“Obesity & Metabolism”by Prof. Catharine Ross

(Assisted by Prof. Yasuo Kagawa and Assoc. Prof. Masaharu Kagawa)Advance unit on Nutrition in English. 2 credit points.

This advanced unit will focus on the interactions of diet, metabolism, and inflammation, organized around 3 main topics, each 4-5 weeks in length.1) Central metabolism, including the development of adipose tissue and the role of high-fat diet in promoting obesity and adipose tissue inflammation.2) Glucose and vascular inflammation.3) Interactions of diet and inflammation in the intestine.

Regulation and Dysregulation of Metabolism during Obesity

Kagawa Nutrition UniversityFormal Undergraduate Unit“Advanced unit on Nutrition in English”2 creditsCourse No. a14154001-3Friday (4:40pm-6:10pm)September 29th, 2017 to February 2nd, 2018Instructor: C. Ross, PhD

Co-instructor: Masaharu Kagawa, PhD; Associate ProfessorYasuo Kagawa, MD, PhD, Professor

Office: Room 62xx, office hours Friday afternoons, Email: catharine.ross@eiyo.ac.jp cc: acr6@psu.edu

I’d like first to introduce you to:

• Penn State University

• My workplace

• Why am I here?

Penn State (1864) an original“Land Grant” university.

Land-grant: The U.S. governmentgave land to the states for the establishment of universities, Morrill Act of 1862.

Focus was on promoting agriculture and mechanical arts.

Now, 45,000 undergraduateand graduate students in 13 colleges

at the University Park campus.

Land Grant Universities in the U.S.

https://www.google.ca/search?as_q=Morrill+Act+1862&as_epq=&as_oq=&as_eq=&as_nlo=&as_nhi=&lr=&cr=&as_qdr=all&as_sitesearch=&as_occt=any&safe=images&as_filetype=&as_rights=

University Park campus

“Old Main” administrationbuilding

ChandleeLaboratory

Home for Nutritional Science

Neuroimaging

Genomics Core Laboratory

Nutritional Sciences—ranked one of top U.S. graduatenutrition programs by the National Research Council

Classroom teaching

What I do…

Research supervision:PhD studentsUndergraduatesPostdoctoral research associatesResearch technologist

Vitamin A researchLiver disease researchBeginning microbiome project in mice and pigs

Why I am here in Japan–

The Fulbright Programhttps://eca.state.gov/fulbright

Named after former Senator William J. Fulbright (1905 – 1995)

The Fulbright Program is the flagship international educational exchange program sponsored by the U.S. government

It is designed to increase mutual understanding between the people of the United States and the people of other countries.

Lecturer/Research –5 months in another country to teach, learn, and conduct research

Why Japan?

Previous associates: Postdocs now working in Japan at several universities and hospitals

Have loved previous visits, but always (too) short

Why here? NUTRITION!

Have met previously and was very fortunate to be accepted by Prof. Kagawa and KNU as a Fulbright Scholar

In 2013, met Prof. Kagawa and gave talk on vitamin A

We continued to share scientific information….

In 2016, I visited again to ask if Fulbright visit was possible…

Goals:

Teach* Content

* Encourage and practice use of English

Research (writing; learning about Japanese diet)

Learn about Japanese nutritional sciences and other aspects of science in Japan

Already:

Fulbright Orientation (Tokyo, 2 days)

Ajinomoto Foundation for Dietary Culture (Shinagawa)

Komagome campus, “mackerel cooking,” with Prof. Haraguchi and tour with Prof. Furukawa

Visit to RIKEN, Waco-shi campus, for International Woman Scientist Colloquium and tour of Archives, with Prof. Kagawa and Prof. Ohta

JUSEC leaders and Fulbright Fellows and Fulbright Scholars

Nancy Sanders, PhD, Education, Cal PolyTeaching at Chuo University

Ajinomoto Foundation for Dietary Culture

Tadashi Tamura , General Secretary, in Library

Founders home garden, still preserved

Mitsuo Furukawa, professor

First visit to KNU Komagome campus, for observation of student lesson, ”Mackerel cooking”

Haruko Kawate, Mitsuo Furukawa

Mackerel dishes from class

Prof. Haraguchi teaching class

RIKEN – long illustrious history in nutrition

Umetaro Suzuki -- purified vitamin B1 in 1920s

Vitamin A from cod oil was a major source of financial support for RIKEN

Unit Main topic Additional activities % grade

Part I – Obesity and inflammation — local and systemic effects

1 Adipose tissue as a dynamic active tissue

2 Inflammation within adipose tissue Brief self-test (0)

3 “Danger signals” and Toll-like receptors in-class 20 minute closed-book Quiz 1 10

