서울대병원 신경외과 Grand Round 2017.4.4.

1. Neuronal Control of
Energy Metabolism
Hyung Jin Choi
Functional Neuroanatomy of Metabolism Regulation (FNMR) Lab, Department of Anatomy,
Seoul National University College of Medicine 1
Animal, Human and Cadaver Research

2. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic/Hedonic Interactions
3. Brain-Body Connections
4. Translational Research
5. Clinical Applications
2

3. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic/Hedonic Interactions
3. Brain-Body Connections
4. Translational Research
5. Clinical Applications
3

4. 왜?
4

5. 고통을 회피하는 것과 쾌락을 원하는 것은
모든 행위의 두 가지 시동장치이다.
Man can do what he wills,
but he cannot will what he wills.
—Arthur Schopenhauer,
On the Freedom of the Will
5
고통을 회피하는 것과 쾌락을 원하는 것은
모든 행위의 두 가지 시동장치이다.
- 베르나르 베르베르 “뇌”

6. Pleasure Pain
Satiety
Libido
Hunger
Approach Avoid
Craving Fear
Anxiety
Appetite
Comfort Physical
Pain
Loneliness
Social Defeat
Love
Social Success
Fear of
starvation
Mania Depression
Anhedonia
Impulsive
Energy
Reproduction
Safety
Addiction Phobia
6

7. 7
2011 Nature. Functional identification of an aggression locus in the mouse hypothalamus.
Male  Male Male  Female
Male  Female +Optogenetic Stim. Male  Glove +Optogenetic Stim.

8. Energy Balance Growth
Fertility
Whole-Body Physiology

9. 9

10. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic/Hedonic Interactions
3. Brain-Body Connections
4.Translational Research
5.Clinical Applications
10
Hedonic Homeostatic

11. 11
Eating for
Survival
Eating for
Pleasure
Nutrient Taste
Hunger Appetite
Physiological Psychological
Homeostatic Hedonic

12. Homeostatic
Regulation
12

13. 2012 JCEM Regulation of food intake, energy balance, and body fat mass- implications for the pathogenesis and treatment of obesity
Appetite
Appetite
Homeostatic Regulation of
Body Fat Mass

14. The Lipostatic Model of
Body Fat Regulation
14
2011 Set points, settling points and some alternative models- theoretical options to understand how genes and environments combine to regulate body adiposity

15. 2012 Nature Medicine Shedding pounds after going under the knife
↑Agrp
↑NPY
↓POMC
↓ Agrp
↓ NPY
↑ POMC

16. 16
2016 TEM Opposite Regulation of Ghrelin and Glucagon-like Peptide-1 by Metabolite G-Protein-Coupled Receptors
Hunger Satiety

17. GLP-1 Treatment for Obesity
JAMA
August 18, 2015July 2, 2015

18. 18

19. Ghrelin
- Before Meals↑
- After Weight Loss↑
2002 NEJM Plasma Ghrelin Levels after Diet-
Induced Weight Loss or Gastric Bypass Surgery

20. Responses of Leptin to
Short-term Fasting and Refeeding
20
1996 Diabetes. Responses of leptin to short-term fasting and refeeding in humans- a link with ketogenesis but not ketones

21. 2011 NEJM Long-term persistence of hormonal adaptations to weight loss.
N=50

22. 1995 NEJM Changes in energy expenditure resulting from altered body weight

23. 1995 NEJM Changes in energy expenditure resulting from altered body weight

24. Weight Change Induced
Energy Expenditure Change
1995 NEJM Changes in energy expenditure resulting from altered body weight

25. ~ 100 kcal/d
Per kg BW/loss
2016 Obesity. How Strongly Does Appetite Counter Weight Loss Quantification of the Feedback Control of Human Energy Intake
SGLT2 inhibitor
(Canagliflozin)

26. Physiological Needs Influence Behavior
through Discrete Hypothalamic Circuits
2013 Neuron. Hypothalamic Survival Circuits- Blueprints for Purposive Behaviors
26

