Department of Clinical Chemistry
Head: Andrew N. Margioris, Emeritus Professor

Obesity and metabolic inflammation:

Background
Obesity is associated with a constant low level systemic inflammation, also termed as Metabolic inflammation originating in the visceral adipose tissue. Adipocytes and various stroma cells initiate the inflammatory response first within visceral adipose tissue which subsequently spreads out into the systemic circulation. More specifically, the large adipocytes of the obese produce chemotactic factors and adhesive molecules which attract monocytes / macrophages from the blood stream. Upon entering the adipose tissue, monocytes are activated to M1 macrophages which further activate adipocytes to produce more chemotactic factors and pro-inflammatory cytokines.

Ours is a laboratory intergrading immunology, enuropeptides and the study of adipose tissue. We have previously published on the effect of the Corticotrophin Releasing Factor (CRF) neuropetides on the cells of innate immunity. We have also published experimental work on the interaction between these neuropeptides and peripheral sympathetic nervous system including the adrenal medulla. Adipose tissue is richly innervated by the sympathetic system. The stress neuropeptides CRF and its related peptides, the Urocortins as well as their receptors (CRF1, CRF2) are all present in the adipose tissue.


Research
Determine the role of neuroendocrine factors in the pathophysiology of adipose tissue in obesity and its metabolic and immune consequences.

a) Corticotrophin Realising Factor affects the expression of TLR4 receptor in adipocytes (E. Dermitzaki)
     Lipo-poly-saccharide (LPS) stimulates macrophages, via the TLR4 receptor, to produce pro-inflammatory mediators. Interestingly, the expression levels of TLR4 control macrophage sensitivity to LPS. LPS transiently downregulates TLR4 promoting macrophage tolerance to further LPS stimulation while, the stress-related peptide CRF augments the effect of LPS by inducing TLR4 gene expression in macrophages.
     Adipocytes and macrophages share several common characteristics including the TLR4-NFkB-pro-inflammatory cytokine cascade. Furthermore, adipocytes and monocytes have a common precursor cells. A complete CRF system exists within the visceral adipose tissue consisting of CRF, the Urocortins, and their receptors CRF1 and CRF2. The aim of the present work was to examine the effect of CRF and Urocortins in the production of adipokines and pro-inflammatory cytokines as well as the expression levels of TLR4 in adipocytes.


b) The role of VIP in the inflammatory response of adipocytes (E. Dermitzaki -, this work is in cooperation with RP. Gomariz, M. Carrion Caballo and S. Perez Garcia from Dept of Cell Biology, Faculty of Biology, Complutense University of Madrid)
     Vasoactive Intestinal Peptide (VIP) affects macrophage sensitivity to bacterial LPS by modulating TLR4 expression. We are currently investigating the signaling mechanism involved as well as the significance of key molecules in the TLR signaling using the 3T3L1 cell line.
The role of stress neuropeptides in the pathophysiology of adrenals:

Background
CRF is the major regulator of the adaptive response to internal or external stresses. An essential component of the adaptation mechanism is the adrenal gland. CRF regulates adrenal function indirectly through the Central Nervous System (CNS) via the Hypothalamus – Pituitary - Adrenal (HPA) axis and via the autonomic nervous system by way of locus coeruleus (LC) in the brain stem. Accumulating evidence suggests that CRF and its related peptides also affect the adrenals directly i.e. not through CNS but from within the adrenal gland where they form paracrine regulatory loops. Indeed, CRF and its related peptides, the Urocortins (UCNs), UCN1, UCN2 and UCN3, their receptors CRF type 1 (CRF1) and 2 (CRF2) as well as the endogenous pseudo-receptor CRF binding protein (CRF-BP) are all expressed in adrenal cortical, medullary chromaffin and resident immune cells. The intra-adrenal CRF-based regulatory system is complex and depends on the balance between the local concentration of CRF ligands and the availability of their receptors.

