Section 1 Introductory Section

**3**

**Chapter 1**

*Po-Shiuan Hsieh*

**1. Introduction**

**2. Main subjects**

Prologue: Energy Metabolism

The prevalence of overweight and obesity has increased remarkably over the past decades and become a global epidemic and health threat. Obesity not only has strong genetic determinants but also results from an imbalance between energy storage and energy expenditure. Control of energy homeostasis involved in multiple complicated processes is essential for the maintenance of body weight and life. It becomes extremely important to understand the underlying mechanisms since obesity due to energy excess represents a major threat to health and quality of life.

For instance, the progress regarding neuronal circuits that control food intake could extend our understanding of energy homeostasis. In particular, the brain has been considered to play a crucial role in the central regulation of energy intake and also energy expenditure. There are many candidate genes in the central nervous system associated with obesity. In traditional view of homeostatic regulation of the body, weight is mainly by the hypothalamus. However, the recent report showed that the hedonic control of appetite by cortical and subcortical brain areas interacts with homeostatic controls to regulate body weight in a flexible manner to respond to the environmental changes [1]. This new concept has several important implica-

On the other hand, the role of adipocytes including brown and white adipocytes has been considered to substantially contribute to the integration of the endocrine and metabolic signaling in energy metabolism regulation. Brown adipose tissue (BAT) thermogenesis is one of the key homeostatic mechanisms for energy expenditure. It is around 60% of "non-shivering" thermogenesis in small mammals attributing to the BAT [2, 3] to sustain their body temperature and survival in the cold [4, 5]. In addition, BAT is currently considered a promising target for the treatment of obesity and T2D [6–10]. Accordingly, there were a number of studies focusing on the related drug development and the underlying mechanism and the several factors implicated in BAT and WAT "browning" such as immune cell-mediated modulation of adipose tissue sympathetic innervation [11]. Nevertheless, although the functional role of BAT in the regulation of energy expenditure, especially thermogenesis and substrate utilization, is dominant in rodent models, the contribution of BAT to energy metabolism and homeostasis in humans is more controversial. The regulation of mitochondrial metabolism and their consequence also crucially participate in the maintenance of energy homeostasis at the cellular and physiological level. Mitochondria play a central role in the regulation of cellular metabolic homeostasis, which is under the control of the balance between nutrient

and Weight Control

tions for the therapeutic strategies of obesity.

#### **Chapter 1**

## Prologue: Energy Metabolism and Weight Control

*Po-Shiuan Hsieh*

#### **1. Introduction**

The prevalence of overweight and obesity has increased remarkably over the past decades and become a global epidemic and health threat. Obesity not only has strong genetic determinants but also results from an imbalance between energy storage and energy expenditure. Control of energy homeostasis involved in multiple complicated processes is essential for the maintenance of body weight and life. It becomes extremely important to understand the underlying mechanisms since obesity due to energy excess represents a major threat to health and quality of life.

#### **2. Main subjects**

For instance, the progress regarding neuronal circuits that control food intake could extend our understanding of energy homeostasis. In particular, the brain has been considered to play a crucial role in the central regulation of energy intake and also energy expenditure. There are many candidate genes in the central nervous system associated with obesity. In traditional view of homeostatic regulation of the body, weight is mainly by the hypothalamus. However, the recent report showed that the hedonic control of appetite by cortical and subcortical brain areas interacts with homeostatic controls to regulate body weight in a flexible manner to respond to the environmental changes [1]. This new concept has several important implications for the therapeutic strategies of obesity.

On the other hand, the role of adipocytes including brown and white adipocytes has been considered to substantially contribute to the integration of the endocrine and metabolic signaling in energy metabolism regulation. Brown adipose tissue (BAT) thermogenesis is one of the key homeostatic mechanisms for energy expenditure. It is around 60% of "non-shivering" thermogenesis in small mammals attributing to the BAT [2, 3] to sustain their body temperature and survival in the cold [4, 5]. In addition, BAT is currently considered a promising target for the treatment of obesity and T2D [6–10]. Accordingly, there were a number of studies focusing on the related drug development and the underlying mechanism and the several factors implicated in BAT and WAT "browning" such as immune cell-mediated modulation of adipose tissue sympathetic innervation [11]. Nevertheless, although the functional role of BAT in the regulation of energy expenditure, especially thermogenesis and substrate utilization, is dominant in rodent models, the contribution of BAT to energy metabolism and homeostasis in humans is more controversial.

The regulation of mitochondrial metabolism and their consequence also crucially participate in the maintenance of energy homeostasis at the cellular and physiological level. Mitochondria play a central role in the regulation of cellular metabolic homeostasis, which is under the control of the balance between nutrient supply and energy demand [12]. Metabolic oversupply is followed by fragmentation of mitochondrial network, which leads to a decrease of mitochondrial bioenergetic efficiency that, in association with an increase in nutrient storage, will avoid energy waste. Conversely, under metabolic undersupply, mitochondria elongate in order to increase mitochondrial bioenergetic efficiency and sustain the energy need. Thereby, the mitochondrial function is crucial for the regulation of energy metabolism and weight control.

