leptin signalling

Leptin circulates at levels proportional to body fat, white adipose tissue is its main source

It enters the central nervous system(CNS) in proportion to its plasma concentration.

Its receptors are found in brain neurons involved in regulating energy intake and expenditure.

In addition to white adipose tissue, it can also be produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach

(lower part of fundic glands), mammary epithelial cells, bone marrow, pituitary and liver

Leptin

leptin

Four-helix bundleSize 2,0x2,5x4,5 nmCys-96 <-> cys-146

Resembles structures of long-chain helical cytokines :G-CSF, granulocyte colony stimulating factorLIF, leucocyte inhibitory factorCNTF, ciliary neurotrophic factorhGH, human growth hormoneIL-6 , interleukin-6

Product of the obese gene (ob) , conserved residues in purple colour (receptor binding sites not yet determined)

PDB : 1ax8

Leptin receptor(s)

Synonym: receptor for obesity facto, Ob-R

five leptin receptor isoforms LRa-e

• LRa lacks intracellular domain and is highly abundantly expressed in brain capillary endothelium and peripheral organs and proposed to mediate leptin transport (across endothelial barriers)

• LRb is restricted to the hypothalamus, brainstem and key regions of the brain that control feeding, metabolism and neuroendrocine systems. This receptor signals into the cell.

Leptin receptor(s)

-Adipose tissue is an anatomical term for loose connective tissue composed of adipocytes (or fat cells).

Adipose tissue

-Its main role is to store fatty acids in the form of triglycerides, thus providing the organism with effective fuel storage

-besides that it cushions and thermally insulates the body.

Adipose tissue Adipocyte + capillary

adipose tissue

-adipose tissue has an important endocrine function as it produces adipokines and inflammatory mediators, amongst others, leptin, adiponectin, resistin , adipsin, TNFα, IL-6 and PAI-1

Because of the production of inflammatory mediators, an excess of adipose tissue leads to a chronic mild inflammatory-state that may play a role in late onset diabetes (insulin resistance).

subcutaneous adipose tissue

mouse adipocytes

congenital leptin deficiency human)

- voracious appetite- morbid obesity- immunosuppression- hypothalamic hypogonadism (failing folliculogenesis (leading to infertility) due to a lack of gonadotrophin releasing hormone, which normally stimulates FSH and LH production in the anterior pituitary)

Similar symptomes can be obtained through prolonged fasting or lipodystrophy. Hypogonadism may occur in athletes or in women on extreme low calory diets)

leptin

Refresh your memory: leptin in the arcuate nucleus promotes POMC-neuron function and inhibits Npy/AgRP-neurons, leading to an anorectic signal (loss of apettite)

focus on leptin signalling

Janus-kinase (JAK) constitutes a small

protein kinase subfamily within the big family of

non-receptor tyrosine kinases:

- JAK1-3- Tyk2

- A8K910

JAK2-mediated STAT3 phosphorylation and translocation into the nucleus

from STAT3 to POMC and AgRP expression

Leptin + insulin, concerted action of FOXO1 and STAT3

Leptin also mobilises the PI 3-kinase/PKB pathway, through JAK2-mediated phosphorylation of IRS2

A lack of glucose interferes with the leptin signal through a pathway that involves 5’-AMP, a monophosphate nucleotide that is generated in a « rescue » pathway where two ADP are used to raise the level of ATP

The global picture of insulin, leptin, glucose and amino-acid –mediated regulation of food intake via mTOR and AMPK

Downregulation of the leptin pathway by expression of SOCS3 that conducts an E3-ubiquitin ligase complex to the receptor (may render neuron resistant)

Downregulation of the leptin pathway by PTP1B (may render the neuron resistant)