Dr Constantinos Christodoulides MRCP

Research Area: Cell and Molecular Biology
Technology Exchange: Ex vivo models, SNP typing, Transcript profiling and Transgenesis
Scientific Themes: Diabetes, Endocrinology & Metabolism and Genes, Genetics, Epigenetics & Genomics
Keywords: Obesity, human metabolism, type 2 diabetes and Wnt signalling
Web Links:

I have an interest on the role of Wnt signalling in determining adipose tissue cellularity and distribution and thereby susceptibility to obesity-associated cardio-metabolic disease. In this work I collaborate closely with Professor Fredrik Karpe. We use human genetic and physiological approaches, accompanied by studies in cellular models to better understand the mechanisms whereby rare and common genetic variants in Wnt pathway genes modulate adipose tissue biology and thereby susceptibility to metabolic diseases.

Name Department Institution Country
Prof Fredrik Karpe OCDEM Oxford University, Oxford Centre for Diabetes, Endocrinology & Metabolism United Kingdom
Dr Celia L Gregson MRCP Muscoloskeletal Research Unit, University of Bristol, Avon Orthopaedic Centre, Southmead Hospital, Bristol BS10 5NB, UK University of Bristol United Kingdom
Prof Jon Tobias FRCP Academic Rheumatology, Musculoskeletal Research Unit, Avon Orthopaedic Centre BS10 5NB University of Bristol United Kingdom
Dr James Minchin The University of Edinburgh United Kingdom
Loh NY, Neville MJ, Marinou K, Hardcastle SA, Fielding BA, Duncan EL, McCarthy MI, Tobias JH, Gregson CL, Karpe F, Christodoulides C. 2015. LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion. Cell Metab, 21 (2), pp. 262-272. | Show Abstract | Read more

Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.

Marinou K, Christodoulides C, Antoniades C, Koutsilieris M. 2012. Wnt signaling in cardiovascular physiology. Trends Endocrinol Metab, 23 (12), pp. 628-636. | Show Abstract | Read more

Wnt signaling pathways play a key role in cardiac development, angiogenesis, and cardiac hypertrophy; emerging evidence suggests that they are also involved in the pathophysiology of atherosclerosis. Specifically, an important role for Wnts has been described in the regulation of endothelial inflammation, vascular calcification, and mesenchymal stem cell differentiation. Wnt signaling also induces monocyte adhesion to endothelial cells and is crucial for the regulation of vascular smooth-muscle cell (VSMC) behavior. We discuss how the Wnt pathways are implicated in vascular biology and outline the role of Wnt signaling in atherosclerosis. Dissecting Wnt pathways involved in atherogenesis and cardiovascular disease may provide crucial insights into novel mechanisms with therapeutic potential for atherosclerosis.

Capatina C, Christodoulides C, Fernandez A, Cudlip S, Grossman AB, Wass JA, Karavitaki N. 2013. Current treatment protocols can offer a normal or near-normal quality of life in the majority of patients with non-functioning pituitary adenomas. Clin Endocrinol (Oxf), 78 (1), pp. 86-93. | Show Abstract | Read more

OBJECTIVE: Non-functioning pituitary adenomas (NFA) may be associated with significant morbidity. Published data on the quality of life (QoL) of patients with NFA are scarce and conflicting. In view of the discordant findings and the advances in the management of these subjects, we aimed to evaluate the QoL in patients with NFA followed up in a tertiary endocrine UK referral centre. SUBJECTS AND METHODS: All consecutive patients with NFA attending the outpatient clinic in the Department of Endocrinology in Oxford over a 6-month period (n = 193) were offered 3 health-related QoL questionnaires [Short Form 36 (SF36), Nottingham Health Profile (NHP), European Quality of Life Scale (EuroQoL)] to complete. Patient outcomes (response rate 93.3%) were compared with age-related UK reference values. RESULTS: None of the QoL scores in the SF-36 or the 5 dimensions of health in the EuroQoL was different from the reference values. The visual analogue scale (VAS) score (EuroQoL) was slightly compromised (P = 0.041). In the NHP questionnaire, males had no parameter significantly affected, whereas females performed worse in 1/6 areas (energy levels). Tumour recurrence was an independent predictor for compromised VAS score and for anxiety/depression (EuroQoL), and visual field defects for more frequent problems with interests/hobbies (NHP). CONCLUSIONS: Overall, the health-related QoL and perception of subjective health in patients with NFA was not compromised to any major extent suggesting that we can now offer the prospect of treatment and replacement, which will provide a normal or near-normal QoL. Specific groups are affected in various dimensions, necessitating measures to compensate for predisposing factors.