Even at rest, we need energy for all of the vital functions known as basal metabolic rate (BMR). The determinant factors such as thyroid hormones T3, T4 [13, 14], and sarcolipin [15] and their impact on energy homeostasis will be the other important issue. Thyroid hormones have been well documented as the key regulator of energy metabolism (calorigenic effect), especially the basal metabolic rate for decades. However, the cellular and molecular mechanisms underlying the regulatory role of thyroid hormones are still not fully understood. For instance, recent investigation showed that T4 has been speculated to have more rapid effect on the regulation of basal metabolic rate than T3 in animals [14]. Sarcolipin (SLN) is a novel regulator of sarcoplasmic reticulum Ca2+ ATPase (SERCA) in muscle and has been speculated as an important determinant of the BMR in animal with diet-induced obesity [15].

#### **Author details**

Po-Shiuan Hsieh Institute of Physiology, National Defense Medical Center, Taipei, Taiwan

\*Address all correspondence to: pshsieh@hotmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**5**

*Prologue: Energy Metabolism and Weight Control DOI: http://dx.doi.org/10.5772/intechopen.87007*

> [8] Schrauwen P, Van Marken Lichtenbelt WD. Combatting type 2 diabetes by turning u the heat. Diabetologia. 2016;**59**:2269-2279. DOI:

10.1007/s00125-016-4068-3

beem.2016.09.001

[9] Virtanen KA. The rediscovery of BAT in adult humans using imaging. Best Practice & Research. Clinical Endocrinology & Metabolism. 2016;**30**:471-477. DOI: 10.1016/j.

[10] Scheele C, Nielsen S. Metabolic regulation and the anti-obesity perspectives of human brown fat. Redox Biology. 2017;**12**:770-775. DOI:

[11] Wolf Y, Boura-Halfon S, Cortese N, Haimon Z, Sar Shalom H, Kuperman Y,

macrophages control tissue innervation and homeostatic energy expenditure. Nature Immunology. 2017;**18**:665-674.

[12] Picard M, Wallace DC, Burelle Y. The rise of mitochondria in medicine. Mitochondrion. 2016;**30**:105-116

[13] Kim B. Thyroid hormone as a determinant of energy expenditure and the basal metabolic rate. Thyroid.

[14] Fernando G. The effects of

10.3389/fphys.2014.00528

3,5-diiodothyronine on energy balance. Frontiers in Physiology. 2015;**5**:1-5. DOI:

[15] Maurya SK, Bal NC, Sopariwala DH, Pant M, Rowland LA, Shaikh SA, et al. Sarcolipin is a key determinant of the basal metabolic rate, and its overexpression enhances energy expenditure and resistance against diet-induced obesity. The Journal of Biological Chemistry. 2015;**290**(17):10840-10849

10.1016/j.redox.2017.04.011

et al. Brown-adipose-tissue

DOI: 10.1038/ni.3746

2008;**18**(2):141-144

[1] Berthoud HR, Munzberg H, Morrison CD. Blaming the brain for obesity: Integration of hedonic and homeostatic mechanisms. Gastroenterology. 2017;**152**:1728-1738

**References**

[2] Foster DO, Frydman ML. Tissue distribution of cold-induced

thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: The dominant role of brown adipose tissue in the replacement of shivering by non-shivering thermogenesis. Canadian Journal of Physiology and Pharmacology. 1979;**57**:257-270. DOI:

[3] Heldmaier G, Buchberger A. Sources of heat during nonshivering thermogenesis in Djungarian hamsters: A dominant role of brown adipose tissue during cold adaptation. Journal of Comparative Physiology. B. 1985;**156**:237-245. DOI: 10.1007/

[4] Himms-Hagen J. Brown adipose tissue thermogenesis: Interdisciplinary

[5] Klingenspor M. Cold-induced recruitment of brown adipose tissue thermogenesis. Experimental Physiology. 2003;**88**:141-148. DOI:

[6] Blondin DP, Carpentier AC. The role of BAT in cardiometabolic disorders and aging. Best Practice & Research. Clinical Endocrinology & Metabolism. 2016;**30**:497-513. DOI: 10.1016/j.