27. 27
2013 Science. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding

28. 2008 Obesity. Central and Peripheral Regulation of Food Intake and Physical Activity

29. 29
2014 J Endocrinol. Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance

30. Energy Set Point
Synaptic Plasticity
30
2013 Trends in Neuroscience. Hypothalamic control of energy balance- insights into the role of synaptic plasticity

31. Mutations in the Leptin-Melanocortin Pathway in Humans
31
2015 Food reward system- current perspectives and future research needs

32. Growth Charts for Two
Children with MC4R Deficiency
32
2003 NEJM Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene

33. MC4R Mutation
33
2003 NEJM Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene
9-year-old boy
homozygous for a mutation in MC4R
His 16-year-old brother

34. Energy Intake in
MC4R Deficiency and Leptin Deficiency
34
2003 NEJM Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene

35. 2016 NEJM Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist
MC4R Agonist for POMC Mutation Patient

36. Hedonic
Regulation
36

37. Modern Obesity
Genetic Environmental
Prader
Willi
Leptin Deficiency

38. Areas of the Human Brain Activated
in Response to Palatable Food or
Food-Associated Cues
38
2011 Neuron. Reward mechanisms in obesity- new insights and future

39. Important Brain Areas Involved in the Regulation of
Eating Behaviour and Body Weight
39
2016 Lancet Diabetes and Endocrinology. Functional neuroimaging in obesity and the potential for development of novel treatments

40. 40
2014 JCEM Obesity-Associated Melanocortin-4 Receptor Mutations Are Associated With Changes in the Brain Response to Food Cues
Activation of Dorsal and Ventral Striatum
in MC4R Deficiency Patients
Response to appetizing foods compared to
non-food objects
N=8 N=10 N=8

42. Stress and Food Intake
2009 Trends in Endocrinology and Metabolism- Stress-induced obesity and the emotional nervous system

43. 2013 Biological Psychiatry. Stress as a Common Risk Factor for Obesity and Addiction
Increased limbic and striatal reactivity to stress and food cues in obese individuals

44. Model of Insulin Resistance, Regional Brain
Activation, and Food Craving in Obese Individuals
2012 Diabetes Care. Neural Correlates of Stress- and Food- Cue-Induced Food Craving In Obesity
Vicious cycle driving weight gain

46. “Obesity and drug addiction may share common hedonic mechanisms”
2011 Neuron. Reward mechanisms in obesity- new insights and future directions

47. 좋아함(Liking) 과 원함
(Wanting)
• 좋아함 “Liking” (쾌감 효과)
• 원함 “Wanting” (유인적 동기부여)
• 학습 Learning (연관만들기, 예측)
• 좋아함 없는 원함 “Wanting”
without “liking”
• 약물중독의 공통적 기전
2010 Brain Research- The tempted brain eats- Pleasure and desire circuits in obesity and eating disorders

48. “Wanting” without “Liking”
48
Movie: Thanks for Sharing (2012)

49. Behavioral Addiction vs. Substance Addiction

50. “Eating Addiction” “Food Addiction”
Behavioral Addiction Substance Addiction

51. Addiction-like Behavioral in Overeating
2012 Feed-forward mechanisms- Addiction-like behavioral and molecular adaptations in overeating

52. Homeostatic – Hedonic
Interaction
HedonicHomeostatic

53. 대사질환 유발하는 현대 환경
현대 환경과 에너지 대사 불균형
쾌락적 과식 운동 부족
비만
당뇨병
고혈압
포만감 과식 억제

54. 2013 Nature Reviews Endocrinology. The endocrinology of food intake
항상성 시스템과 쾌락 추구 시스템
항상성 조절
시스템
쾌락 추구 시스템
항상성 불균형 유발
배고픔/포만감
항상성 균형 조절

