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Obesity

George A. Bray, David A. York

10.1002/cphy.cp070234

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Definitions and Measurement of Body Fat, Fat Distribution, and Weight
1.1 The Problem Posed by Obesity
2 Methods Used to Study Obesity
2.1 Animal Models Used to Produce Obesity
3 Obesity as a Disturbance of Energy Balance
4 Obesity as a Disturbance of Nutrient Feedback
4.1 Controlled System
4.2 Afferent Feedback
4.3 The Controller
4.4 Efferent Controls
5 Recent Experimental Findings
5.1 Single Genes
5.2 Polygenic Obesity
5.3 Diet‐Related Obesities
5.4 Hypothalamic Obesity
5.5 Endocrine Obesity
5.6 Features Common to Many Models of Obesity
6 Summary
Figure 1. Figure 1.

Hypothalamic areas where damage produces obesity. Comparison of VMN and PVN lesions. The PVN lesion produces hyperphagia as its main mechanism for accumulating fat. A VMN lesion alters sympathetic activity and can produce an increase in body fat without hyperphagia.

[Copyright 1993, George A. Bray.]
Figure 2. Figure 2.

A diagram of factors affecting the formation of visceral fat and how visceral fat affects metabolic signals to produce diseases.
Figure 3. Figure 3.

Schematic diagram to show the periodicity of food intake. The first meal (q1) begins at time 1 and ends at time 2. Following the intermeal interval between 2 and 3 a second meal begins at 3 and ends at 4, with a quantity q2 that is smaller than q1.

[Copyright 1995, George A. Bray.]
Figure 4. Figure 4.

First Law of Thermodynamics Rewritten to include feedback from fat (leptin) and energy expenditure (sympathetic nervous system).

(Copyright 1996, George A. Bray).
Figure 5. Figure 5.

Diagram of a controlled system. The controller for food intake is located in the brain, which receives afferent signals from the periphery and integrates them into efferent controls that modulate food intake and the controlled system of nutrient intake storage and oxidation.
Figure 6. Figure 6.

Body and energy composition. The four bars on the left side of the graph represent the chemical composition of a lean and obese individual expressed as proportion of body weight for a 70 kg and 100 kg man and a 56 kg and 86 kg woman (i.e. an extra 30 kg for the obese person of each gender). The corresponding energy contribution from this chemical composition is shown in the right side of the graph, with the ordinate to the right.
Figure 7. Figure 7.

Relationship of macronutrient intake to body stores of that macronutrient. A diet containing 40En% fat, 40En% carbohydrate, and 20En% protein is shown on the left. The relationship of each of these components to the body stores of the corresponding nutrient is shown on the left side as a percentage of nutrient stores.
Figure 8. Figure 8.

Negative Feedback Signals
Figure 9. Figure 9.

Components of energy expenditure.
Figure 10. Figure 10.

Cartoon of afferent signals controlling food intake. MSH = melanocyte stimulating hormone; CCK = cholecystokinin; VPDPR = enterostatin; GRP = gastrin releasing hormone; SNS = sympathetic nervous system; NTS = nucleus tractus solitarius; NE = norepinephrine; BAT – brown adipose tissue; ARC = arcuate nucleus; GR = glucocorticoid receptor; db‐R = receptor for Ob protein (absent or defective in db mouse).
Figure 11. Figure 11.

Autonomic Nervous System Modulation of Food Seeking
Figure 12. Figure 12.

Diagram showing the anatomic location of the hypothalamic nuclei. Damage to the ventromedial or paraventricular nucleus will produce obesity. Damage to the more lateral hypothalamus produces weight loss and anorexia.
Figure 13. Figure 13.

Schematic of controller. The peptides and monoamines involved in food intake. NTS = nucleus of the tractus solitarius; CCK = cholecystokinin; 5‐HT = serotonin; NE = norepinephrine; CRH = corticotropin‐releasing hormone; MPG = motor pattern generator; SNS = sympathetic nervous system; DMV = dorsal motor nucleus of the vagus.
Figure 14. Figure 14.