[7] Schlein C, Heeren J. Implications of thermogenic adipose tissues for metabolic health. Best Practice & Research. Clinical Endocrinology & Metabolism. 2016;**30**:487-496. DOI:

10.1016/j.beem.2016.08.002

studies. The FASEB Journal. 1990;**4**:2890-2898. DOI: 10.1096/

fasebj.4.11.2199286

10.1113/eph8802508

beem.2016.09.002

10.1139/y79-039

BF00695778

*Prologue: Energy Metabolism and Weight Control DOI: http://dx.doi.org/10.5772/intechopen.87007*

#### **References**

*Cellular Metabolism and Related Disorders*

lism and weight control.

diet-induced obesity [15].

supply and energy demand [12]. Metabolic oversupply is followed by fragmentation of mitochondrial network, which leads to a decrease of mitochondrial bioenergetic efficiency that, in association with an increase in nutrient storage, will avoid energy waste. Conversely, under metabolic undersupply, mitochondria elongate in order to increase mitochondrial bioenergetic efficiency and sustain the energy need. Thereby, the mitochondrial function is crucial for the regulation of energy metabo-

Even at rest, we need energy for all of the vital functions known as basal metabolic rate (BMR). The determinant factors such as thyroid hormones T3, T4 [13, 14], and sarcolipin [15] and their impact on energy homeostasis will be the other important issue. Thyroid hormones have been well documented as the key regulator of energy metabolism (calorigenic effect), especially the basal metabolic rate for decades. However, the cellular and molecular mechanisms underlying the regulatory role of thyroid hormones are still not fully understood. For instance, recent investigation showed that T4 has been speculated to have more rapid effect on the regulation of basal metabolic rate than T3 in animals [14]. Sarcolipin (SLN) is a novel regulator of sarcoplasmic reticulum Ca2+ ATPase (SERCA) in muscle and has been speculated as an important determinant of the BMR in animal with

**4**

**Author details**

Po-Shiuan Hsieh

Institute of Physiology, National Defense Medical Center, Taipei, Taiwan

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: pshsieh@hotmail.com

provided the original work is properly cited.

[1] Berthoud HR, Munzberg H, Morrison CD. Blaming the brain for obesity: Integration of hedonic and homeostatic mechanisms. Gastroenterology. 2017;**152**:1728-1738

[2] Foster DO, Frydman ML. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: The dominant role of brown adipose tissue in the replacement of shivering by non-shivering thermogenesis. Canadian Journal of Physiology and Pharmacology. 1979;**57**:257-270. DOI: 10.1139/y79-039

[3] Heldmaier G, Buchberger A. Sources of heat during nonshivering thermogenesis in Djungarian hamsters: A dominant role of brown adipose tissue during cold adaptation. Journal of Comparative Physiology. B. 1985;**156**:237-245. DOI: 10.1007/ BF00695778

[4] Himms-Hagen J. Brown adipose tissue thermogenesis: Interdisciplinary studies. The FASEB Journal. 1990;**4**:2890-2898. DOI: 10.1096/ fasebj.4.11.2199286

[5] Klingenspor M. Cold-induced recruitment of brown adipose tissue thermogenesis. Experimental Physiology. 2003;**88**:141-148. DOI: 10.1113/eph8802508

[6] Blondin DP, Carpentier AC. The role of BAT in cardiometabolic disorders and aging. Best Practice & Research. Clinical Endocrinology & Metabolism. 2016;**30**:497-513. DOI: 10.1016/j. beem.2016.09.002

[7] Schlein C, Heeren J. Implications of thermogenic adipose tissues for metabolic health. Best Practice & Research. Clinical Endocrinology & Metabolism. 2016;**30**:487-496. DOI: 10.1016/j.beem.2016.08.002

[8] Schrauwen P, Van Marken Lichtenbelt WD. Combatting type 2 diabetes by turning u the heat. Diabetologia. 2016;**59**:2269-2279. DOI: 10.1007/s00125-016-4068-3

[9] Virtanen KA. The rediscovery of BAT in adult humans using imaging. Best Practice & Research. Clinical Endocrinology & Metabolism. 2016;**30**:471-477. DOI: 10.1016/j. beem.2016.09.001

[10] Scheele C, Nielsen S. Metabolic regulation and the anti-obesity perspectives of human brown fat. Redox Biology. 2017;**12**:770-775. DOI: 10.1016/j.redox.2017.04.011

[11] Wolf Y, Boura-Halfon S, Cortese N, Haimon Z, Sar Shalom H, Kuperman Y, et al. Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nature Immunology. 2017;**18**:665-674. DOI: 10.1038/ni.3746

[12] Picard M, Wallace DC, Burelle Y. The rise of mitochondria in medicine. Mitochondrion. 2016;**30**:105-116

[13] Kim B. Thyroid hormone as a determinant of energy expenditure and the basal metabolic rate. Thyroid. 2008;**18**(2):141-144

[14] Fernando G. The effects of 3,5-diiodothyronine on energy balance. Frontiers in Physiology. 2015;**5**:1-5. DOI: 10.3389/fphys.2014.00528

[15] Maurya SK, Bal NC, Sopariwala DH, Pant M, Rowland LA, Shaikh SA, et al. Sarcolipin is a key determinant of the basal metabolic rate, and its overexpression enhances energy expenditure and resistance against diet-induced obesity. The Journal of Biological Chemistry. 2015;**290**(17):10840-10849

**7**

Section 2

Energy Metabolism