Earlier work from our group has shown that CRF promotes apoptosis in adrenal chromaffin cells via activation of several signaling cascades including selective isoforms of PKC and MAPKinases such as ERK1/2 and p38MAPK. Moreover, we have demonstrated that CRF receptor signals orchestrate a complex regulation of catecholamine production from adrenal medulla cells.

Research
Determine the mechanism through which CRF and the Urocortins induce catecholamine production in adrenal chromaffin cells; potential role in neuronal cell differentiation. (E. Dermitzaki, E. Tretsi)

We have previously shown that CRF exerts multiple actions on chromaffin cells including induction of apoptosis and stimulation of catecholamine synthesis and secretion. We have identified several signaling molecules involved in these processes including P38MAPK, ERK1/2 and PKC. We are currently investigating the role of CRF peptides on the activation of the transcription factor family NFAT and its role on catecholamine production and/or secretion. NFAT transcription factors are also important in neuronal cell differentiation. We therefore study the role of CRF on neuronal cell differentiation, an event that will most probably occur via NFAT activation.


Representative Publications

  1. Peripheral factors in the metabolic syndrome: the pivotal role of adiponectin.
    Tsatsanis C, Zacharioudaki V, Androulidaki A, Dermitzaki E, Charalampopoulos I, Minas V, Gravanis A, Margioris AN.
    Ann N Y Acad Sci. 2006 Nov;1083:185-95.

  2. Fatty acids and postprandial inflammation.
    Margioris AN.
    Curr Opin Clin Nutr Metab Care.2009 Mar;12(2):129-37. Review.

  3. Corticotropin-releasing factor (CRF) and the urocortins differentially regulate catecholamine secretion in human and rat adrenals, in a CRF receptor type-specific manner.
    Dermitzaki E, Tsatsanis C, Minas V, Chatzaki E, Charalampopoulos I, Venihaki M, Androulidaki A, Lambropoulou M, Spiess J, Michalodimitrakis E, Gravanis A, Margioris AN.
    Endocrinology. 2007 Apr;148(4):1524-38. Epub 2006 Dec 28.

  4. Corticotropin-releasing factor and the urocortins induce the expression of TLR4 in macrophages via activation of the transcription factors PU.1 and AP-1.
    Tsatsanis C, Androulidaki A, Alissafi T, Charalampopoulos I, Dermitzaki E, Roger T, Gravanis A, Margioris AN.
    J Immunol. 2006 Feb 1;176(3):1869-77.

  5. Venihaki M, Ain K, Dermitzaki E, Gravanis A, Margioris AN. KAT45, a noradrenergic human pheochromocytoma cell line producing corticotropin-releasing hormone. Endocrinology. (1998) 139(2):713-22.

  6. Dermitzaki E., C. Tsatsanis, A. Gravanis and A.N. Margioris. Corticotropin-Releasing Hormone (CRH) induces Fas ligand production and apoptosis in PC12 cells via activation of p38 MAPK. (2002) J Biol Chem. 277:12280-7

  7. E. Dermitzaki, C. Tsatsanis, I. Charalmpopoulos, A. Androulidaki, I. Alexaki, E. Castanas, A. Gravanis and A. N. Margioris. Corticotropin-Releasing Hormone differentially regulates Protein Kinase C isoforms in PC12 cells. Biochem. Biophys. Res. Commun. (2005) 18;327(3):828-36

  8. Tsatsanis C, Dermitzaki E, Venihaki M, Chatzaki E, Minas V, Gravanis A, Margioris AN. The corticotropin-releasing factor (CRF) family of peptides as local modulators of adrenal function. Cell Mol Life Sci. (2007) Jul;64(13):1638-55.


Funding sources
Hellenic General Secretariat for Research and Technology (ΠENEΔ)
Ministry of Education (Pythagoras)
Medicon Hellas


Contact
Andrew N. MARGIORIS
Dept. of Clinical Chemistry-Biochemistry
School of Medicine
University of Crete
PO BOX 2208
Heraklio 71003
Crete
Greece

Tel:+30-2810-394588
Fax: +30-2810-394581
email: andym@med.uoc.gr
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