Cited:

49

Scopus

Marinou K, Christodoulides C, Antoniades C, Koutsilieris M. 2012. Wnt signaling in cardiovascular physiology Trends in Endocrinology and Metabolism, 23 (12), pp. 628-636. | Show Abstract | Read more

Wnt signaling pathways play a key role in cardiac development, angiogenesis, and cardiac hypertrophy; emerging evidence suggests that they are also involved in the pathophysiology of atherosclerosis. Specifically, an important role for Wnts has been described in the regulation of endothelial inflammation, vascular calcification, and mesenchymal stem cell differentiation. Wnt signaling also induces monocyte adhesion to endothelial cells and is crucial for the regulation of vascular smooth-muscle cell (VSMC) behavior. We discuss how the Wnt pathways are implicated in vascular biology and outline the role of Wnt signaling in atherosclerosis. Dissecting Wnt pathways involved in atherogenesis and cardiovascular disease may provide crucial insights into novel mechanisms with therapeutic potential for atherosclerosis. © 2012 Elsevier Ltd.

Cited:

44

Scopus

Vaiopoulos AG, Marinou K, Christodoulides C, Koutsilieris M. 2012. The role of adiponectin in human vascular physiology International Journal of Cardiology, 155 (2), pp. 188-193. | Show Abstract | Read more

Adiponectin (ApN) is an adipose tissue-derived hormone which is involved in a wide variety of physiological processes including energy metabolism, inflammation, and vascular physiology via actions on a broad spectrum of target organs including liver, skeletal muscle, and vascular endothelium. Besides possessing insulin sensitizing and anti-inflammatory properties ApN also exerts a pivotal role in vascular protection through activation of multiple intracellular signaling cascades. Enhancement of nitric oxide generation and attenuation of reactive oxygen species production in endothelial cells along with reduced vascular smooth muscle cell proliferation and migration constitute some of ApN's vasoprotective actions. Additionally, recent data indicate that ApN has direct myocardio-protective effects. Decreased plasma ApN levels are implicated in the pathogenesis of the metabolic syndrome and atherosclerosis and may serve as a diagnostic and prognostic biomarker as well as a rational pharmaco-therapeutic target to treat these disorders. This review article summarizes recent work on the cardiovascular actions of ApN. © 2011 Elsevier Ireland Ltd. All rights reserved.

Vaiopoulos AG, Marinou K, Christodoulides C, Koutsilieris M. 2012. The role of adiponectin in human vascular physiology. Int J Cardiol, 155 (2), pp. 188-193. | Show Abstract | Read more

Adiponectin (ApN) is an adipose tissue-derived hormone which is involved in a wide variety of physiological processes including energy metabolism, inflammation, and vascular physiology via actions on a broad spectrum of target organs including liver, skeletal muscle, and vascular endothelium. Besides possessing insulin sensitizing and anti-inflammatory properties ApN also exerts a pivotal role in vascular protection through activation of multiple intracellular signaling cascades. Enhancement of nitric oxide generation and attenuation of reactive oxygen species production in endothelial cells along with reduced vascular smooth muscle cell proliferation and migration constitute some of ApN's vasoprotective actions. Additionally, recent data indicate that ApN has direct myocardio-protective effects. Decreased plasma ApN levels are implicated in the pathogenesis of the metabolic syndrome and atherosclerosis and may serve as a diagnostic and prognostic biomarker as well as a rational pharmaco-therapeutic target to treat these disorders. This review article summarizes recent work on the cardiovascular actions of ApN.