4 Carbohydrate metabolism in adipose and skeletal muscle

5 Effects of adiposity on central metabolism

6 Student presentations on Part I Short (10 minute) student presentations 10*

Take-home written exam 10

Part II – Glucose and vascular inflammation 7 Principles of glucose metabolism

8 Roles of diet and age in the progression of atherosclerosis Brief self test (0)

9 Receptors as factors in vascular disease In-class 20 minute closed-book Quiz 2 10

10 Diet and coronary heart disease Short (10 minute) student presentations 10*

11 The liver in reverse cholesterol transport and lipid catabolism Take-home written examination 15

Part III – Interaction of diet and inflammation in the intestine12 The small and large intestine13 Inflammation in the intestine; diet and microbes Topics for unit 15 will be assigned

14 Intestinal motility and diet In-class 20 minute closed-book Quiz 3 10

15 Summing up and integrating Short (10 minute) student presentations 10*

Take home written exam 20

Let’s begin with the human body-- What is it composed of? Where are these components found? 人体から始めましょう。組成は？分布は？

Think biochemically of its basic components – WATER, CHO, PROT, FAT

Largest component? 最大の成分は？

Least variable component? 最も変動の少ない成分は？

Most variable component? 最も変動の大きい成分は？

Some very old data – on Fuel Reserves in the normal human body ｴﾈﾙｷﾞｰ貯蔵量

Tissue Glucoseand glycogen

Mobilizable proteins

Triglycerides

(Wt in kg) g kJ g kJ g kJBlood (10) 15 255 100 1700 5 185Liver (1) 100 1700 100 1700 50 1850Intestine (1) 0 0 100 1700 0 0Brain (1.4) 2 34 40 680 0 0Muscle (30) 300 5,100 4000 68,000 600 22,200Adipose tissue (15)

20 340 300 51,000 12000 444,200

Skin, lung, spleen (4)

13 220 240 4080 40 1480

Total 450g 7,649 kJ 5000g 82,280kJ 12695g 469,715kJ

= ?

Truism: You are what you eat.

On average,

Our diets provide macronutrients in the form of CHO > FAT > PROTEINUS In Japan:

Acceptable Macronutrient CHO = 45-65% CHO = __%Distribution Ranges (adults): PROT = 10-35% PROT = __%

FAT = 20-35% FAT = __%

Our bodies contain FAT > PROTEIN >> CHO (little glycogen and glucose)

Therefore, the functions of metabolism are

_____________________ and _________________________?

No matter what we consume, the human body has limited capacity to store carbohydrate.

No matter what we consume, the human body has limited capacity to store protein.

No matter what we consume, the human body has an almost unlimited capacity to store fat.

Yes, or No? 下記の文の正否は？炭水化物、蛋白質、脂肪の人体への貯蔵。

The body can make: 人体で合成できるのは

Protein from fat? 脂肪からたんぱく質は作れる？

Carbohydrate from fat? 脂肪から炭水化物は作れる？

Fat from protein? 蛋白質から脂肪は作れる？

Fat from Carbohydrate? 炭水化物から脂肪は作れる？

Carbohydrate from Protein? 蛋白質から炭水化物は作れる？

1) Central metabolism, including the development of adipose tissue and the role of high-fat diet in promoting obesity and adipose tissue inflammation.

Let’s begin here-- What do we mean?

Central metabolism – conversion of dietary substrates* into new products, that become the building blocks for tissues to 1) store energy (lipids); 2) produce energy (oxidation); 3) make compounds needed for self renewal;

Development of adipose tissue: Stromovascular cells*; preadipocytes#; adipocytes (fat cells); then what?

During the development of obesity, what changes occur in adipose tissue that make it unhealthy?

When adipose tissue becomes unhealthy, what is the consequence? What may be the effects on “central” organs? On the Liver? Pancreas*? Gut? Muscle?

1) 中心的な代謝: 脂肪組織の発達と、

高脂肪食の肥満と脂肪組織炎症の促進作用

＊間質血管細胞 #脂肪前駆細胞

*食事由来の基質

＊膵臓

Enlarged adipocytes 拡張脂肪細胞

High calorie diet?High carbohydrate diet?

High sugar diet?High fat diet?

Excess free fatty acids過剰遊離脂肪酸 / Saturated fatty acids過剰飽和脂肪酸

Hypoxia (too little oxygen) to adipocytes

What common types of diets are associated with obesity?

低酸素

http://www.webmd.com/diet/obesity/body-fat-distribution

Body fat differs in:

Amount (wide range of BMI)

Distribution

Type of cells

Sensitivity to diet?

Enlarged adipocytes 拡張脂肪細胞

High calorie diet?High carbohydrate diet?

High sugar diet?High fat diet?

Excess free fatty acids過剰遊離脂肪酸 / Saturated fatty acids過剰飽和脂肪酸

Hypoxia (too little oxygen) to adipocytes

What common types of diets are associated with obesity?

低酸素

Lesson 1： Adipose tissue as an active tissue.

Adipocytokinesアディポサイトカイン

This unit will present the anatomy of adipose tissue and discuss how it undergoes biochemical and cellular changes during the onset of obesity.

Topics will include the formation of adipocytes from precursor cells, and the changes in the adipose tissue composition that accompany adipocyte enlargement. The concept of adipose tissue inflammation will be introduced.