A model of food intake and satiety. Food seeking, physiologically, may be initiated by gastric contractions and/or a dip in glucose. Following ingestion of food 3 mechanisms, including nutrient and hormonal, gastric distension and the sympathetic nervous system serve to signal satiety. In the post‐absorptive period the decline in activity of the sympathetic nervous system may lower the threshold for increasing vagal activity, which in turn stimulates gastric contractions and the rise in insulin leading to the glucose dip.
Figure 15. Figure 15.

Shows a detailed diagram of the controller system for food intake. Both stimulatory (+) and inhibitory (−) signals are generated and fed to the brain through the sensory system, through circulating nutrients and hormones, or through the vagus and the sympathetic afferent nervous system. All of this information is integrated in the controller, where serotonin (5‐HT), the β‐adrenergic system, and the α‐adrenergic system are important. A number of peptides also modulate feeding. The transduced signals control motor activity for food selection as well as the sympathetic and parasympathetic (vagus) nervous system. These efferent systems in turn modulate the control of food intake and the metabolism within the controlled system. (5‐HT = serotonin; NE = norepinephrine; CCK = cholecystokinin; NPY = neuropeptide Y; CRF = corticotropin‐releasing factor (hormone); NTS = nucleus of the tractus solitarius; F.I. = food ingestion; SNS = sympathetic nervous system; DMV = dorsomotor vagal nucleus; BAT = brown adipose tissue; Panc = pancreas.)
Figure 16. Figure 16.

Splicing and mutations of the leptin receptor gene. Either a short form (a) or long form (b) of the receptor result from alternative splicing in the wild‐type mouse. A G‐to‐T mutation in the diabetes (db/db) mouse forms a new splice donor site that results in a single longer form of mRNA that includes an additional 106‐base insertion from exon 2. This mRNA is not fully translated into protein because of the premature stop codon in exon 2. Thus the leptin receptor of db/db mice lacks the intracellular arm of the receptor that is coded by exon 3. TM = transmembrane.
Figure 17. Figure 17.

Potential sites of action of leptin to modulate energy balance and peripheral metabolism. Leptin synthesis and secretion is increased by body fat, insulin, and glucocorticoids (GC). Through actions in the hypothalamus, possibly mediated by inhibition of neuropeptide Y (NPY) secretion and stimulation of corticotropin releasing hormone (CRH) secretion, leptin decreases food intake, stimulates sympathetically (SNS)‐mediated brown adipose tissue (BAT) thermogenesis, and reduces the parasympathetically (PNS)‐mediated insulin secretion. The increased thermogenesis and decreased energy intake lead to the energy deficit that is satisfied by mobilization of body fat stores. In addition, leptin may enhance glucose uptake into nonadipose tissues, such as muscle, to improve glucose disposal and insulin sensitivity. + − stimulation, inhibition.
Figure 18. Figure 18.

Adrenalectomy and sympathetic activity. Diagram of peripheral and central signals that regulate body fat, food intake, and autonomic activity. In the normal animal, the balance between NPY and CRH is seen to be critical to the control of food intake and autonomic balance modulating insulin secretion and brown fat thermogenesis. Leptin probably is an important signal to regulate the NPY‐CRH axis. In obesity, absence of appropriate leptin signaling leads to increased NPY activity. Increased activity of the HPA axis results in excessive glucocorticoid influences on the autonomic system. These effects are exacerbated by the development of central insulin resistance and loss of central serotoninergic activity. Dotted lines (—) indicate reduced activity, thin lines (–) normal activity, double lines (=) excessive activity.
Figure 19. Figure 19.

Hepatic androgenization and diabetes in db/db and Ay/a mice. Sulphation of steroids increases solubility but prevents binding to the steroid receptor. High levels of sex steroid transferase (STS) and low dehydroepiandrosterone (DHEA) sulphotransferase (DST) activity in males and estrogen sulphotransferase (EST) activity in females maintain the androgenic and estrogenic states, respectively, in males and females. In obese males and obese females that become diabetic, inhibition of DST and activation of EST promote androgenization. This alters the balance between hepatic glucose storage and output, promotes the deposition of visceral fat and leads to the development of diabetes. Other abbreviations: S = sulphate; EST = estrogen; TESTOST = testosterone.
Figure 20. Figure 20.