Lagathu C, Christodoulides C, Tan CY, Virtue S, Laudes M, Campbell M, Ishikawa K, Ortega F, Tinahones FJ, Fernández-Real JM et al. 2010. Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity. Int J Obes (Lond), 34 (12), pp. 1695-1705. | Show Abstract | Read more

AIM: The Wnt/β-catenin signaling network offers potential targets to diagnose and uncouple obesity from its metabolic complications. In this study, we investigate the role of the Wnt antagonist, secreted frizzled-related protein 1 (SFRP1), in promoting adipogenesis in vitro and adipose tissue expansion in vivo. METHODS: We use a combination of human and murine, in vivo and in vitro models of adipogenesis, adipose tissue expansion and obesity-related metabolic syndrome to profile the involvement of SFRP1. RESULTS: SFRP1 is expressed in both murine and human mature adipocytes. The expression of SFRP1 is induced during in vitro adipogenesis, and SFRP1 is preferentially expressed in mature adipocytes in human adipose tissue. Constitutive ectopic expression of SFRP1 is proadipogenic and inhibits the Wnt/β-catenin signaling pathway. In vivo endogenous levels of adipose SFRP1 are regulated in line with proadipogenic states. However, in longitudinal studies of high-fat-diet-fed mice, we observed a dynamic temporal but biphasic regulation of endogenous SFRP1. In agreement with this profile, we observed that SFRP1 expression in human tissues peaks in patients with mild obesity and gradually falls in morbidly obese subjects. CONCLUSIONS: Our results suggest that SFRP1 is an endogenous modulator of Wnt/β-catenin signaling and participates in the paracrine regulation of human adipogenesis. The reduced adipose expression of SFRP1 in morbid obesity and its knock-on effect to prevent further adipose tissue expansion may contribute to the development of metabolic complications in these individuals.

Christodoulides C, Vidal-Puig A. 2010. PPARs and adipocyte function. Mol Cell Endocrinol, 318 (1-2), pp. 61-68. | Show Abstract | Read more

For long viewed as passive lipid storage depots, adipocytes are now recognised as key players in the pathogenesis of insulin resistance and metabolic disease. In parallel, the last two decades of research have seen the emergence of transcription factors of the peroxisome proliferator-activated receptor (PPAR) family as central regulators of lipid and glucose homeostasis and molecular targets for drugs to treat hyper-lipidaemia and type 2 diabetes mellitus. In this review we discuss the characteristics of PPARs and the role of the different isotypes in adipocyte biology.

Christodoulides C, Dyson P, Sprecher D, Tsintzas K, Karpe F. 2009. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man. J Clin Endocrinol Metab, 94 (9), pp. 3594-3601. | Show Abstract | Read more

CONTEXT: Murine fibroblast growth factor (FGF) 21 is a nutritionally regulated hormone secreted by the liver principally in response to peroxisome proliferator-activated receptor-alpha (PPAR alpha) activation, which plays a critical role in regulating metabolism during ketosis. FGF21 is also a PPAR gamma target gene in mouse adipose tissue. Little information is available on FGF21 functions in humans. OBJECTIVE: The aim of the study was to measure plasma FGF21 during fasting, ketogenic diet, and PPAR agonist treatment in humans. DESIGN AND SETTING: We conducted a prospective study involving three patient groups at two university hospitals. PATIENTS: Eight healthy male volunteers underwent a 48-h period of starvation followed by 24-h refeeding (group 1); seven obese individuals were allocated to a low-carbohydrate diet for 3 months (group 2); and three groups of healthy, overweight or obese male volunteers received treatment with a PPAR alpha (20 microg/d GW590735) (n=6), PPAR delta (10 mg/d GW501516) (n=6), or PPAR gamma agonist (rosiglitazone) (n=10) for 2 wk (group 3). MAIN OUTCOME MEASURES: Fasting plasma FGF21 and serum 3-hydroxybutyrate were measured. RESULTS: There was no significant variation in human plasma FGF21 during fasting and refeeding. A 3-month ketogenic diet was associated with a 42% decline in plasma FGF21 levels. Circulating FGF21 increased significantly in response to treatment with PPAR alpha (39%) and PPAR delta (32%), but not PPAR gamma agonists. CONCLUSION: FGF21 does not play a major role in regulating the fasting response or ketosis in man. However, plasma FGF21 is elevated in response to pharmacological activation of PPAR alpha and PPAR delta and may contribute to the beneficial metabolic effects observed in response to pharmacotherapy with these compounds.

Lagathu C, Christodoulides C, Laudes M, Virtue S, Kumar S, Considine R, Sethi J, Vidal-Puig A. 2009. SFRP1 (Secreted Frizzled-Related Protein 1), antagonist of the Wnt path, is a proadipogenic factor and a marker of adipose tissue expansion and insulin resistance in mice and humans DIABETES & METABOLISM, 35 pp. A5-A5.