55. 55
2014 Cell Metabolism. Neural pathways that control feeding

56. GWAS
N=339,224 individuals
97 BMI-associated loci

57. Tissue Specific Expression
of BMI Regulating Genes
2015 Nature. Genetic studies of body mass index yield new insights for obesity biology
- Hypothalamus, Pituitary gland
(appetite regulation)
- Hippocampus, Limbic system
(learning, cognition, emotion,
memory)

58. 2015 Cell. Sensory Detection of Food Rapidly Modulates Arcuate Feeding Circuits
AgRP POMC
hunger satiety

59. 2015 Nature. Neurons for hunger and thirst transmit a negative-valence teaching signal

60. 2015 Cell. Sensory Detection of Food Rapidly Modulates Arcuate Feeding Circuits

61. 2017 Nature. (News and Views) Physiology- Gut feeling for food choice
Bariatric Surgery and Pleasure for Food

62. 2015 TEM Distinctive striatal dopamine signaling after dieting and gastric bypass
Homeostatic Reward and Hedonic
Reward
Hedonic Reward
Homeostatic Reward
Hedonic Reward
Homeostatic Reward
Hedonic Reward
Homeostatic Reward
Hedonic Reward
Homeostatic Reward

63. Homeostatic
Drive to Eat
Hedonic
Drive to Eat
Homeostatic
Energy Expenditure
(Resting Energy
Expenditure)
Hedonic Reward Driven
Energy Expenditure
(Exercise Energy
Expenditure)
HomeostaticHedonic
2013 Principles of Neural Science. Fifth Edition. Kandel et al.

64. Homeostatic
Drive to Eat
Hedonic
Drive to Eat
Homeostatic
Energy Expenditure
(Resting Energy
Expenditure)
Hedonic Reward Driven
Energy Expenditure
(Exercise Energy
Expenditure)
HomeostaticHedonic
2013 Principles of Neural Science. Fifth Edition. Kandel et al.
Slow Adaptation of
Set Point to New Level
(Network Change,
Synaptic plasticity?)
Weight Gain

65. Determination of the Settling
Point for Food Intake
Food
Availability
Palatability
Leptin Resistance↑Adiposity↑ Leptin↑
2010 Trends in Endocrinology and Metabolism- Obesity and leptin resistance- distinguishing cause from effect
New Set Point

66. 66
Set Point Energy Storage Temperature Glucose Blood Pressure
Normal Normal Weight Normal BT Normal Glucose Normal BP
Physiologic
Alteration
Pregnancy
Hibernation
Hibernation Exercise?
Acute Stress?
Exercise?
Acute Stress?
Disease Obesity Febrile
Disease
Diabetes? Hypertension?
Set Point Alteration and Diseases

67. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic/Hedonic Interactions
3. Brain-Body Connections
4.Translational Research
5.Clinical Applications
67
Pancreas
Gut
Liver
Fat

68. 68
2013 Trends in Neuroscience. Hypertension in obesity- is leptin the culprit

69. 2015 Cell. Sympathetic neuro-adipose con
nections mediate leptin-driven lipolysis

70. 70
2010 BBA The role of the autonomic nervous liver innervation in the control of energy metabolism

71. 2015 TEM. Brain glucose sensing in homeostatic and hedonic regulation.

72. 2015 TEM. Brain glucose sensing in homeostatic and hedonic regulation.

73. 2015 NRGH Towards a systems view of IBS
Stress-Brain-Gut-Microbiota Axis
73

74. 74
2016 Cell. Sensory Neurons that Detect Stretch and Nutrients in the Digestive System
Imaging Single Neuron Responses in
Vagal Ganglia In Vivo
GLP1R GPR65

75. 2016 Cell. Sensory Neurons that Detect Stretch and Nutrients in the Digestive System

76. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic Mechanism
3. Hedonic Mechanism
4. Homeostatic/Hedonic Interactions
5. Brain-Body Connections
6.Translational Research
7.Clinical Applications
76

