Obesity 2 - ME

Question 1

What are the Hallmarks of the Metabolic Syndrome?

Answer 1

• visceral obesity 
• dyslipidemia (abnormal blood lipids):
↑TG (insulin-stimulated synthesis in liver)
↓HDL-cholesterol 
• high blood pressure 
• insulin resistance 
• hyperglycemia

Question 2

Define insulin resistance

Answer 2

the failure of blood glucose levels to

decline normally in a glucose tolerance test, despite the presence of elevated levels of circulating insulin

Question 3

What occurs in the muscles in a patients with insulin resistance?

Answer 3

• Sk. muscle: IR →↓ glucose uptake

Question 4

What occurs in the liver in a patients with insulin resistance?

Answer 4

• Liver: IR → ↑glucose output

Question 5

What occurs in the adipose in a patients with insulin resistance?

Answer 5

• Adipose: IR → ↓glucose uptake ↓Lp lipase, ↓TG storage

↑lipolysis (↑circulating NEFA) ↓adiponectin release ↑inflammatory cytokine release

Question 6

What are the substances released from adipose tissue that induce insulin resistance in skeletal muscle and liver?

Answer 6

1. NEFA
   2.Fat tissue consists of
   adipocytes and resident
   macrophages, both of
   which release signaling
   molecules that are collectively referred to as adipokines.

Question 7

What happens to the levels of adiponectin in obese individuals?

Answer 7

adiponectin production is reduced with obesity

Question 8

Lipotoxicity theory?

Answer 8

Increased circulating NEFA released from numerous fat cells of obese persons somehow interfere with glucose disposal in muscle and glucose release in liver.
The reduced production of adiponectin in obese people further increases NEFA level in liver which aggravates insulin resistance.

Question 9

Describe the role of DAG in the muscle

Answer 9

Diacylglycerol (DAG) inhibits the translocation of GLUT4 (glucose transporter) to the muscle cell membrane, thus impairing insulin-stimulated uptake of glucose into muscle cells.

Question 10

Describe the role of DAG in the liver

Answer 10

Diacylglycerol (DAG) inhibits the glycogen synthase and activates gluconeogenic enzymes in liver, which increases hepatic glucose release.

Question 11

What are the five main causes of net DAG accumulation?

Answer 11

(1) excessive caloric intake (therefore increased lipid synthesis);
(2) defects in adipocyte metabolism (including lipid storage and lipolysis);
(3) defects in mitochondrial function (therefore reduced fatty acid β-oxidation);
(4) gene variation in apolipoprotein C3, which reduces lipoprotein lipase activity;
(5) reduced AMP-activated protein kinase (AMPK) signaling.

Question 12

AMP-activated protein kinase (AMPK) plays a key role in modulating FA oxidation by integrating endocrine and neural signals. How does decreasing its activity effect the cell?

Answer 12

Reduced AMPK activity and β-oxidation lead to DAG over-accumulation and insulin resistance.

Question 13

What drug stimulate AMPK activity?

Answer 13

Metformin stimulates AMP-activated protein kinase (AMPK)

Question 14

List three factors affecting the development of insulin resistance

Answer 14

1. Severe mitochondrial dysfunction could lead to FA overload and insulin resistance
2. Specific macronutrients (fructose and alcohol) may contribute to Metabolic Syndrome by increasing ectopic lipid accumulation in liver.
3. Visceral fat predisposes to T2DM

Question 15

Why is visceral fat bad?

Answer 15

1.direct drainage to the liver
2.high expression of β3-adrenergic receptors on the cell surface, which increases lipolytic response to catecholamines
3. Visceral fat may be more active in secreting proinflammatory molecules
capable of inducing insulin resistance in other organs.

Question 16

PPARα

Answer 16

• Mainly expressed in liver, also in muscle
• Unsaturated FA are endogenous ligands
• Fibrate drugs are agonists
• Upregulates: β-oxidation, ketogenesis and gluconeogenesis

Question 17

PPARγ

Answer 17

• Highest expression in fat; also liver, muscle
• Endogenous ligands not established
• PGC-1 is co-activator
• TZD drugs are agonists
• PPARγ activity
♦Upregulates lipoprotein lipase, FA transporter, FA- binding protein, FA-CoA synthase — promoting insulin action and FA uptake
♦Downregulates lipolysis

Question 18

Besides looking good, what are the benefits of exercising and glucose homeostasis?

Answer 18

Exercise increases fat oxidation and reduces fat accumulation.
Exercise induces the expression of a PGC1-α, This in turn increases muscle mitochondrial content
exercise-induced over-expression of PGC1-α
induces the secretion of a new hormone, named irisin from skeletal muscle
Irisin induces subcutaneous white adipose tissue to acquire characteristics typical of brown adipose tissue, which includes increased UCP1 expression, mitochondrial density and oxygen consumption. This leads to increased energy expenditure and improved glucose homeostasis.