12. Obesity (2) - adipose tissue biology

Question 1

What happens to adipose tissue in obesity? (5)

Answer 1

1. adipocyte growth
   - hypertrophy (increased size)
   - hyperplasia (increase #)
2. lipoxia - FA spillover into blood
3. decreased adipose blood flow, angiogenesis - hypoxia
4. infiltration by macrophages
5. unregulated production/secretion of adipokines

Question 2

Why do adipocytes become hypoxic?

Answer 2

tissue expands, vasculature unable to meet oxygen demands

• hypoxic
• leads to inflammation
• recruit macrophages

Question 3

What causes macrophage infiltration?

Answer 3

Monocyte chemoattractant protein (MCP-1)

• inflammatory cytokine
• produced my adipose tissue during obesity/diabetes
• recruits “monocytes” and other inflammatory cells

Question 4

What do macrophages do? (3)

Answer 4

1. Angiogenesis - formation of new blood vessels
2. Clearing of necrotic tissue
3. Secretion of inflammatory cytokines
   * communicate with adipocytes to influence whole body inflammation and insulin sensitivity

Question 5

2 phenotypes of adipose macrophages?

- which is prevalent in obesity?

Answer 5

M2 - alternatively activated macrophages
- promote angiogenesis, clear pathogens

M1 - classically activated macrophages
- promote inflammation, extracellular matrix destruction

*shift from M2 to M1 in obesity

Question 6

Visceral (VAT) vs. Subcutaneous (SAT) fat

- macrophage infiltration

Answer 6

MCP-1 higher in visceral fat

- both lean and obese individuals

Question 7

Macrophage infiltration change with weight loss

Answer 7

Decrease MCP-1 with weight loss
- exercise and calorie restricted diet

*point: protein is modifiable with lifestyle change

Question 8

Portal theory

• why does excess visceral adipose tissue lead to insulin resistance?
• problem with theory?

Answer 8

Portal vein carries blood from abdomin to the liver

• VAT drains directly into portal vein
• VAT highly lipolytic
• excess FFAs drain into portal vein and go to liver
• accumulation of FFA in liver increases insulin resistance

Wrong

• mouse study, SC fat placed in VIS fat depot improves whole insulin sensitivity
• fat types are intrinsically different

Question 9

Study: transplant visceral or subcutaneous fat from donor mouse to visceral or subcutaneous regions of another

Result?

Answer 9

Subcutaneous fat into visceral depot

• improved whole body insulin sensitivity “independent of location”
• mostly adipose, little change in muscle
• suggests that crosstalk exists between SC fat regardless of location
• SC fat has some “cell-autonomous” properties (independent under its own control)

Question 10

What are the cell-autonomous properties of subcutaneous fat?

Answer 10

differences in

• gene expression
• degree of cell proliferation
• capacity to differentiate
• lipid content
• unknown secreted factors

*little is known about this yet

Question 11

What is rosiglitazone?

Answer 11

• insulin-sensitizing drug used in diabetes
• PPAR-gamma agonist
• leads to weight gain
• increase “subcutaneous” adipose tissue**
• decrease plasma FFAs
• decrease muscle and liver lipid content

Question 12

Study: Rosiglitazone on fat distribution and insulin sensitivity
- 7 days

result?

Answer 12

shift adipose tissue to “safe” subcutaneous depots

• improved whole body insulin
• some weight gain

Question 13

PPAR-gamma

Answer 13

Transcription factor
- increase adipocyte differentiation

(rosiglitazone drug is an agonist to this)