Lecture 13: WAT Expansion And Accumulation

What is the difference between metabolically healthy and pathologic obesity patients?

What can WAT mass change be a result from?

WAT mass changes may result from hypertrophy, hyperplasia, or of a combination of both

What is hypertrophy?

Swelling of existing adipocytes to accommodate excess nutrients as triglycerides

Is hypertrophy normal?

• Yes

  • Acts as a buffer to manage to nutrient storage and mobilization

  • Can help normal tissue expansion

  • Chronic hypertrophy disrupts normal physiological

What happened to mice on a high fat diet for weeks?

Chronic hypertrophy

What does chronic hypertrophy promote?

WAT dysfunction

What does chronic adipocyte hypertrophy lead to?

1. Swelling of existing adipocytes to accommodate excess nutrients as triglycerides

2. Continued over nutrition leads to the dysregulation in lipid droplet biogenesis

3. Leads to max lipid droplet size = dysfunctional adipocyte

4. Leads to hypoxia, fibrosis, and inflammation

5. Leads uncontrolled lipolysis and lipid spillover

What does hypertrophy promote?

Hypoxia, fibrosis, and inflammation

What is hypoxia?

A reduction or lack of oxygen (cellular or organ level)

What does hypertrophy lead to?

Hypoxia

Is having less oxygen at the cellular level a problem?

• Yes

  • Lack of oxygen for cellular process

  • ER-Stress

  • Mitochondria Dysfunction

  • Adipocyte death

What is the acute hypertrophy hypoxic response?

• Adipocytes quickly expand in size and, in the process, reach the diffusional limit of oxygen

• The ensuing hypoxia is mild but induces a stress signal that drives new blood vessel formation to facilitate further expansion of WAT and reduce hypoxia. This acute effect can be thought of as “healthy” AT expansion

Is acute hypoxia normal?

• Yes

  • Hypoxia causes the release of blood vessel forming (angiogenesis) factors from cells (adipocytes)

  • This promotes new capillary formation within the tissue to support its growth and function

What is the chronic hypertrophy response?

• Adipocytes keep expanding in size and, in the process, exhaust the ability of WAT to produce new blood vessels. The ensuing hypoxia is greater and induces stress signals resulting in adipocyte cell death

• Unhealthy

How does hypoxia alter WAT?

1. Tissue stress: nutrient deprivation

2. Stimulate inflammatory signals

3. Force adipocyte cell death and necrosis: stimulating lipid release

What are the drawbacks of stimulating vascular growth with hypoxia?

1. Increase vascularity in all tissues

2. Increase the risk of cancer

3. Would not solve the WAT expansion problem...only promote healthier WAT expansion in the short-term

What can hypertrophy induce?

WAT fibrosis

What is fibrosis?

The formation of excess connective tissue in an organ or tissue in a reparative or reactive process

How is fibrotic tissue made?

Fibroblast within the tissue/organ control the amount of collagen fiber and other extracellular matrix deposition

Is the fibrogenic process normal?

Yes, as a tissue repairs, connective tissue deposition is normal and precedes inflammatory signals and prepare the tissue for the regenerative or healing process. If not fully removed after regeneration or healing this effect can lead to scarring

What are the 4 phases of fibrogenesis?

1. Initiation of the response (Poor diet, adipocyte hypertrophy, hypoxia)

2. Activation of effector cells (fibroblast)

3. Elaboration of extracellular matrix (production of collagen and fibers in between adipocytes)

4. Full progression of fibrosis and organ failure

What initiates WAT fibrosis?

Hypoxic conditions and adipocyte hypertrophy stimulate the secretion of pro-fibrotic signals that stimulate fibroblast cells within WAT to expand themselves and to produce collagen and other matrix materials

What does fibrosis mean for adipose tissue?

1. Increased tissue stiffness

2. Disruption of tissue organization and architecture

   1. interfere with cell-cell communication

   2. adipocyte-blood vessel communication

3. Activated fibroblast will secret hormones and factors that disrupt WAT biology

What can hypertrophy induce?

Adipose tissue inflammation

What are macrophages?

