insulin signalling

Neuro-anatomy of homeostatic regulation of food intake; opposing actions of AgRP/NPY and POMC/CART containing neurons

Increased concentration of glucose in the blood, after a meal, leads to increased ATP production in the pancreatic b-cell and this in turn reduces K+ outflow, leading to membrane depolarisation. The subsequent C2+ entry constitutes the secretion signal

Release of insulin in response to glucose leads to glucose uptake and storage in the form of glycogen (in muscle and liver)

the insulin receptor

insulin receptor activation and recruitment of signalling complex

Recruitment of adaptors and effectors through domains that bind phosphotyrosine-containing peptides SH2 domain (or PTB domain) phosphotyrosine peptide from IRS1 (or insulin receptor)

PI 3-kinase is an important effector for insulin signalling

Molecular structure of PI 3-kinase ATP P110 PI 3-kinase

PI 3-kinase products (relevant to insulin signalling is the production of PI- 3,4,5-P3

A downstream effector of PI 3-kinase is the protein kinase PKB PDK2 : phosphatidyl inositol-dependent protein kinase 2 was so named because the identity was unclear. It is now generally agreed that the mTOR/Rictor complex provides the initial phosphorylation

the protein kinase B family

Detail of the mechanism of activation of protein kinase B

PKB phosphorylates FOXO1 and this prevents if from going into the nucleus

Loss of FoxO1 in the nuclear leads to increased POMC and reduced AgRP expression

PKB stimulates the mTOR pathway, which also provides a anorectic signal (via an as yet unclear pathway)

Rheb is a GTPase which, in its GTP-bound state, binds FKBP38

mTOR is a huge atypical protein kinase of which still a lot has to be learned

A lack of glucose blocks the mTOR-mediated anorectic signal. This occurs through an increase of 5’-AMP which is produced in a « rescue » pathway where two ADP are combined 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

from PKB to glycogen synthase