77. Translational Research
Animal + Human Research
Animal
Genetics
Human
Data Science
Surgical Model
Physiology Study
College of Medicine
Imaging
Biobank
Clinical Insight
Pharmacological Model
Genetic Model
Clinical Trial
Mechanistic Insight
Tools
Understanding of
Biology and Mechanism
Understanding of
Human Metabolism and
Disease
Brain Imaging
Cadaver Study

78. Stereotaxic Brain Modulation
Stereotaxic Surgery
Pharmacologic Treatment
Genetic Modification
(Cre/flox, CRISP)
Optogenetics/Chemogenetics
Genetic Profiling
1. Animal Study
78

79. Human Brain Mapping for
Metabolism Regulation
Paraventricular Nucleus (PVN)
Lateral Hypothalamus Area (LHA)
Arcuate Nucleus (ARC)
Cadaver Donor
2. Cadaver Study
Immunofluorescence
Immunohistochemistry
Micro+Macro Functional Mapping
79

80. Metabolism
Control
Motivation
Cortex
Food
Intake
Energy
Expenditure
Visual Stimulus
Olfactory Stimulus
Taste Stimulus
fMRI/PET
Hormone
Drug
Neuromodulation
Behavior
3. Human Study
Functional Neuro-Anatomy for
Metabolism Regulation
80

81. Role of GLP-1 on Brain-Gut Axis
1. GLP-1 on Brain-Gut Axis

82. 82
GLP-1 GIP
GLP-1
+ GIP
Vehicle
Acute
Chronic
Food intake
Body weight change
Behavior
Energy expenditure
Mechanism
1. GLP-1 on Brain-Gut Axis
2016 Trends in Molecular Medicine. Reappraisal of GIP Pharmacology for Metabolic Diseases

83. Chronic Brain Infusion Model
83
GLP-1
GIP
GLP-1
+ GIP
Vehicle
2 weeks
1. GLP-1 on Brain-Gut Axis

84. 1. GLP-1 on Brain-Gut Axis

85. 85(2014) Diabetes. GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK
2016 Trends in Molecular Medicine. Reappraisal of GIP Pharmacology for Metabolic Diseases
1. GLP-1 on Brain-Gut Axis

86. 1. GLP-1 on Brain-Gut Axis
2014 JCI. Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight

87. 87
GLP-1R (red)
POMC (green)
Nucleus (blue)
Mouse Hypothalamus
ARC Nucleus
GLP-1R localization

88. Minsun Kim
Functional Neuroanatomy of Metabolism Regulation (FNMR) Lab
Human Brain
Hypothalamus
1. GLP-1 on Brain-Gut Axis

89. GLP-1R+GFAP x20 z-stack
1. GLP-1 on Brain-Gut Axis

90. Human Brain GLP-1R Mapping
GFAP+GLP-1R
Orthogonal projection
GFAP+GLP-1R
1. GLP-1 on Brain-Gut Axis

91. 91
1. GLP-1 on Brain-Gut Axis
No effect in lean individuals
In obese subjects, exenatide infusion caused an increase in
the hypothalamic fMRI signal but had no effect in lean
individuals
2016 Diabetes Care. Discordance Between Central (Brain) and Pancreatic Action of Exenatide in Lean and Obese Subjects
GLP-1 human fMRI study
GLP-1 analog

92. GLP-1 fMRI Human Study
3
+
Food presentation
max 4sec
Feedback
1sec
Fixation
1~10sec
Time
GLP-1 agonist or
placebo
Visual task
(food image)
Blood test/survey
Resting
T1 structure/DTI 17 min
12 min
12 min
Survey
Crossover, placebo-controlled trial
Subjects
1) Lean T2DM BMI<23 (n=15)
2) Obese T2DM BMI>26 (n=15)
Survey
Buffet
1. GLP-1 on Brain-Gut Axis

93. 1. GLP-1 on Brain-Gut Axis

94. Buffet
1. GLP-1 on Brain-Gut Axis

95. Chemogenetic Activation of
Brain-Body Connections
95
Pancreas
Gut
Liver
2. Chemogenetic Activation of Brain-Body Connections

