Lecture 9 Flashcards
1
Q
Why is adipose tissue central to obesity?
A
It is the main store of fat
2
Q
What is adipose tissue made up of?
A
- Adipose tissue is connective tissue - Contains several cell types: –> Adipocytes (white/brown/beige) –> Stromal vascular cells –> Preadipocytes –> Fibroblasts –> Endothelial cells –> Macrophages
3
Q
What are the functions of adipose tissue?
A
- Energy storage - Insulation - Cushion organs
4
Q
Where are white adipocytes typically found? What are their key features and what do they do?
A
- Typically found subcutaneously - Spherical shape - Single lipid droplet - Few mitochondria - Flattened peripheral nucleus - Little ER - Function: Storing energy
5
Q
Where are brown adipocytes typically found? What are their key features and what do they do?
A
- Found in the neck region (cervical, supraclavicular) - Multiple small lipid droplets - Large number of mitochondria - Elliptical and smaller than white adipocytes - Function: Expending energy and heat production (non-shivering thermogenesis)
6
Q
Where are beige adipocytes typically found? What are their key features and what do they do?
A
- Form from white adipocytes in response to stimuli like cold - Start with single lipid droplet which breaks up upon stimulation - Lots of mitochondria after stimulation - Spherical shape - Function: Thermogenic potential
7
Q
Where is white adipose tissue found?
A
- White adipose tissue is found in subcutaneous depots, e.g. cheeks, hips, upper body
8
Q
Where is visceral white adipose tissue found?
A
- Surrounds internal organs
9
Q
Where is brown adipose tissue found?
A
- Around the neck and spine
10
Q
What is visceral obesity linked to?
A
- Visceral obesity is associated with metabolic syndrome and type II diabetes - Not always visibly apparent despite a similar waist circumference as someone with less visceral fat
11
Q
What are adipocytes derived from?
A
- Mesenchymal stem cells (MSCs)
12
Q
What stimulates the maturation of preadipocytes?
A
- Stimulated by insulin, glucagon, and free fatty acids - Approximately 20% of white adipose tissue cells are in the preadipocyte stage
13
Q
Describe the process of lipogenesis in adipocytes
A
- Free fatty acids (FFAs) are released from lipoproteins by lipoprotein lipase (LPL) - FFAs enter adipocytes through diffusion and transporters - Converted to triacylglycerols (TAGs) within the ER - TAGs are stored in lipid droplets
14
Q
When can lipolysis occur?
A
- Occurs during high energy demands - FFAs are released from TAGs through lipolysis, mediated by hormone-regulated enzymes, mainly insulin
15
Q
How were mice used to identify the mutation responsible for obesity in mice? What was found out?
A
- Mutant mice (ob/ob) were hyperphagic and gained excessive weight, up to 3x the body weight of wild-type mice - Mutation identified in 1994: encodes leptin, a hormone secreted by adipose tissue
16
Q
How many adipokines are there?
A
- Hundreds of secreted peptides/hormones from adipose tissue have been identified
17
Q
What are the 4 classes of adipokines? Give a few examples of each
A
- Metabolic: leptin, adiponectin - Pro-inflammatory: TNF-alpha, interleukins (1 beta 4, 6, 8, 18) - ECM components: collagens, matrix metalloproteinases (MMPs), fibronectin - Mitogenic/angiogenic: growth factors
18
Q
What is leptin? Where is it secreted from? What is its function?
A
- Leptin is a 16.7kDa peptide hormone secreted mainly from white adipose tissue (subcutaneous > visceral fat) - Secreted by BAT, placenta, muscle, and stomach - Role: Regulates satiety
19
Q
What type of receptor is the leptin receptor?
A
- Leptin receptor is a receptor tyrosine kinase (RTK)
20
Q
How are leptin receptors activated?
A
- Ligand binding to the receptor induces intracellular phosphorylation cascades via JAK/STAT
21
Q
What happens to mice that have no leptin receptors (either missing or non-functional)?
A
- These mice become obese because the leptin feedback mechanism is disrupted
22
Q
How does leptin counteract the action of ghrelin?