A model for the effect of glucocorticoids on the production of CRH, on the level of CRH binding protein (CRHBP) or on the activity of CRH2 receptor.


Figure 1.

Hypothalamic areas where damage produces obesity. Comparison of VMN and PVN lesions. The PVN lesion produces hyperphagia as its main mechanism for accumulating fat. A VMN lesion alters sympathetic activity and can produce an increase in body fat without hyperphagia.

[Copyright 1993, George A. Bray.]


Figure 2.

A diagram of factors affecting the formation of visceral fat and how visceral fat affects metabolic signals to produce diseases.



Figure 3.

Schematic diagram to show the periodicity of food intake. The first meal (q1) begins at time 1 and ends at time 2. Following the intermeal interval between 2 and 3 a second meal begins at 3 and ends at 4, with a quantity q2 that is smaller than q1.

[Copyright 1995, George A. Bray.]


Figure 4.

First Law of Thermodynamics Rewritten to include feedback from fat (leptin) and energy expenditure (sympathetic nervous system).

(Copyright 1996, George A. Bray).


Figure 5.

Diagram of a controlled system. The controller for food intake is located in the brain, which receives afferent signals from the periphery and integrates them into efferent controls that modulate food intake and the controlled system of nutrient intake storage and oxidation.



Figure 6.

Body and energy composition. The four bars on the left side of the graph represent the chemical composition of a lean and obese individual expressed as proportion of body weight for a 70 kg and 100 kg man and a 56 kg and 86 kg woman (i.e. an extra 30 kg for the obese person of each gender). The corresponding energy contribution from this chemical composition is shown in the right side of the graph, with the ordinate to the right.



Figure 7.

Relationship of macronutrient intake to body stores of that macronutrient. A diet containing 40En% fat, 40En% carbohydrate, and 20En% protein is shown on the left. The relationship of each of these components to the body stores of the corresponding nutrient is shown on the left side as a percentage of nutrient stores.



Figure 8.

Negative Feedback Signals



Figure 9.

Components of energy expenditure.



Figure 10.

Cartoon of afferent signals controlling food intake. MSH = melanocyte stimulating hormone; CCK = cholecystokinin; VPDPR = enterostatin; GRP = gastrin releasing hormone; SNS = sympathetic nervous system; NTS = nucleus tractus solitarius; NE = norepinephrine; BAT – brown adipose tissue; ARC = arcuate nucleus; GR = glucocorticoid receptor; db‐R = receptor for Ob protein (absent or defective in db mouse).



Figure 11.

Autonomic Nervous System Modulation of Food Seeking



Figure 12.

Diagram showing the anatomic location of the hypothalamic nuclei. Damage to the ventromedial or paraventricular nucleus will produce obesity. Damage to the more lateral hypothalamus produces weight loss and anorexia.



Figure 13.

Schematic of controller. The peptides and monoamines involved in food intake. NTS = nucleus of the tractus solitarius; CCK = cholecystokinin; 5‐HT = serotonin; NE = norepinephrine; CRH = corticotropin‐releasing hormone; MPG = motor pattern generator; SNS = sympathetic nervous system; DMV = dorsal motor nucleus of the vagus.



Figure 14.

A model of food intake and satiety. Food seeking, physiologically, may be initiated by gastric contractions and/or a dip in glucose. Following ingestion of food 3 mechanisms, including nutrient and hormonal, gastric distension and the sympathetic nervous system serve to signal satiety. In the post‐absorptive period the decline in activity of the sympathetic nervous system may lower the threshold for increasing vagal activity, which in turn stimulates gastric contractions and the rise in insulin leading to the glucose dip.



Figure 15.