アペリン

エストロジェン

ビスファチン

レプチン

アディポネクチン

レジスチン

腫瘍壊死因子

インターロイキン

脂肪組織の組成変化に伴う脂肪細胞拡大→炎症

Defining Inflammation

Nature Reviews Immunology 2; 787-795 (2002)Basically, an adaptive repair process… followed by resolution

Some common adipokines and their functions

• Appetite-regulatory adipokines• Leptin -- "satiety hormone", a hormone made by adipose

cells that helps to regulate energy balance by inhibiting hunger.• Ghrelin, ”hunger hormone", opposes leptin. Acts on hypothalamus in brain.• Adiponectin

Some common inflammatory “kines” and their functions• IL-1, IL-6, Tumor necrosis factor (TNF)alpha; IL-8, IL-17

Recruit monocytes and other factors for repair;If too much or too long, result in damage.

Chronic low-grade inflammation

• May not observe all of these main signs

• Cytokines may be elevated (can be difficult to measure)

• Damage may be local, slow to develop, but insidious

• Instead of resolution, becomes long-term and damaging

(Save next 2 slides for next week)

Study of:WAT (morphology, immunostaining)Mouse (db/db (lacks leptin receptor, hsl-/-)Human biopsy tissues (subcutaneous and viseral) from obese (BMI > 30); and lean (BMI 20-24.9) male and female subjects undergoing elective surgery

A research study that set the stage --脂肪細胞の変化段階を決める研究

研究内容白色脂肪細胞（形態学、免疫染色法）マウス（db/db=ﾚﾌﾟﾁﾝ受容体欠損型、hsl欠損型ヒト生検組織（BMI30以上の肥満者の皮下脂肪と内臓脂肪、BMI20-24.9の正常者の男女の選択手術患者から得た試料）

Cinti et al. J. Lipid Res. 2005:

Lean mice 非肥満ﾏｳｽ Genetically obese (db/db) mice

MAC2 = Macrophage marker＃

MGC = multinucleate giant cell

Key findings: Obese WAT exhibits large cells, surrounded by “crown-like structures” consisting of multinucleate giant cells 肥満白色脂肪の冠状構造*

*冠状構造は多核巨細胞からなる。

#免疫染色で褐色の細胞はﾏｸﾛﾌｧｰｼﾞ２．

ﾚﾌﾟﾁﾝ受容体欠損肥満ﾏｳｽ

Review points 復習の要点

1. Diets can vary widely; the human body composition is relatively constant (homeostasis)

2. Obesity (I > O) can result from a variety of types of diet

4. Inflammation develops when adipocytes enlarge, become hypoxic, and die

3. Inflammation is a normal repair process; when it does not resolve and, instead, becomes chronic, problems arise

Additional readings 追加文献

• Useful Review: 有用な総説

• de Heredia, P., Gómez-Martinez, S., Marcos, A. Obesity, inflammation and the immune system. Proc Nutr Soc 2012; 71: 332-8.

• Going deeper: より深い理解へ

• Cinti, S. et al. (Greenberg, Obin lab). Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005; 46:2347-55.

Perez de Heredia et al. 2012

Adipocytes send signals that they are overly fat, and macrophages send signals that they are activated. These signals interact to contribute to whole-body insulin resistance.脂肪細胞は過剰肥満の信号を送り、ﾏｸﾛﾌｧｰｼﾞは活性化の信号を送る。これらの信号は全身のインスリン抵抗性を高める。ﾏｸﾛﾌｧｰｼﾞ

小胞体ｽﾄﾚｽ低酸素

脂肪細胞

インスリン抵抗性

脂肪滴

核

褐色脂肪細胞 (熱産生） 白色脂肪細胞 （脂肪貯蔵）brown adipocyte white adipocytes

(specialized in thermogenesis) (primary site in fat storage)

核

Oil droplet

New concepts: 新しい考え方

Can WAT become more BAT-like? “Browning” or “Beiging” of WAT1) During differentiation2) As a result of environmental changes3) Diet?

Discuss more later ---詳細は後の講義で

Quality of muscle and adipose cells depends on developmental signals, which are influenced by the environment(cold, exercise, PPAR signaling).

2014

白色脂肪は褐色脂肪のように変えられるか？白色脂肪の「褐色化」または「ﾍﾞｰｼﾞｭ化」

１） 脂肪細胞分化の過程で。２） 環境の変化*の結果として。３） 食事で？

＊寒冷刺激など

環境誘因例：寒冷､

PPARγ作動薬

間葉幹細胞

PDGFα発現 生理活性脂肪前駆細胞 白色脂肪細胞

褐色脂肪細胞

ﾍﾞｰｼﾞｭ細胞

骨格筋

皮筋節前駆細胞

褐色前駆脂肪細胞

筋原細胞

ﾍﾞｰｼﾞｭ前駆細胞

筋肉と脂肪細胞の質は寒冷、運動PPARｼｸﾞﾅﾙ等の分化の信号による。

褐色､白色脂肪細胞の階層的分化

MyoD等は転写制御因子UCP1は脱共役因子１でﾐﾄｺﾝﾄﾞﾘｱで発熱作用。