A
- Ghrelin stimulates hunger signals, acting via the vagus nerve and arcuate nucleus in the hypothalamus - Leptin counteracts ghrelin’s effect by acting on the same neurons, promoting satiety
23
Q
How is leptin deficiency treated?
A
- Leptin deficiency causes obesity - Rare in humans, treated with leptin replacement
24
Q
What are the circulating levels of leptin like in obesity? What does this cause?
A
- Leptin levels are excessively high in obesity, leading to leptin resistance (receptors become desensitized, disrupting satiety signaling)
25
Describe the process of leptin resistance
- Weight gain leads to increased fat and inflammation, causing leptin resistance - The brain senses low leptin levels despite high fat stores, causing overeating and continued weight gain
26
How can you treat leptin resistance?
- Early stages are reversible with diet and exercise - Leptin sensitisers (e.g. amylin, pramlintide) can counteract leptin resistance
27
Where are leptin sensitisers produced and how might they help counteract leptin resistance?
- Amylin is secreted by pancreatic beta cells and hypothalamic neurons - Mechanism unclear, may act through IL-6 production to activate leptin-resistant neurons
28
What are some key strategies to counteract leptin resistance?
- Increase leptin uptake across the blood-brain barrier (BBB) - Better leptin receptor agonists - Activate downstream signaling pathways independent of the receptor
29
What is adiponectin and where is it secreted from?
- Adiponectin is a 30kDa peptide hormone secreted from white adipose tissue - It promotes glucose uptake in muscle and counteracts leptin
30
What are some of the key functions of adiponectin?
- In heart: anti-apoptotic, decreased inflammation, decreased hypertrophy - In immune system: decreases macrophage and leukocyte activation
31
What happens if adiponectin levels are too high?
- It can cause insulin resistance
32
What are the 2 types of adiponectin receptor?
- ADIPOR1 in skeletal muscle - ADIPOR2 in liver
33
Describe the structure of the adiponectin receptors
- Resemble "inside-out" GPCRs - External C-terminal domain, intracellular GPCR at N-terminal
34
How are ADIPORs different?
- ADIPOR1 binds trimeric and HMV adiponectin - ADIPOR2 has low affinity for trimeric adiponectin
35
How do ADIPORs signal?
- ADIPORs don’t use G-proteins but signal through AMPK, PPARα, and p38 MAPK to regulate energy metabolism
36
What are the key functions of adiponectin?
- Suppresses TNF-α and IL-6, suppresses hepatic gluconeogenesis, stimulates FFA oxidation and glucose uptake in muscle, anti-cancerous
37
What are the levels of adiponectin like in obesity?
- Adiponectin levels are low in obesity, which results in the loss of its beneficial effects
38
In the ob/ob mutant mice, adiponectin levels are low. Can adiponectin reverse obesity?
- No, adiponectin does not reverse obesity but can make the mice healthier
39
How may adiponectin promote cardiovascular health?
- Exogenous adiponectin, receptor agonists, or supplements may promote heart health by enhancing adiponectin’s beneficial effects
40
What are some of the other adipokines?
- Resistin: correlates with obesity and T2DM - Visfatin: insulin-sensitizing enzyme - Non-peptide: fatty acids, cholesterol, steroid hormones
41
Why do we care about preventing obesity?
- Obesity contributes to mechanical issues, fertility problems, mental health issues, and chronic diseases (diabetes, cardiovascular disease, dyslipidemia)
42
How does obesity cause inflammation? What are the effects?
- Adipocytes release pro-inflammatory cytokines (e.g., IL-6) - Chronic inflammation leads to DNA, tissue, and cell damage, contributing to metabolic syndrome
43
What is metabolic syndrome?
- A cluster of conditions (e.g., increased triglycerides, insulin resistance, hypertension, etc.) that increase the risk of heart disease, stroke, and type 2 diabetes
44
Why is weight loss difficult to maintain?
- Epigenetic changes in adipocytes during obesity make them pro-inflammatory, and these changes persist long after weight loss, making them more susceptible to fat accumulation
