This document summarizes research on how the brain regulates appetite and food intake. It discusses both homeostatic and hedonic mechanisms. Homeostatic mechanisms involve hormones and specific hypothalamic circuits that sense hunger and satiety. Mutations impacting the leptin-melanocortin pathway can cause obesity. Hedonic mechanisms in reward centers drive overeating for pleasure rather than nutrition. Stress and highly palatable foods can override homeostatic controls. Interactions between these systems determine the body weight set point. Clinical applications aim to target these brain regions and pathways to treat obesity.

1. 우리 뇌는 식욕을 어떻게 조절할까?
Hyung Jin Choi
Functional Neuroanatomy of Metabolism Regulation (FNMR) Lab,
Department of Anatomy,
Seoul National University College of Medicine
1

2. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic Mechanism
3. Hedonic Mechanism
4. Interactions
5. Clinical Applications
2

3. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic Mechanism
3. Hedonic Mechanism
4. Interactions
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 mousehypothalamus.
Male  Male Male  Female
Male  Female +Optogenetic Stim. Male  Glove +Optogenetic Stim.

8. Food Availability Growth
Fertility
Whole-Organism Physiology

9. 9
Eating for
Survival
Eating for
Pleasure
Nutrient Taste
Hunger Appetite
Physiological Psychological
Homeostatic Hedonic

10. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic Mechanism
① Hormones
② Neuroanatomy
③ Genetics
3. Hedonic Mechanism
4. Interactions
5. Clinical Applications
10

11. 2012 JCEM Regulation of food intake, energy balance,
and body fat mass- implications for the pathogenesis
and treatment of obesity
식욕
식욕
식욕
음식 섭취 제한
소식 자유식 과식 자유식

12. The Lipostatic Model of
Body Fat Regulation
12
2011 Set points, settling points and some alternative models- theoretical options to understand how genes and environments combine to regulate body adiposity

13. Physiological Consequences of
Changes from Body Weight Set Point
13
2014 Cell Metabolism. A Missing Link in Body Weight Homeostasis - The Catabolic Signal of the Overfed State

14. 2012 Nature Medicine Shedding pounds after going under the knife
↑Agrp
↑NPY
↓POMC
↓Agrp
↓NPY
↑POMC

15. 15
2016 TEM Opposite Regulation of Ghrelin and Glucagon-like Peptide-1 by Metabolite G-Protein-Coupled Receptors
Hunger Satiety

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

17. 1998 JCEM Diurnal and ultradian rhythmicity of plasma leptin-
effects of gender and adiposity
Insulin
Glucose
Leptin
Change (%)
Plasma
Leptin
Insulin
- Rapidly changing
- Every meal
Leptin
- Slowly changing
- Days ~ weeks

18. Responses of Leptin to
Short-term Fasting and Refeeding
18
1996 Diabetes. Responses of leptin to short-term fasting and refeeding in humans- a link with ketogenesis but not ketones

19. 2011 NEJM Long-term persistence of hormonal adaptations to weight loss.
N=50

20. 2013 NRE The endocrinology of food intake

21. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic Mechanism
① Hormones
② Neuroanatomy
③ Genetics
3. Hedonic Mechanism
4. Interactions
5. Clinical Applications
21

22. 22

23. Physiological Needs Influence Behavior
through Discrete Hypothalamic Circuits
2013 Neuron. Hypothalamic Survival Circuits- Blueprints for Purposive
23

24. 2013 Nature Reviews Endocrinology. The endocrinology of food intake

25. 2008 Obesity. Central and Peripheral Regulation of Food Intake and Physical Activity

26. Melanocortin
System in
the Arcuate
Nucleus
26
2014 Nature Review Endocrinology. Mitochondrial dynamics in the central regulation of metabolism
MC4R
(+) α-MSH (POMC)
(-) AgRP

27. 2016 Nature Neuroscience. Melanocortin-4 receptor–regulated energy homeostasis
Functional Topography of Mc4r Function

28. Feeding Inhibiting
Emergency Neurocircuits
28
2014 Nature Review Neuroscience. Neurobiology of food intake in health and disease
Illness, trauma, injury
Eating disorders (anorexia and malaise associated
with cancer and other chronic disease states)

29. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic Mechanism
① Hormones
② Neuroanatomy
③ Genetics
3. Hedonic Mechanism
4. Interactions
5. Clinical Applications
29

30. Mutations in the Leptin-Melanocortin Pathway in Humans
30
2015 Food reward system- current perspectives and future research needs

31. Growth Charts for Two
Children with MC4R Deficiency
31
2003 NEJM Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene

32. MC4R Mutation
32
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

33. Energy Intake in
MC4R Deficiency and Leptin Deficiency
33
2003 NEJM Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene

34. 2016 NEJM Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist
MC4R Agonist for POMC Mutation Patient

35. Genetics of Eating Behavior
2011 Nutrition Reviews. Genetics of eating behavior: established and emerging concepts

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

37. 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)

38. 2015 Nature. Genetic studies of
body mass index yield new
insights for obesity biology
Blue: Previous
Red: Novel

39. Genetic Prediction of Obesity
2015 Nature. Genetic studies of body mass index yield new insights for obesity biology

40. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic Mechanism
3. Hedonic Mechanism
4. Interactions
5. Clinical Applications
40

