Lecture 17 - Metabolic consequences of obesity

3 main metabolic consequences of obesity

- Loss of regulation of body weight

- Inflammation

- Insulin resistance

Regulation of body weight by leptin

Leptin is involved in the control of appetite

- the rate of β-oxidation and FA synthesis in the various tissues

Control of appetite by leptin

Leptin sends signals to our brain on the status of our adipose tissue

Low levels of leptin tells the brain

we have low storage amounts ∴ we should eat more, less energy expenditure

High levels of leptin tells the brain

we have high storage amounts ∴ we should eat less, more energy expenditure

Insulin and leptin

decrease appetite

Ghrelin

hormone from stomach mechanoreceptors, tells brain we need to eat

PYY3-36 and GLP-1

hormone from gut tells, brain we're full

with weight loss, what happens to leptin levels?

decreased leptin to stimulate more food intake

with healthy weight gain, what happens to leptin levels?

increased leptin to decrease food intake

leptin gene abbreviation

LEP

What is observed in a mouse that has two defective copies of LEP? (ob/ob)

becomes obese

suffers from hyperphagia (abnormal increase in appetite)

If we see an increase in leptin in obese individuals, should we observe a decrease in appetite and increase in energy expenditure?

Theoretically yes

But in reality we don't see that. People become resistant to leptin

Leptin resistance

decrease in leptin sensitivity, obese individuals lose the ability to regulate body weight through their appetite

Hyperleptinemia

High leptin levels

Leptin's evolutionary role

to make sure we don't die of starvation, not control obesity

How does obesity cause low-grade chronic inflammation?

Hypoxia of adipocytes leads to an increase in IL-6 and TNF-α

What are IL-6 and TNF1α?

adipokines that trigger pro-inflammatory responses

MCP-1

(monocyte chemotaxis protein)

protein produced by enlarged adipocytes

How does MCP-1 promote inflammation?

Macrophages infiltrate adipose tissue in response to MCP-1

Macrophages in adipose tissue produce TNFα, which favours export of fatty acids to ectopic places

What cells secrete TNFα?

adipose tissue-resident macrophages

Action of TNFα (pro-inflammatory response)

1. stimulate lipolysis

2. Decreased TAG biosynthesis

3. Block entry of new free fatty acid

4. TNF-α counteracts the action of insulin

How does TNFα decrease TAG biosynthesis?

by inhibiting PPARγ

How does TNFα counteract insulin?

prevents binding to the receptor and lowers the expression of GLUT4

Effect of TNF-α on LPL (Lipoprotein Lipase)

LPL is inhibited and therefore it cannot pick up new FAs so VLDLs continue circulating and eventually fats get 'dropped off' in ectopic places

The TNFα pathway stimulates what?

the expression of proinflammatory genes

How does TNFα block the downstream activation of insulin signalling?

it inhibits the kinase activity of IRS1

IL-6 effect on IRS1

IRS1 can be destabilized by the Interleukin-6 (IL-6) signaling cascade

What does inhibiting IRS1 eventually lead to?

insulin resistance

IL-6 paradox

transient/acute expression of IL-6 in response to exercise causes an increase in insulin sensitivity

chronic elevated level of IL-6 leads to a decrease in insulin sensitivity

In healthy subjects, what percent of circulating IL-6 is produced by adipose tissue?

10-35%

What is the metabolic consequence of becoming resistant to insulin?

insulin-secreting cells will die off (overworked pancreas), lose glucose receptors and blood sugar levels become uncontrolled (T2D)

What is the inevitable fate of long-term obesity?

Type 2 diabetes

Effect of insulin resistance on muscle

decreased glucose uptake

Effect of insulin resistance on adipose tissue

increase fatty acid in blood → Ectopic fat storage

Effect of insulin resistance on liver

increased glucose production

Why does the liver produce more glucose in response to insulin resistance?

Without insulin response (due to insulin resistance), the liver believes we have no sugar so it increases glucose production

Adiponectin (Acrp30)

Peptide hormone produced uniquely in adipose tissue.

Role of adiponectin in the liver

- Decreased glucose output

- Increased fatty acid oxidation

Role of adiponectin in the muscle

- Increased glucose uptake

- Decreased fatty oxidation

As visceral fat increases,

there is a decrease in adiponectin secretion

Rescue (lab method)

Take a knockout specimen and introduce the removed gene in a diff way (via a virus) if function is restored we can confirm the effects are due to lost gene

Adiponectin can bind to which two receptors?

- AdipoR1

- AdipoR2

AdipoR1

Function: Activation of AMPK

Expressed mainly in the liver, muscle and hypothalamus

AdipoR2

Function: Activation of PPAR𝛼, 𝛿, and 𝛾

Expressed mainly in the liver, VAT and vasculature

PPAR𝛼, 𝛿, and 𝛾

transcription factors that increase fatty acid oxidation and insulin sensitivity

- control multiple genes

AdipoR1 and AdipoR2 are responsible for what?

fatty acid oxidation

mitochondrial biogenesis

increased insulin sensitivity

Why does increased mitochondrial biogenesis increase FA oxidation efficiency?

because FA oxidation occurs in mitochondria

AMPK effect

inhibits ACC and HMGR

stimulates PGC1α

PGC1α effects

stimulates mitochondrial biosynthesis

key to training/exercise we become more efficient at using Fas

Role of adiponectin on the vascular network

↓ Inflammation

↓ Endothelial adhesion

↓ Foam cell formation

All effects of adiponectin on the vascular network prevents what?

atherosclerosis

Obesity and PPAR concentration

Obesity leads to a decrease in PPARs concentration

PPAR𝛾 is essential for the differentiation of what?

preadipocytes

Since PPAR𝛾 oversees adipocyte maturation, how would its inhibition lead to obesity?

By inhibiting PPAR𝛾, adipogenesis (hyperplasia) is decreased, so the only way left to store fat is the unhealthy way: hypertrophy