Lagathu C, Christodoulides C, Virtue S, Cawthorn WP, Franzin C, Kimber WA, Nora ED, Campbell M, Medina-Gomez G, Cheyette BN et al. 2009. Dact1, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the Wnt/beta-catenin signaling network. Diabetes, 58 (3), pp. 609-619. | Show Abstract | Read more

OBJECTIVE: Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Wnt modulator Dapper1/Frodo1 (Dact1) as a new preadipocyte gene involved in the regulation of murine and human adipogenesis. RESEARCH DESIGN AND METHODS: Changes in Dact1 expression were investigated in three in vitro models of adipogenesis. In vitro gain- and loss-of-function studies were used to investigate the mechanism of Dact1 action during adipogenesis. The in vivo regulation of Dact1 and Wnt/beta-catenin signaling were investigated in murine models of altered nutritional status, of pharmacological stimulation of in vivo adipogenesis, and during the development of dietary and genetic obesity. RESULTS: Dact1 is a preadipocyte gene that decreases during adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation of the Wnt/beta-catenin signaling pathway, and this is reversed by treatment with the secreted Wnt antagonist, secreted Frizzled-related protein 1 (Sfrp1). In contrast, constitutive Dact1 overexpression promotes adipogenesis and confers resistance to Wnt ligand-induced antiadipogenesis through increased expression of endogenous Sfrps and reduced expression of Wnts. In vivo, in white adipose tissue, Dact1 and Wnt/beta-catenin signaling also exhibit coordinated expression profiles in response to altered nutritional status, in response to pharmacological stimulation of in vivo adipogenesis, and during the development of dietary and genetic obesity. CONCLUSIONS: Dact1 regulates adipogenesis through coordinated effects on gene expression that selectively alter intracellular and paracrine/autocrine components of the Wnt/beta-catenin signaling pathway. These novel insights into the molecular mechanisms controlling adipose tissue plasticity provide a functional network with therapeutic potential against diseases, such as obesity and associated metabolic disorders.

Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A. 2009. Adipogenesis and WNT signalling. Trends Endocrinol Metab, 20 (1), pp. 16-24. | Show Abstract | Read more

An inability of adipose tissue to expand consequent to exhausted capacity to recruit new adipocytes might underlie the association between obesity and insulin resistance. Adipocytes arise from mesenchymal precursors whose commitment and differentiation along the adipocytic lineage is tightly regulated. These regulatory factors mediate cross-talk between adipose cells, ensuring that adipocyte growth and differentiation are coupled to energy storage demands. The WNT family of autocrine and paracrine growth factors regulates adult tissue maintenance and remodelling and, consequently, is well suited to mediate adipose cell communication. Indeed, several recent reports, summarized in this review, implicate WNT signalling in regulating adipogenesis. Manipulating the WNT pathway to alter adipose cellular makeup, therefore, constitutes an attractive drug-development target to combat obesity-associated metabolic complications.

Barber TM, Hazell M, Christodoulides C, Golding SJ, Alvey C, Burling K, Vidal-Puig A, Groome NP, Wass JA, Franks S, McCarthy MI. 2008. Serum levels of retinol-binding protein 4 and adiponectin in women with polycystic ovary syndrome: associations with visceral fat but no evidence for fat mass-independent effects on pathogenesis in this condition. J Clin Endocrinol Metab, 93 (7), pp. 2859-2865. | Show Abstract | Read more