• Phagocytic cells

• Sentinels of the innate immune system to fight off infections

• Macrophages are part of the innate immune response functions as the first line of defense against infection

• Macrophages comprise the largest population of resident immune cells in visceral AT, constituting up to 10%

• Macrophages are responsible for many housekeeping processes, such as removal of apoptotic and necrotic cells, modulation of angiogenesis, ECM remodeling, and differentiation of adipocyte precursors

What are crown-like structures?

Signals cell death and macrophage engulfment

What does brown staining represent?

Brown staining represents a lipid droplet associated protein (note the loss of staining demonstrating dead adipocytes)

How do adipocytes signal to immune system?

1. Hypertrophy adipocytes secrete cytokines that attract immune cells to the WAT

2. Immune cells and macrophages elicit/mount a pro-inflammatory response

3. Encircle and engulf adipocyte

What is WAT inflammation?

• Obesity is characterized by low-grade inflammation

• Impaired adipokine secretion

• Recruitment of harmful macrophages instead of health macrophages

• Enhances adipocyte cell death and lipid release into the blood

• Impairs insulin signaling pathways

• TNFalpha(α) is a major driver of WAT inflammation

How does hypertrophy induce adipocyte death?

• By secreting TNFα (Tumor necrosis factor alpha)

  • Proinflammatory adipokine

  • Lowly expressed in adipose tissue but increases in response to obesity

  • Changes the immune cell composition in adipose tissue

  • Serves as a macrophage attractant-–bringing the macrophage to the dysfunctional adipocyte

  • Impairs insulin signaling in adipose tissue and muscle

  • Impairs pancreatic insulin secretion

What does TNFα correlate with?

Fat mass and adipocyte hypertrophy

What do TNF-α secreting adipocytes recruit?

TNF-α secreting adipocytes recruit macrophages that secret TNF-α – vicious cycle

Can we target TNFa to stop WAT inflammation?

This has failed in mice: While anti-TNF therapy has reduced other symptoms of obesity such as fatty liver disease there has been NO impact on adipose tissue inflammation! Must be more to the story.....

What does adipocyte hypertrophy alter?

Adipocyte hypertrophy alters the immune cell composition of our adipose tissue

How is adipose tissue inflammatory attack sustained?

• Elevated fatty acids, adipocyte hypertrophy, and hypoxia initiate the inflammatory response

• Adipose tissue inflammation recruits' macrophages to sustain the inflammatory response

• Macrophages account for 10% of lean adipose tissue mass but increases to 50% in obesity

What is the difference between classical and alternatively macrophages?

Classically activated macrophages: M1 OBESE STATE!

• Stimulates the deconstruction of extracellular matrixes

• Promotes apoptosis and necrosis

• Visceral fat tends to have more M1 macrophages

Alternatively activated macrophages: M2 LEAN STATE

• Stimulates extracellular matrixes

• Cellular proliferation

• Angiogenesis

• Subcutaneous fat tends to have more M2 macrophages

Why do M1 macrophage have negative health consequences?

• M1 macrophages will:

  • Breakdown tissue integrity

  • Promote adipocyte cell death

  • Kills other cell types

  • Prevents angiogenesis

  • Alters WAT environment leading to overall changes in adipokine secretion

  • Recruits more M1 macrophages

What is lipolysis?

• Normal function of adipocytes to control energy levels

• Lipolysis is turned on in the fasted state

• Increase cyclic AMP

• cAMP levels phosphorylate hormone sensitive lipase (HSL, an enzyme)

• HSL hydrolyzes triglycerides into free fatty acids

• Free fatty acids released into the blood

• Utilized for energy

Why is lipolysis turned off in the fed state?

Glucose is available, do not need free fatty acids

Why does insulin block lipolysis?

• Insulin is telling the fat cell to stop converting triglycerides to free fatty acids (blocking lipolysis) and use glucose for energy and store excess as triglycerides

• This does not happen in the obese state because fat cells are becoming enlarged and desensitized to insulin mediated signaling

• Less insulin signaling means that insulin cannot turn off lipolysis in the fed state

What consequence does adipocyte hypertrophy have on WAT biology?

Adipocyte hypertrophy has a negative consequences on WAT biology