96. Optogenetic and Chemogenetic
Modulation of Neuronal Activity
96
2016 Cell. Sensory Neurons that Detect Stretch and Nutrients in the Digestive System
2. Chemogenetic Activation of Brain-Body Connections

97. 97
Target specific cre mouse
Stereotaxic Injection of Chemogenetic Virus
Expression of
Chemogenetic
Receptor
Specific Drug (CNO)
Intraperitoneal Injection
Specific Neuron Modulation Using
Chemogenetics
2. Chemogenetic Activation of Brain-Body Connections

98. Chemogenetic Virus Injection
98
AL:-7.83mm, L0.25mm, D 4.5mm
DREADD
DREADD
2. Chemogenetic Activation of Brain-Body Connections

99. Effect of Parasympathetic Activation on
Food Intake and Glucose Metabolism
99
Gluconeogenesis
Insulin Secretion
Appetite
Gut
?
2. Chemogenetic Activation of Brain-Body Connections

100. Chemogenetic Modulation of
Vagus Nerve Electrophysiology
100
2. Chemogenetic Activation of Brain-Body Connections

101. Brain- Gut Connections
서울대학교 소화기내과 고성준, SNU FNMR. unpublished
X20
ChAT 1:1000
ChAT 1:1000
X10 X20
TH 1:1000
TH 1:1000
X10
X20
ParasympatheticSympathetic
Human Colon
3. Visualization of Brain-Body Connections

102. Brain-Liver
Brain-Pancreas
102
ChAT DNA Liver
SNU FNMR, unpublishe
ChAT DNA Pancreas
3. Visualization of Brain-Body Connections

103. Neuro-adipose connections
서울대병원 성형외과 홍기용. unpublished
SNU FNMR. unpublish
Sympathetic Parasympathetic
1. Perilipin 647
2. CD34 568
3. TH 488
4. DAPI
5. Merge
1. Perilipin
647
2. CD34 568
3. ChAT 488
4. DAPI
5. Merge

104. Mouse and Human Nodose Ganglion
104
Merge
MergeNPY 1:250
ChAT 1:1000
DAPI
SNU FNMR, unpublished
3. Visualization of Brain-Body Connections

105. Brain CLARITY
• 신경 사이의 연결 네트워크 분석 가능
• 3차원적 신경 구조 분석 가능
105Human hypothalamus
2차원 단면 이미징 3차원 투명화 신경 연결 분석
(Nature Biotechnology, 2016)(JCEM, 2015)
4. Human Brain Functional Mapping

106. 106
DAPI – blue, POMC – green, AgRP - red
Schematic Illustration of Study Goal
ARH
PVH
LHA
Kwanghun Chung, Nature Biotechnology. 2016
Neuronal Network Analysis Using CLARITY
3mm tracing
4. Human Brain Functional Mapping
Neuroanatomy and Network of
Metabolism Regulation
Geographic Functional Mapping
Micro-Meso Neural Circuit
Synaptic Plasticity (Obesity, DM)

107. 4. Human Brain Functional Mapping

108. 1. Tissue Preparation
2. Hydrogel
Infusion
3. Hydrogel
Polymerization
37
℃
X-CLARITY system
4. Electric
Tissue
Clearing (ETC)
5. Washing
& Staining
6. Imaging
7.
3D reconstruction
& processing
Final
Data
Human Brain Clarity
4. Human Brain Functional Mapping

109. Human Brain Cortex
Vasculature
Seoul National University, Unpublished
4. Human Brain Functional Mapping
581X581X240 μm

110. Human Hypothalamus AgRP
Neuron
Seoul National University, Unpublished
4. Human Brain Functional Mapping
650X650X520 μm

111. 4. Human Brain Functional Mapping
Human Hypothalamus ARC
CLARITY(-)
NPY (Red)
GFAP (Green)
DAPI (blue)
63x
Seoul National University, Unpublished
100X100X26 μm