CONTEXT: Insulin resistance, which associates with levels of retinol-binding protein 4 (RBP4) and adiponectin, is implicated in the development of polycystic ovary syndrome (PCOS). OBJECTIVE: The objective of the study was to explore the potential contribution of RBP4 and adiponectin in the etiology of PCOS and their relationships with specific fat depot measurements. DESIGN: This was a cross-sectional study. SETTING AND PARTICIPANTS: Serum RBP4 and adiponectin levels were compared between 50 PCOS cases and 28 female controls (including 22 body mass index/fat mass-matched pairs) and correlated with specific fat depot (including visceral) axial magnetic resonance imaging cross-sectional area measurements. All subjects were of U.K. British/Irish origin. MAIN OUTCOME MEASURE(S): Serum levels of RBP4 (automated immunonephelometric assay) and adiponectin [immunoassay: total and high molecular weight (HMW)]. Data are reported as geometric mean (sd, range) and optionally adjusted for fat mass and age. RESULTS: Between the 50 PCOS cases and 28 controls, serum RBP4 levels were indistinguishable [39.0 microg/ml (31.0, 49.0) vs. 41.6 microg/ml (32.7, 52.9), respectively, unadjusted P = 0.24; adjusted P = 0.55]. Total (and HMW) adiponectin levels were lower in PCOS cases [total adiponectin 19.9 microg/ml (14.2, 27.8) vs. 25.8 microg/ml (17.7, 37.7), respectively, unadjusted P = 2.4 x 10(-3); adjusted P = 0.10]. For the paired-sample analyzes, there were no differences in RBP4 (P = 0.09), total adiponectin (P = 0.06), HMW adiponectin (P =0.19), or HMW to total adiponectin ratio (P = 0.98). In PCOS cases, L4-visceral fat area was associated positively with RBP4 (r(2) = 0.34, P = 0.01) and negatively with HMW to total adiponectin ratio (r(2) = -0.44, P = 1.3 x 10(-3)). Controls showed similar relationships. CONCLUSIONS: Although associated with visceral fat, serum RBP4 and adiponectin levels do not play important, fat-mass-independent primary roles in the development of PCOS.

Lagathu C, Christodoulides C, Kimber W, Dalla-Nora E, O'Rahilly S, Sethi J, Vidal-Puig A. 2007. Dapper-1, inhibitor of the Wnt pathway, is necessary for differentiation of adypocytes in vitro DIABETES & METABOLISM, 33 pp. S72-S72.

Christodoulides C, Laudes M, Cawthorn WP, Schinner S, Soos M, O'Rahilly S, Sethi JK, Vidal-Puig A. 2006. The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis. J Cell Sci, 119 (Pt 12), pp. 2613-2620. | Show Abstract | Read more

Secretion of Wnts by adipose cells has an important role in the control of murine adipogenesis. We present the first evidence that a Wnt antagonist, Dickkopf 1 (Dkk1), is secreted by human preadipocytes and promotes adipogenesis. DKK1 mRNA increases six hours after onset of human adipogenesis and this is followed by an increase in Dkk1 protein. With further differentiation, the mRNA and protein levels progressively decline such that they are undetectable in mature adipocytes. The transient induction in DKK1 correlates with downregulation of cytoplasmic and nuclear beta-catenin levels, this being a surrogate marker of canonical Wnt signalling, and Wnt/beta-catenin transcriptional activity. In addition, constitutive expression of Dkk1 in 3T3-L1 preadipocytes promotes their differentiation, further supporting the functional significance of increased Dkk1 levels during human adipogenesis. Concomitant downregulation of the Dkk1 receptors LRP5 and LRP6 is likely to potentiate the ability of Dkk1 to inhibit Wnt signalling and promote differentiation. Notably, Dkk1 is not expressed in primary murine preadipocytes or cell lines. The involvement of Dkk1 in human but not murine adipogenesis indicates that inter-species differences exist in the molecular control of this process. Given the public health importance of disorders of adipose mass, further knowledge of the pathways involved specifically in human adipocyte differentiation might ultimately be of clinical relevance.

Christodoulides C, Scarda A, Granzotto M, Milan G, Dalla Nora E, Keogh J, De Pergola G, Stirling H, Pannacciulli N, Sethi JK et al. 2006. WNT10B mutations in human obesity. Diabetologia, 49 (4), pp. 678-684. | Show Abstract | Read more

AIMS/HYPOTHESIS: Recent studies suggest that wingless-type MMTV integration site family, member 10B (WNT10B) may play a role in the negative regulation of adipocyte differentiation in vitro and in vivo. In order to determine whether mutations in WNT10B contribute to human obesity, we screened two independent populations of obese subjects for mutations in this gene. SUBJECTS AND METHODS: We studied 96 subjects with severe obesity of early onset (less than 10 years of age) from the UK Genetics of Obesity Study and 115 obese Italian subjects of European origin. RESULTS: One proband with early-onset obesity was found to be heterozygous for a C256Y mutation, which abrogated the ability of WNT10B to activate canonical WNT signalling and block adipogenesis and was not found in 600 control alleles. All relatives of the proband who carried this allele were either overweight or obese. Three other rare missense variants were found in obese probands, but these did not clearly cosegregate with obesity in family studies and one (P301S), which was found in three unrelated subjects with early-onset obesity, had normal functional properties. CONCLUSIONS/INTERPRETATION: These mutations represent the first naturally occurring missense variants of WNT10B. While the pedigree analysis in the case of C256Y WNT10B does not provide definitive proof of a causal link of this variant with obesity, the finding of a non-functioning WNT10B allele in a human family affected by obesity should encourage further study of this gene in other obese populations.

