Biochemistry of obesity

Question 1

What is metabolism equal to?

Answer 1

Total energy expenditure of the body.

Question 2

What are the 3 types of ways to expend energy in the body?

Answer 2

1. Adaptive thermogenesis (using energy to stay warm)
2. Physical activity (variable)
3. Obligatory energy expenditure (to keep alive)

Question 3

What are the 3 types of adipose tissue?

Answer 3

1. White adipose tissue, energy storage (low UPC-1 gene expression)
2. Beige adipose tissue (medium UPC-1 gene expression)
3. Brown adipose tissue, adaptive thermogenesis (high UPC-1 gene expression)

Question 4

What is the UPC-1 gene?

Answer 4

It stands for he uncoupling protein-1 gene. When it is expressed, it produces a mitochondrial protein that mediates thermogenesis in the brown adipose tissue.

Question 5

How is beige adipose tissue created in the body?

Answer 5

When the body is exposed to cold conditions for an extended period of time, then white adipose cells are converted into beige cells.

Question 6

Do white and brown adipose cells have the same lineage?

Answer 6

No. Brown adipose cells arise from skeletal muscle cells. White adipose cells and beige cells have the same progenitor.

Question 7

Adipose cells are accompanied by immune cells. What is the key difference in this arrangement b/w the adipose cells of an obese person compared to a lean person?

Answer 7

Obese adipose tissue contains proinflammatory immune cells like M1 macrophages and the tissue is insulin resistant. Lean adipose tissue contains normal immune cells, like M2 macrophages and the tissue is insulin sensitive.

Question 8

What is the biochemical process behind white adipose tissue being converted to brown adipose tissue?

Answer 8

increased exercise causes muscle to express more of the PGC-1 alpha gene, which produces a transcriptional coactivator.
PGC-1 alpha causes increased expression in the muscle of the mitochondrial membrane protein Fndc5.
The Fndc5 protein is cleaved and its active peptide forms a new protein hormone called Irisin.
Irisin targets the white adipose tissue, forcing it to express the UCP-1 causes change from white to beige adipose.

Question 9

What is leptin?

Answer 9

Leptin is a peptide hormone that regulated sateity and increases oxidation of energy molecules by communicating with the hypothalamus.

Question 10

How does leptin work?

Answer 10

White adipose cells get bigger after eating, and then leptin is secreted by this adipose tissue in response.
Leptin travels in the blood to the brain and tells the hypothalamus that we are full.
During fasting, energy is taken from the adipose cells and they shrink. The shrinkage causes the cells to stop secreting leptin. This means there is no more leptin stimulating the hypothalamus to tell it we are full and thus we feel hungry.

Question 11

What is leptin’s role with regards to fatty acids metabolism?

Answer 11

Leptin promotes fatty acid oxidation (break down for energy) whilst the absence of leptin promotes fatty acid synthesis.

Question 12

How does the hypothalamus regulate energy usage and hunger?

Answer 12

The hypothalamus has a region called the arcuate nucleus.
The arcuate nucleus has two kinds of cells that when stimulated either promote or inhibit hunger.
They are the anorexigenic and orexigenic nerves.
Leptin stimulates the anorexigenic nerves.

Question 13

What does stimulation of the anorexigenic neurons by leptin do?

Answer 13

The anorexigenic neurons when stimulated send signals to the white adipose tissue that activate PKA.
PKA mobilises fatty acids from triglycerides so they can undergo uncoupled oxidation in the mitochondria and produce energy.

Question 14

What is the gene that expresses leptin receptors?

Answer 14

The DB gene, stands for the diabetic gene.

Question 15

Refer to the diagram given in the lectures and explain how leptin receptors are activated.

Answer 15

1. Leptin binds to the leptin receptor
2. The 2 leptin receptor monomers undergo dimerisation (they fuse together).
3. The JAK enzymes are now autophosphorylated.
4. The phosphorylated JAK enzymes now phosphorylate important tyrosines within the inner domains of the leptin receptor
5. JAK 2 phosphorylates tyrosine-1188, which acts as a special docking site for the DNA transcriptors, STAT3.
6. STAT3 binds to the docking site on tyrosine 1188 of the leptin receptor, and is phosphorylated.
7. The phosphorylated STAT3 now leaves the receptor and enters the nucleus of the hypothalamic cell and initiates transcription of SOCS3 and POMC genes, both of which reduce appetite.

Question 16

What is the relationship between the SOCS3 gene and obesity?

Answer 16

By blocking or not expressing the SOCS3 gene in the brain (hypothalamus), there is nothing to inhibit the leptin receptors.
Thus leptin receptors could be continually activated, and fatty acid oxidation would always be high.
The same amount of leptin would result in a greater anorexigenic effect.

Question 17

What is ER stress?

Answer 17

ER stress is when the organelle is degrading more misfolded proteins than it is folding more correct ones.

Question 18

What genes are expressed within the cell during ER stress?

Answer 18

The UPR gene is expressed. It increases the protein folding capacity of the ER, inhibits translation and promotes degradation of misfolded proteins.
If the ER stress occurs for a long period of time, then the UPR gene can initiate apoptosis of the cell.

Question 19

How does obesity induce the ER stress state in cells?

Answer 19

Increased body fat levels cause chronic inflammation. Cytokines levels and free fatty acids in the blood increase.
the mTOR pathway is activated in the cell.

Question 20

How does ER stress cause leptin resistance?

Answer 20

A cell in ER stress will express its protective UPR gene. The UPR gene actually inhibits the activation of STAT3, and so the leptin receptor is blocked.
This means that the cell automatically becomes leptin resistant because its receptor has been inhibited from signalling.

