Adipocyte biology and Obesity

Adipose is a specialised form of connective tissue. How is it specialised?

Long term storage of energy as triglycerides

Thermal properties: Heat retention (thick insulatory layer, Generation of heat by uncoupling of oxidative phosphorylation in brown adipose tissue

Protection of other structures

Secretion of hormones/cytokines/substances with paracrine or endocrine activity

ADIPOKINES

Define obesity?

An accumulation of excess adipose tissue in the body

What is the Body fat % for humans?

33% Women

25% Men

What does plasia and trophy mean very simple?

Anything plasia means number of cells a

Trophy means bigger/enlarged

What is white adipose tissue more potential to mature into? Hypertrophy or hyperplasia, visceral fat?

Hyper plasia in the visceral fat

Where precursors cells show hyperplasia?

Stromal vascular fraction (SVF), RATHER THAN MATURE ADIPOSE.

What is the importance of body fat distribution?

Adipose tissue exist in dinstinct anatomical depots; its distribution varies between individuals ??

In humans, visceral adipose tissue is associated with a greater likelihood of developing diabetes and cardiovascular disease than subcutaneous adipose tissue. WHY?

This may be because the hepatic portal vein draining this depot delivers increased concentrations of fatty acids or adipokines direct to the liver, impairing insulin sensitivity here

What are the causes of obesity?

Genetic; single gene defects, chromosomal defects, large number of genes implicated, having incremental effect, ethnic groups

Environmental, ingestion of excess calories, insufficient exercise

Perinatal programming- ‘Foetal origins Hypothesis’: exposure of the foetus or neonates to a particular environemnt results in long effects on metabolism and thus adiposity

Disease: hypothyroidism

Drugs: Glucocorticoids

Reproductive status: sexual dimorphism, neutering of animals

Individuals cases of obesity may be the result of interaction between more one of these aetiogies

What are the monogenic causes of obesity?

Single gene defects that result in obesity

Passed on in simple mendelian fashion

These are very rare causes of obesity

Example:

• leptin (ob gene)

• leptin receptor (db gene)

Mutations passed on in dominant fashion are commoner in the population (MC4R)

Leptin, discovered in 1994. Deletion of leptin gene results in severe obesity! Leptin deficiency! How can we fix this?

Just inject leptin into the blood stream

How is leptin regulated?

Food INTAKE

PVN neuron leads to downregulation of food regulate

REDUCING FOOD UPTAKE AND INCREASING EE

What is going on here?

Obesity has so much negativity in the insulin receptor: hepatic glucose production increases, it is unrestricted and this causes by time diabetes etc.

Leptin inhibits secretion from pancreatic beta-cell. HOW?

Leptin binds to ObRb, Inhibiting glucose intake (GLUT-2),

and it also inhibits PLC/PKS

Obesity is typically a polygenic disorder. What study is used to idetify regions of genome associated with obesity?

Genome wide association studies (GWAS)

Icelanders represent a genetically extremely well characterised characterised population of these studies, this could be because of isolation, no migration blah blah

How do we classify WAT and BAT?

What adipose tissue do small hibernating animals have?

Brown

How does Non-shivering thermogenesis happen?

What is Cold induced thermogenesis?

Metabolic rate increases

Thermonutrality for mice with intact coat is 30C FOR NAKES HUMANS IT IS 28C

Non-shivering thermogenesis involves activation of BAT and browning of WAT depots

BAT is important in thermoregulation

What is Thermonutrality?

Temperature at which an animal does not need to regulate its body temperature

What was the problem with the use of 2,4Dinitrophenol when its was used as a pil (not anymore)?

Stopped mitochondria from working

What is diet induced thermogenesis?

Apparent compensatory mechanism to limit

weight gain that becomes inadequate in obesity

What evidence are there for obesity being a subacute inflammatory disease?

Pro-inflammatory cytokine (TNF-a) CAUSES INSULIN RESISTENCE in vitro and in vivo

Serum markers of inflammation elevated obesity

High fat diet-induced insulin resistance in rodents is prevented by salicylate (aspirin)

Increased macrophages infiltration into adipose tissue occurs in obesity and insulin resistence

Obesity→ inflammation-→ insulin resistence!

Revision!!

What ist he role of adipokines in diseae?

Cytokines that are secreted by adipose tissue

the rate of secretion of many of these changes in obesity

Apokines have been shown to affect cell growth, metabolism, insulin sensitivity, vascular function, inflammation in other tissue, in most causing or exacerbating disease processes

ADIPONECTIN IS HIGHLY STUDIED EXAMPLE

What is Adiponectin?

What ist he action of adiponectin?

Activated AMPK to activate PGC-1alpha

READ THE SLIDES AT THE END OF THE LECTURE THERE ARE 2 EXAMPLES OF THE CAUSES OF OBESITY!!