Shows a detailed diagram of the controller system for food intake. Both stimulatory (+) and inhibitory (−) signals are generated and fed to the brain through the sensory system, through circulating nutrients and hormones, or through the vagus and the sympathetic afferent nervous system. All of this information is integrated in the controller, where serotonin (5‐HT), the β‐adrenergic system, and the α‐adrenergic system are important. A number of peptides also modulate feeding. The transduced signals control motor activity for food selection as well as the sympathetic and parasympathetic (vagus) nervous system. These efferent systems in turn modulate the control of food intake and the metabolism within the controlled system. (5‐HT = serotonin; NE = norepinephrine; CCK = cholecystokinin; NPY = neuropeptide Y; CRF = corticotropin‐releasing factor (hormone); NTS = nucleus of the tractus solitarius; F.I. = food ingestion; SNS = sympathetic nervous system; DMV = dorsomotor vagal nucleus; BAT = brown adipose tissue; Panc = pancreas.)



Figure 16.

Splicing and mutations of the leptin receptor gene. Either a short form (a) or long form (b) of the receptor result from alternative splicing in the wild‐type mouse. A G‐to‐T mutation in the diabetes (db/db) mouse forms a new splice donor site that results in a single longer form of mRNA that includes an additional 106‐base insertion from exon 2. This mRNA is not fully translated into protein because of the premature stop codon in exon 2. Thus the leptin receptor of db/db mice lacks the intracellular arm of the receptor that is coded by exon 3. TM = transmembrane.



Figure 17.

Potential sites of action of leptin to modulate energy balance and peripheral metabolism. Leptin synthesis and secretion is increased by body fat, insulin, and glucocorticoids (GC). Through actions in the hypothalamus, possibly mediated by inhibition of neuropeptide Y (NPY) secretion and stimulation of corticotropin releasing hormone (CRH) secretion, leptin decreases food intake, stimulates sympathetically (SNS)‐mediated brown adipose tissue (BAT) thermogenesis, and reduces the parasympathetically (PNS)‐mediated insulin secretion. The increased thermogenesis and decreased energy intake lead to the energy deficit that is satisfied by mobilization of body fat stores. In addition, leptin may enhance glucose uptake into nonadipose tissues, such as muscle, to improve glucose disposal and insulin sensitivity. + − stimulation, inhibition.



Figure 18.

Adrenalectomy and sympathetic activity. Diagram of peripheral and central signals that regulate body fat, food intake, and autonomic activity. In the normal animal, the balance between NPY and CRH is seen to be critical to the control of food intake and autonomic balance modulating insulin secretion and brown fat thermogenesis. Leptin probably is an important signal to regulate the NPY‐CRH axis. In obesity, absence of appropriate leptin signaling leads to increased NPY activity. Increased activity of the HPA axis results in excessive glucocorticoid influences on the autonomic system. These effects are exacerbated by the development of central insulin resistance and loss of central serotoninergic activity. Dotted lines (—) indicate reduced activity, thin lines (–) normal activity, double lines (=) excessive activity.



Figure 19.

Hepatic androgenization and diabetes in db/db and Ay/a mice. Sulphation of steroids increases solubility but prevents binding to the steroid receptor. High levels of sex steroid transferase (STS) and low dehydroepiandrosterone (DHEA) sulphotransferase (DST) activity in males and estrogen sulphotransferase (EST) activity in females maintain the androgenic and estrogenic states, respectively, in males and females. In obese males and obese females that become diabetic, inhibition of DST and activation of EST promote androgenization. This alters the balance between hepatic glucose storage and output, promotes the deposition of visceral fat and leads to the development of diabetes. Other abbreviations: S = sulphate; EST = estrogen; TESTOST = testosterone.



Figure 20.

A model for the effect of glucocorticoids on the production of CRH, on the level of CRH binding protein (CRHBP) or on the activity of CRH2 receptor.

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Article Title: Obesity
 

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George A. Bray, David A. York. Obesity. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 1015-1056. First published in print 2001. doi: 10.1002/cphy.cp070234