Question 21

What is the melanocortin system?

Answer 21

A series of peptide hormones that are all derived from a single polypeptide called POMC.
One protein hormone called alpha-MSH is derived from POMC.
There are two receptors for alpha-MSH: MCR3 and MCR4.

Question 22

How does the alpha-MSH stimulation of the MC4R receptor have the potential to cause obesity?

Answer 22

When the anorexigenic neurons of the arcuate nucleus are stimulated by leptin, the neurons produce alpha-MSH from the protein POMC in response.
Alpha-MSH hormone binds to the MCR3 and MCR4 receptors, which induces a smaller appetite in the individual.
Individuals with mutations in the MCR3 and MCR4 receptors will have larger appetites and consume more, leading to obesity.
The absence of one or both MC receptors will result in large and larger appetites respectively.
MCR4 also induces diet-induced thermogenesis when a high fat diet is consumed.

Question 23

Does MC4R act independently of leptin in regulating appetite or not?

Answer 23

MCR4 does not need to be activated by leptin stimulating anorexigenic neurons of the arcuate nucleus. It often controls appetite without this leptin signalling.

Question 24

What is the relationship between obesity and chronic inflammation?

Answer 24

Visceral, not subcutaneous fat, in excessive amounts alerts the immune system, and macrophage infiltration occurs.
The adipose tissue of obese people is 40% immune cells inducing inflammation.
Low level inflammation causes an increase in cytokines in the blood.
Increased cytokines in the blood causes cells of the hypothalamus to enter the ER state and leptin resistance occurs.

Question 25

How does hypothalamic IKKB/NF-KB affect ER stress?

Answer 25

Increased visceral fat levels leads to increased macrophage numbers within the adipose tissue.
Low level chronic inflammation from the macrophages results in increased cytokine levels in the blood.
This increased pressure on cells and increases their protein misfolding rate, inducing the ER stress state.
The ER state induces activation of the IKKB/NF-KB, which disrupts leptin and insulin signalling and creates cellular resistance to both hormones.
Thus, supressing IKKB/NF-KB prevents obesity.

Question 26

How does inhibition or removal of hypothalamic IKKB/NF-KB help to prevent obesity?

Answer 26

Studies have shown that by removing IKKB/NF-KB or inhibiting it, then leptin sensitivity is kept high and weight loss occurs.
Preventing ER stress of hypothalamic cells can also inhibit IKKB/NF-KB levels and keep leptin sensitivity high.

Question 27

What is AMPK? Is it different to AMP?

Answer 27

It is a heterotrimeric protein (with 2 groups of 3 proteins).
AMP is produced when ATP levels decrease. AMP is produced by the enzyme adenylate kinase.
When AMP:ATP ratio is small (AMP doesn’t change, only ATP does), then AMPK is inactive.
When AMP:ATP ratio is large (ATP levels decrease), then more AMP is produced. The AMP levels increase, they bind to the gamma subunit of the AMPK protein.
This causes the AMPK to become phosphorylated.
The enzyme AMPKK comes along and phosphorylates AMPK again so that now it is maximally activated.
AMP+AMPK (phosphorylated by AMPKK)= activated

Question 28

What is the point of activating AMPK?

Answer 28

When a cell has decreased ATP, then AMPK can be phosphorylated to allow increased appetite.
Increased appetite can fix the problem of low energy.

Question 29

What is ACC and how does it work?

Answer 29

ACC is an enzyme that catalyses fatty acid synthesis.
So, if ACC were inhibited, then malonyl-CoA would be decreased, which allows carnitine acyltransferase type 1 to import fatty acids into the mitochondria, which increases fatty acid oxidation.

Question 30

How does leptin affect ACC in skeletal muscle?

Answer 30

Leptin phosphorylates ACC, to inhibit fatty acid synthesis and promote fatty acid oxidation instead in the skeletal muscle cell.

Question 31

How does leptin affect AMPK in the skeletal muscle?

Answer 31

Leptin activates AMPK in the muscle by phosphorylating the Thr172 of the alpha 2 catalytic subunit of AMPK. Leptin does this to make the muscle consume stored energy (fatty acid oxidation) rather than put energy into storage (fatty acid synthesis). During times of high energy levels, leptin will inhibit AMPK in the muscle to enable fatty acid synthesis.

Question 32

How does leptin affect AMPK in the hypothalamus?

Answer 32

Leptin inhibits AMPK in the hypothalamus, when energy levels are adequate. This prevents overreating and minimises appetite. During periods of low energy, leptin would phosphorylate and activate AMPK in the brain, to allow increased appetite.

Question 33

What is pSTAT3 and how does leptin interact with it?

Answer 33

Leptin binds to its receptor to the STAT 3 becomes phosphorylated. STAT3 is a transcription factor that enters the nucleus of hypothalamic cells and induces expression of other appetite reducing genes.

Question 34

Why does leptin want to activate AMPK in the skeletal muscle, but inhibits AMPK in the hypothalamus?

Answer 34

Leptin is secreted when we are full, because it wants our bodies to use more energy and to eat less (e.g anorexigenic neurons). So, it inhibits AMPK in the hypothalamus because it increases appetite. It activates AMPK in the skeletal muscle because it increases fatty acid oxidation and not synthesis.

Question 35

Why does AMPK in the muscles want to inhibit ACC?

Answer 35

Because, AMPK in the muscles wants to increase fatty acid oxidation and so it must inhibit fatty acid synthesis, which is catalysed by the enzyme ACC.