Biochemistry of Inherited Obesity Flashcards
Obesity
- Results from the chronic imbalance of energy intake and energy expenditure
- Major health crisis rising
- Positive correlation with CVD and Type 2
Adipose Tissue Distribution
Visceral:
- Found deep within the abdominal cavity, surrounding internal organs such as the liver, pancreas, and intestines providing protection and support
Subcutaneous:
- Just beneath skin, distributed throughout the body but more concentrated in areas such as the thighs, hips, and abdomen
- insulator, helping to maintain body temperature
- cushions muscles and bones
White AT - Stores energy
Brown AT - Burns energy
Adipose Tissue Expansion
Hyperplasia - Number of adipocytes increases in adipose tissue
Hypertrophy - Increase in size of existing adipocytes
WNT Signalling
Canonical WNT determines Mesenchymal stem cell fate in Adipogenesis
- Activation of WNT signalling leads commitment of stem cells down a myogenic or osteogenic fate
- WNT signalling restrains adipocyte differentiation by inhibiting expression of adipogenic master regulators PPARG and CEBPA
- In response to adipogenic stimuli WNT signalling is inhibited and CEBPb initiates transcription of PPARG and CEBPA during mitotic clonal expansion.
WNT Signalling Pathway
Canonical:
1) signalling is activated when WNTs bind to frizzled (FZD1) receptors and LRP co-receptors
2) Leads to dishevelled phosphorylation and Axin degradation
3) Subsequent hypophosphorylation of b-catenin (b-cat) which accumulates in cytoplasm and translocates to nucleus to activate transcription factors that inhibit adipogenesis.
Non-Canonical (Alternate inactive mech)
1) signalling also inhibits adipogenesis by activating CAMKII
2) CAMKII activates TGFB-activated protein kinase 1 (TAK1) leading to phosphorylation of nemo-like kinase (NLK).
3) NLK phosphorylates SETDB1 which inhibits PPARg transcription.
4) Pro-adipogenic stimuli lead to inhibition of WNT proteins directly by secreted frizzled related proteins (sFRPs).
5) DKK1 inhibits WNT signaling by binding as a high-affinity antagonist to LRP co-receptors
6) WNT5b promotes adipogenesis by preventing WNT/B-catenin signalling
Stage of Adipogenesis
Clonal Expansion
- WNT Signalling inhibited
- Proliferation of MSCs
Adipocyte Commitment
- Lipid and triglycerides are accumulated
Terminal differentiation
- Droplets expand and resemble mature cells
Adipose tissue expansion in obesity is associated with inflammation
Some cells become unhealthy due to being further from blood supply => influx of CD8 T cells and m1 macrophages causing inflammation which can spread around.
- Once adipose tissues reach maximum capacity, lipids can “spill out” and enter liver, heart and muscles causing lipotoxicity
- Build up of harmful by-products of lipid metabolism such as ceramides lead to insulin resistance
- Inflammatory cytokines released from visceral adipose tissue results in systemic inflammation
- Lower adiponectin levels and leptin signalling combine with lipotoxicity and inflammation to negatively impact on insulin signalling.
Ecotopic Fat Accumulation
Fat deposited in blood vessels causing plaque leading to heart attacks etc
Lipodystrophies
Example: Mutation in Seipin gene, lacks expression of lipids for fat,
Glucose Homeostasis
- Liver responds to high glucose and insulin by increasing glycolysis (breakdown of glucose to pyruvate) and de novo lipogenesis (conversion of acetyl CoA to triacylglycerol/triglyceride) (TAGs).
De novo lipogenesis in liver in response to feeding
Unlike most enzymes in the pathway, GK is not inhibited by its catalytic product, thus enabling the liver to continuously use glucose for glycolysis even under conditions of increased glucose availability.
1) Series of enzymatic reactions catalyzed by enzymes phosphofructokiase 1(PFK1) which converts G6P to fructose 1,6 bisphosphate; liver pyruvate kinase (L-PK) converts phosphoenolpyruvate (PEP) to pyruvate
2) Pyruvate enters mitochondria where it is oxidized to Acetyl CoA
3) L-PK is inhibited by ATP, acetyl CoA and long-chain fatty acids which signal an energy abundance
4) Conversion of Acetyl CoA to malonyl CoA is the first step in lipogenesis and catalyzed by ACC
5) Transcription factors chREBP and SREBP-1c are activated by insulin and increase transcription of key lipogenic enymes including ACC and FAS which act in the lipogenesis pathway.
6) TAGs are secreted into blood as very low density lipoproteins (VLDL) that are either stored as re-esterified TAG or mobilized to FA and used as an energy source in adipose tissue.
Non alcoholic fatty liver disease (NAFLD)
Chronic and excessive lipid storage damages liver cells. Most common form of liver disease
- May be detected by elevates liver enzymes
Result of overfeeding/obesity is therefore the increased production of stored TAGs from glucose (de novo lipogenesis)
- Exacerbated by hyperinsulinemia which activate chREBP and SREBP1c which increase transcription of lipogenic enzymes and promote fatty acid biosynthesis.
Liver ceramide-LDL complex
activates inflammation in muscle which promotes insulin resistance
Adipose tissue cytokines inhibit insulin signaling
1) Pro-inflammatory cytokines TNFa and IL6 bind to receptors in liver, muscle and adipose tissue where they increase insulin receptor substrate (IRS) 1 phosphorylation
2) results in decrease in AKT activation and reduced insulin signalling and glucose transporter 4 (GLUT4) translocation (muscle + adipose) resulting in insulin resistance
Lipolysis
In fasting or exercise glucagon and norepinephrine induce lipolysis
Breaking down TAGs into FA and glycerol
- In response to signaling cascade induced by glucagon and norepinephrine, perilipin is phosphorylated and activates HSL which breaks down TAG to DG and MG and eventually FFAs.