41. Modern Obesity
Genetic Environmental
Prader
Willi
Leptin Deficiency

42. Physiologic Control of Energy Metabolism
Energy ExpenditureAppetite
Obesity
T2DM
Hypertension
Modern Environment

43. Areas of the Human Brain Activated
in Response to Palatable Food or
Food-Associated Cues
43
2011 Neuron. Reward mechanisms in obesity- new insights and future

44. Important Brain Areas Involved in the Regulation of
Eating Behaviour and Body Weight
44
2016 Lancet Diabetes and Endocrinology. Functional neuroimaging in obesity and the potential for development of novel treatments

45. Visual Food (Picture) Task
Procedure During fMRI
2014 Diabetes Care. Leptin Is Associated With Exaggerated Brain Reward and Emotion Responses to Food Images in Adolescent Obesity
Obese (N=25, BMI 34.4 kg/m2, age 15.7 years)
Lean (N=15, BMI 20.96 kg/m2, age 15.5 years)
45

46. Neural response differences in cue condition contrasts
2014 Diabetes Care. Leptin Is Associated With Exaggerated Brain Reward and Emotion Responses to Food Images in Adolescent Obesity
High Calorie Food > Non-Food46

47. Whole-brain, Voxel-based
Correlation Analyses with Leptin
2014 Diabetes Care. Leptin Is Associated With Exaggerated Brain Reward and Emotion Responses to Food Images in Adolescent Obesity
High Calorie Food > Non-Food47

48. 48
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

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

50. 2013 Biological Psychiatry. Stress as a Common Risk Factor for Obesity and Addiction

51. Stress and Addiction
(Substance or Food)
51
2013 Biological Psychiatry. Stress as a Common Risk Factor for Obesity and Addiction

52. 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

53. 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

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

55. Wanting without Liking
• “Liking”
• hedonic impact
• “Wanting”
• incentive motivation
• Addictive incentive-sensitization
• A mechanism of drug addiction
• Sensitized “wanting” can rise even if
“liking” declines for the same reward
• Compulsively crave and seek food, but not
derive higher pleasure from it.
2009 Dissecting components of reward- ‘liking’, ‘wanting’, and learning
2010 Brain Research- The tempted brain eats- Pleasure and desire circuits in obesity and eating disorders

56. “Wanting” without “Liking”
56

57. Behavioral Addiction vs. Substance Addiction

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

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

60. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic Mechanism
3. Hedonic Mechanism
4. Interactions
5. Clinical Applications
60
Hedonic Homeostatic

61. 2013 Nature Reviews Endocrinology. The endocrinology of food intake

62. 62
2014 Cell Metabolism. Neural pathways that control feeding

63. Altered Brain Response to
Glucose
63
2016 Diabetes. Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents

64. Palatability Can Drive Feeding
Independent of AgRP Neurons
64
2015 Cell Metabolism. Palatability Can Drive Feeding Independent of AgRP Neurons
Model of "comfort feeding“
- Exaggerated hyperphagia on a palatable diet
- Greater anorexia during stress

65. 2015 Cell. Sensory Detection of Food Rapidly Modulates Arcuate Feeding Circuits
AgRP POMC
hunger satiety

66. 2015 Cell. Sensory Detection of Food Rapidly Modulates Arcuate Feeding Circuits

67. 2015 Cell. The Hunger Genes- Pathways to Obesity

68. 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

69. 69
Energy Glucose Blood Pressure
Normal Set
Point
Normal Normal Normal
Altered Set
Point
Increased
Adiposity
Hyperglycemia Hypertension

70. Contents
1. Motivation: What Drives Our Mind and Body?
2. Homeostatic Mechanism
3. Hedonic Mechanism
4. Interactions
5. Clinical Applications
70

71. BELVIQ

72. 2015 Cell. Neural Control of Energy Balance- Translating Circuits to Therapies
Selected
Therapeutic
Options for
Treating
Obesity and
Diabetes by
Targeting
the Brain

73. Multidimensional Architecture
73
Gene
Hormone
Brain
Psychology
Behavior
Phenotype
Outcome
Metabolic
Disease
Vascular
Disease
Environment

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

75. Neuroscience of
Metabolism Regulation
Hyung Jin Choi
Functional Neuroanatomy of Metabolism Regulation (FNMR) Lab, Department of Anatomy,
Seoul National University College of Medicine 75
Animal, Human and Cadaver Research

76. Stereotaxic Brain Modulation
Stereotaxic Surgery
Pharmacologic Treatment
Genetic Modification
(Cre/flox, CRISP)
Optogenetics/Chemogenetics
Genetic Profiling
1. Animal Study
76

77. Metabolism
Control
Motivation
Cortex
Food
Intake
Energy
Expenditure
Visual Stimulus
Olfactory Stimulus
Taste Stimulus
fMRI/PET
Hormone
Drug
Neuromodulation
Behavior
2. Human Study
Functional Neuro-Anatomy for
Metabolism Regulation
77

78. 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

79. Spectrum of
Personalized Obesity Treatment
79
FDA approval
JAMA February 24, 2015
2015 Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and obesity

80. 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
80

81. Human Brain Mapping for
Metabolism Regulation
Paraventricular Nucleus (PVN)
Lateral Hypothalamus Area (LHA)
Arcuate Nucleus (ARC)
Cadaver Donor
3. Cadaver Study
Immunofluorescence
Immunohistochemistry
Micro+Macro Functional Mapping
81

82. 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