NUTR 4210 - Diet and Exercise as Modulators of Leptin and Adiponectin Response in Skeletal Muscle

What is the only known hormone to decrease in obesity?

Adiponectin

What happens to muscle cells in the presence of fat cells?

They become insulin resistant

Why was the co-culture experiment carried out in mammary fat cells?

Mammary fat cells include extra fat stores for increased energy for milk production

When is short term insulin resistance good?

During infection - immune cells use glucose instead of fat, however insulin resistance keeps glucose available for other important functions

What does the presence of adiponectin do in co-culture experiments?

It decreases inflammatory cytokines and therefore insulin resistance doesn’t occur

What processes/responses do increased fatty acids cause in the skeletal muscle?

Oxidation, lipid accumulation, and an inflammatory response

What cytokine is released at the same time as adipocytes?

TNF-alpha

What causes inflammation of visceral fat?

Increased TNF-alpha, resistin, interleukin-6 and -8, decreased adiponectin, and increased fatty acids

How do increased fatty acids affect the skeletal muscles?

Binding to other receptors such as toll-like receptor 4, which increases the inflammatory response

What type of cells increase in obese individuals?

Immune cells

What happens when fat cells get too big?

They have hypoxic areas

What is a hypoxic area?

An area that doesn’t receive sufficient oxygen to maintain adequate homeostasis

What type of fat improves insulin sensitivity in aging/diabetic rats when removed?

Visceral fat

How is insulin sensitivity measured in rats?

They clamp insulin, infuse it at a specified rate and measure clearance

What type of diet has a large effect on longevity of aging and diabetic rats?

Caloric restriction

What type of fat removal has no effect on aging and diabetic rats insulin sensitivity?

Subcutaneous fat removal (liposuction)

What is lipoatrophy (or lipodistrophy)?

The absence of peripheral adipose tissue

Why is lipoatrophy a concern?

When fat, or carbs that are converted to fat, is ingested it has nowhere to go, so it accumulates in organs such as the liver, pancreas, heart, etc.

What happens when fat stores are implanted into lipoatrophic mice?

They can hold the fat stores, they just can’t produce them

How are lipoatrophic mice effected when transplanted with fat stores from a healthy mouse vs a mouse that is leptin deficient?

There’s increased insulin sensitivity when stores from healthy mice are transplanted, but there is no improvement when transplanted from mice that don’t produce leptin

What two adipokines improve insulin responses?

Leptin and adiponectin

How was leptin concentration in lipoatrophic mice?

Very low, however leptin therapy was very beneficial

Why were pharmaceutical companies excited about decreased leptin concentrations having negative effects on metabolic processes?

A potential new market for a product that could decrease obesity and diabetes - lots of money

Why didn’t leptin take off as a pharmaceutical?

The effects it had in mice were different from the effects of leptin in humans

What does leptin increase to prevent lipotoxicity in non-adipocytes?

AMPK, PGC1-alpha, HSL, and lipolysis

How does AMPK prevent lipotoxicity?

Increases fatty acid oxidation

How does PGC1- alpha prevent lipotoxicity?

Increases mitochondrial synthesis

How do HSL and lipolysis prevent lipotoxicity?

Decrease lipid content

Where does leptin act to prevent lipotoxicity?

Numerous peripheral tissues including muscle, heart, liver, and pancreas

What process can aid in avoiding fatty acid accumulation?

Beta oxidation

What does ceramide inhibit?

Akt

What does diacylglycerol (DAG) inhibit?

IRS-1

How long does it take for leptin to improve insulin resistance in rats?

2 weeks - almost totally protects it

How is adiponectin related to obesity and insulin resistance?

Inversely

What are the main functions of adiponectin?

• Increases AMPK and FA oxidation

• Increases mitochondrial biogenesis (PGC1 alpha via AMPK, CAMKII)

• Restores insulin-stimulated glucose uptake in high fat fed rodents

What response indicates a good glucose tolerance test result?

The least response

Is adiponectin increased or decreased in overweight individuals?

Decreased

How does adiponectin effect mice fed a high-fat, high-sucrose diet?

There’s a decrease in fat mass and an improved glucose tolerance

What goes wrong in obesity?

Leptin increases - increasing fat mass and decreasing insulin resistance

How is skeletal muscle resistance effected in obese individuals?

Skeletal muscle becomes resistant to the ability of leptin and adiponectin to stimulate FA oxidation

• larger increase in both leptin and adiponectin concentrations in lean individuals than obese

What does a high fat diet lead to?

Leptin and adiponectin resistance and therefore a decreased fat oxidation/increased storage and therefore decreased insulin resistance

What happens to fatty acid transporter when fed a high-fat diet?

By 2-4 weeks, there are more FA transporters - accumulating fat in muscles (bringing fat in but not burning it)

What happens to muscle lipids (DAG and ceramide) when fed a high-fat diet?

By 2-4 weeks, there are increased amounts of DAG and ceramide in the muscle

What happens to insulin response when fed a high-fat diet?

By 4 weeks, there was a decreased insulin response in the muscle

Does fish oil supplementation prevent leptin and adiponectin resistance?

Yes, fish oil supplementation prevents diet-induced leptin and adiponectin resistance in muscle

Does exercise prevent leptin and adiponectin resistance?

Treadmill training has shown to prevent leptin resistance in rats

Can leptin and adiponectin resistance be reversed?

With the restoration of leptin and adiponectin responses, insulin response is restored as well as a decrease in fatty acids (ceramide) in the muscle, however the leptin resistance wasn’t restored until after these occurred (not in the correct order)

Is leptin and adiponectin resistance related to inflammation?

There are no signs of inflammation after 3 days of feeding a high-fat diet (resistance occurs during this time period)

How does aspirin affect adiponectin response during a high-fat diet?

It decreases the adiponectin response

Is restoring leptin and adiponectin responses required before insulin response can be restored after being fed a high-fat diet?

No, the insulin response recovers before the leptin and adiponectin resistance

Does reactive oxygen species (ROS) production impair the ability of leptin and adiponectin to stimulate mitochondrial fatty acid uptake and oxidation?

No

Is there a difference in energy expenditure between wild type mice and adiponectin knock-out mice?

There is no significant difference

Is there a difference in mitochondrial content between wild type mice and adiponectin knock-out mice?

There is no significant difference

Is there a difference in fat oxidation between wild type mice and adiponectin knock-out mice?

There is no significant difference