Intracellular signalling pathways activated by leptin by Gema FRUHBECK Presentation by Amnesiacs Anonymous
Introduction to Leptin By Ahrial Young
Why is Leptin important? Pleiotropic = it controls the phenotype of other seemingly unrelated traits It talks alot! - Connections to: insulin receptor substrates, phosphoinositide 3-kinase, protein kinase B, protein kinase C, extracellular-signal-regulated kinase, mitogen-activated protein kinases, phosphodiesterase, phospholipase C and nitric oxide, has been observed. The impact of leptin on several equally relevant signalling pathways extends also to Rho family GTPases in relation to the actin cytoskeleton, production of reactive oxygen species, stimulation of prostaglandins, binding to diacylglycerol kinase and catecholamine secretion, among others - Translation= works with systems that deal with: energy regulation, growth, immune response, and cell function
The evolution of our understanding of leptin - Discovered in 1944 - Folds like cytokines - Cytokine = a category of proteins; ALL the cells around them - Hormones = specific cells all over the BODY - Leptin = fat cells = body fat - Initially thought leptin was only centrally located - Turns out to be just about everywhere - Has implications in: general endocrinology, metabolism, reproduction, immunology, cardiovascular pathophysiology, respiratory function and wound healing, as well as in growth and development
Binding Proteins and Clearance Leptin exists unbound outside the cell and bound inside the cell - Free leptin is broken down more often processed quickly - People who fast have less unbound but bound doesn t change Benefits of being bound: - Can stick around longer and regulate processes in the body
Leptin Receptors Receptors look very similar to class 1 cytokine receptors Leptin motifs (the defining amino acids that make it work) - 4 cyteseine residues - WSXWS (Trp-Ser-Anything-Trp-Ser) - Extracellular domain contains two cytokine-like receptor motifs There s a few different forms of leptin aka isoforms *choroid plexus = cells that produce CSF - OB-R: OB-Ra, OB-Rb, OB-Rc, OB-Rd, OB-Re - Classes: short, long, secreted - Main difference is in the part that s intercellular The isoforms and where they are: OB-R = hypothalamus and other areas associated with food and energy regulation OB-Rb = hypothalamus Ra and Rb = in extraneuronal tissue Ra and Rc = choroid plexus*, seem to be involved with leptin transport Re= buffering for free leptin
Receptor Internalization When they bind with a ligand they are either taken apart or brought back to the surface of the cell Ra and Rb = lysosomal degradation Heavily implicated in leptin resistance - OB-R internalized (not on cell surface) too much leptin leptin resistance - We don t know why it happens
Big Picture Leptin is widely distributed so there is hope that by understanding it better we can combat pathologies more effectively Energy regulation is tied to brain/cognitive function Leptin and insulin are bffs Other cool things leptin seems to have it s hands in: adaptive response to starvation 1, and emotional stress 2. 1.Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS (July 1996). "Role of leptin in the neuroendocrine response to fasting". Nature. 382 (6588): 250 52. Bibcode:1996Natur.382..250A. doi:10.1038/382250a0. PMID 8717038. 2. Otsuka, R., Yatsuya, H., Tamakoshi, K., Matsushita, K., Wada, K. and Toyoshima, H. (2006), Perceived Psychological Stress and Serum Leptin Concentrations in Japanese Men. Obesity, 14: 1832-1838. doi:10.1038/oby.2006.211
JAK/STAT Pathway By Derek Jow
JAK Family of intracellular, non-receptor tyrosine kinases Originally named Just Another Kinase Changed to Janus, Roman god of duality, aptly named for its two phosphate transfering domains that regulate each other
STAT Family of intracellular transcription factors Signal Transducer and Activator of Transcription Involved in proliferation, apoptosis, and immune system Dysregulation leads to angiogenesis which increases tumor growth
The receptor Leptin mediates cytokine receptor-like signaling, activating JAKs and STATs Only one isoform, OB-Rb contains the intracellular domain to produce a signal in the JAK/STAT pathway Receptor is composed of an OB-Rb homodimer
JAK/STAT pathway composition Consists of 4 JAK proteins and 7 STAT proteins Box1 and Box2 - the binding sites of JAK proteins on the receptor Gateway to other pathways (These will be discussed later) MAPK cascade PI3K/PDE3B/cAMP Pathway AMPK pathway
JAK/STAT signal transduction cascade
JAK/STAT continued
Ras/Raf/MAPK pathway By Quinn
Ras/Raf/MAPK Pathway: Introduction MAPK = Mitogen-Activated Protein Kinase The Ras/Raf/MAPK pathway is one of the better known cascades in cell biology, in part due to being activatable by a wide range of stimuli No doubt because it can be activated by many things and lead to several cascades, the exact leptin-activated pathway is not precisely known Can be activated by OB-Rb or OB-Ra, albeit more weakly
Ras/Raf Pathway: Breakdown of normal process Can trigger either with assistance from JAK2 or without Receptor attracts SHP2 or GRB2, which can bind to protein SOS SOS binds to membrane-bound protein Ras, which in its inactive form is bound to a GDP (guanosine diphosphate) nucleotide. This activates it by adding an extra phosphate, making GTP (guanosine triphosphate). Ras-GTP, now active and no longer bound to SOS, can now bind to one of several effector proteins. The most common of these is B-Raf, which can lead to well-known further cascades such as MEK, ERK, and MAPK According to our article, a strong candidate for the final result of the leptin cascade is the transcription factor NF-κB, which helps regulate cytokines
MAPK Pathway: Chart
PI3K/cAMP/PDE3B pathway By Monica Chao
PI3K PI3Ks are a family of enzymes involved in cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking Have been implicated in long-term potentiation Most insulin-dependent actions involve PI3K activation Mostly stimulate protein kinases such as Akt and PKC isoforms
PDE3B Has a role in regulating heart muscles, vascular smooth muscles, and platelet aggregation Has also been suggested that PDE3B has a role in mitochondrial function, energy dissipation, and adipocyte metabolism Also regulates certain camp-signaling pathways such as lipolysis, insulin-induced anti-lipolysis, and camp-mediated insulin secretion
camp Used for intracellular signal transduction in many different organisms Derivative of ATP (adenosine triphosphate)
Study on Mice IRS2-null mice exhibited hyperphagia and a hypometabolic state in the presence of increased adiposity and hyperleptinaemia, which was not as marked as for db/db mice. Release of insulin from pancreatic islets in ob/ob mice in response to PKC stimulation is shown to be weakened by leptin.
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