112. 112
x20 x20
POMC Neuron POMC Neuron

113. 113
Mouse Hypothalamus ARC
CLARITY(+)
POMC (Green)
Seoul National University, Unpublished
650X650X300 μm

114. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic/Hedonic Interactions
3. Brain-Body Connections
4.Translational Research
5.Clinical Applications
114

115. 2015 Cell. Neural Control of Energy Balance- Translating Circuits to Therapies
Selected
Therapeutic
Options for
Treating
Obesity and
Diabetes by
Targeting
the Brain

116. Pharmacological Management of
Obesity
2015 JCEM Pharmacological Management of Obesity- An Endocrine Society Clinical Practice Guideline

117. 117http://medigatenews.com/news/4199249594?rccode=lvRc
눈여겨 볼 것은 출시 3개월 된 '콘트라브'의 반향이다.
'콘트라브'는 다른 식욕억제제와 달리 향정신성 의약품으로 지정되지 않아 처방 및 관리면에서 자유로운 편이다.
북미에서는 최근 출시된 3개 비만 신약(큐시미아, 벨빅, 콘트라브) 가운데 가장 늦게 발매됐음에도 시장점유율 1
위(2015년12월 기준, IMS헬스)를 기록한 바 있다.

119. Bupropion for
Smoking Cessation

120. 2015 Cell. Neural Control of Energy Balance- Translating Circuits to Therapies
Transcranial Direct Current Stimulation (tDCS) VBLOC: vagal blocking therapy
2015 Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and
2015 FDA approved

121. Spectrum of Personalized Obesity
Treatment
121
FDA approval
JAMA February 24, 2015

122. tDCS Decreases Food Craving
Real tDCS
Sham tDCS
Real tDCS
Sham tDCS
Craving Trouble resisting
2011 Appetite. Prefrontal cortex transcranial direct current stimulation (tDCS) temporarily reduces
food cravings and increases the self-reported ability to resist food in adults with frequent food craving
122
5. tDCS neuromodulation for Obesity

123. Long-term tDCS Treatment
Decreases Food Intake
2014 AJCN Repetitive electric brain stimulation reduces food intake in humans
123
5. tDCS neuromodulation for Obesity

124. Experimental Protocol
3
+
Food presentation
max 4sec
Feedback
1sec
Fixation
1~10sec
Time
tDCS or sham
stimulation
Visual task
(food image
ratings)
Blood test/survey
Resting MRI
T1 structure MRI
5-6min
7min
5-6min
20min
Blood test/survey
124
1. Single Treatment Study

125. Experimental Protocol
125
2. Two-week Treatment Study

126. Green Lines: orexigenic pathways
Red lines: dopaminergic pathways
2013 The contribution of brain reward circuits to the obesity epidemic
2014 Obesity – A neuropsychological disease- Systematic review and neuropsychological mode
A, amygdala;
H, hypothalamus;
NA, nucleus accumbens,
PFC, prefrontal cortex;
VTA, ventral tegmental area
126
tDCS Neuromodulation Controls
Feeding Behavior via
Food Reward Activity and Connectivity
Neuromodulation Brain Activity Feeding Behavior
Brain Connectivity
5. tDCS neuromodulation for Obesity

127. Research Projects
1. GLP-1 on Brain-Gut Axis
2. Chemogenetic Activation of Brain-Body
Connections
3. Visualization of Brain-Body Connections
4. Human Brain Functional Mapping
5. tDCS neuromodulation for Obesity
127

128. 2008 Obesity Central and Peripheral Regulation of Food Intake and Physical Activity
Human Brain

129. 2008 Obesity Central and Peripheral Regulation of Food Intake and Physical Activity
Human Brain
CLARITY
Chemogenetics

130. Environment Survey
NeuroimagingGenetics Lab/Hormone Hospital
Cognitive
Personalize
Psychotherapy
Dietary
Intervention
Exercise
Intervention
Food
Exercise
Glucose
Mobile
Drug
Neuromodulation
Monitoring

131. 대사조절
기능신경해부학 연구실