocturnal animals such as rats and mice eat mainly in the dark period (night). In a resting state, glucose is continuously supplied to the brain by glycogen stored in the liver, irrespective of animal species or lighting conditions. Because of a limitation of glycogen storage in the liver, gluconeogenesis must also occur during sleep to supplement the supply of glucose to the brain. This is reflected in Figure 1,^3,4 showing the daily fluctuation of activity of phosphoenolpyruvate carboxykinase (PEPCK), a key gluconeogenic enzyme, in rat liver. As seen in this figure, PEPCK activity continues to increase in the light period when rats do not eat and to decrease in the dark period when they do eat.

FIGURE 1. Daily variations of phosphoenolpyruvate carboxykinase (PEPCK) activity in the liver and kidney of rats under free feeding and an LD (12:12 h) cycle. Animals were maintained in a room illuminated for 12 h (08:00 to 20:00 h) every day. Data are expressed as means ± standard errors of means (SEM). Each five rats were used at the time points.

Hepatic gluconeogenesis is regulated by the autonomic nervous system. We presented evidence indicating that stimulation of the sympathetic nervous system caused an increase while stimulation of the parasympathetic nervous system caused a decrease in gluconeogenesis.^5-7 Furthermore: (1) hexamethonium blocked circadian changes in liver PEPCK activity; (2) peripheral injections of adrenaline (Figure 2) and noradrenaline (sympathomimetic agents) increased the liver PEPCK activity; (3) peripheral injection of carbachol (a parasympathomimetic agent) decreased liver PEPCK activity (Figure 3); (4) peripheral injection of atropine (a muscarinic cholinergic antagonist) elevated liver PEPCK activity (Figure 4); and (5) vagotomy increased liver PEPCK activity. In addit...