Medina-Gomez G, Virtue S, Lelliott C, Boiani R, Campbell M, Christodoulides C, Perrin C, Jimenez-Linan M, Blount M, Dixon J et al. 2005. The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-gamma2 isoform. Diabetes, 54 (6), pp. 1706-1716. | Show Abstract | Read more

The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) is critically required for adipogenesis. PPARgamma exists as two isoforms, gamma1 and gamma2. PPARgamma2 is the more potent adipogenic isoform in vitro and is normally restricted to adipose tissues, where it is regulated more by nutritional state than PPARgamma1. To elucidate the relevance of the PPARgamma2 in vivo, we generated a mouse model in which the PPARgamma2 isoform was specifically disrupted. Despite similar weight, body composition, food intake, energy expenditure, and adipose tissue morphology, male mice lacking the gamma2 isoform were more insulin resistant than wild-type animals when fed a regular diet. These results indicate that insulin resistance associated with ablation of PPARgamma2 is not the result of lipodystrophy and suggests a specific role for PPARgamma2 in maintaining insulin sensitivity independently of its effects on adipogenesis. Furthermore, PPARgamma2 knockout mice fed a high-fat diet did not become more insulin resistant than those on a normal diet, despite a marked increase in their mean adipocyte cell size. These findings suggest that PPARgamma2 is required for the maintenance of normal insulin sensitivity in mice but also raises the intriguing notion that PPARgamma2 may be necessary for the adverse effects of a high-fat diet on carbohydrate metabolism.

Rochford JJ, Semple RK, Laudes M, Boyle KB, Christodoulides C, Mulligan C, Lelliott CJ, Schinner S, Hadaschik D, Mahadevan M et al. 2004. ETO/MTG8 is an inhibitor of C/EBPbeta activity and a regulator of early adipogenesis. Mol Cell Biol, 24 (22), pp. 9863-9872. | Show Abstract | Read more

The putative transcriptional corepressor ETO/MTG8 has been extensively studied due to its involvement in a chromosomal translocation causing the t(8;21) form of acute myeloid leukemia. Despite this, the role of ETO in normal physiology has remained obscure. Here we show that ETO is highly expressed in preadipocytes and acts as an inhibitor of C/EBPbeta during early adipogenesis, contributing to its characteristically delayed activation. ETO prevents both the transcriptional activation of the C/EBPalpha promoter by C/EBPbeta and its concurrent accumulation in centromeric sites during early adipogenesis. ETO expression rapidly reduces after the initiation of adipogenesis, and this is essential to the normal induction of adipogenic gene expression. These findings define, for the first time, a molecular role for ETO in normal physiology as an inhibitor of C/EBPbeta and a novel regulator of early adipogenesis.

Laudes M, Christodoulides C, Sewter C, Rochford JJ, Considine RV, Sethi JK, Vidal-Puig A, O'Rahilly S. 2004. Role of the POZ zinc finger transcription factor FBI-1 in human and murine adipogenesis. J Biol Chem, 279 (12), pp. 11711-11718. | Show Abstract | Read more

Poxvirus zinc finger (POZ) zinc finger domain transcription factors have been shown to play a role in the control of growth arrest and differentiation in several types of mesenchymal cells but not, as yet, adipocytes. We found that a POZ domain protein, factor that binds to inducer of short transcripts-1 (FBI-1), was induced during both murine and human preadipocyte differentiation with maximal expression levels seen at days 2-4. FBI-1 mRNA was expressed in human adipose tissue with the highest levels found in samples from morbidly obese subjects. Murine cell lines constitutively expressing FBI-1 showed evidence for accelerated adipogenesis with earlier induction of markers of differentiation and enhanced lipid accumulation, suggesting that FBI-1 may be an active participant in the differentiation process. Consistent with the properties of this family of proteins in other cell systems, 3T3L1 cells stably overexpressing FBI-1 showed reduced DNA synthesis and reduced expression of cyclin A, cyclin-dependent kinase 2, and p107, proteins known to be involved in the regulation of mitotic clonal expansion. In addition, FBI-1 reduced the transcriptional activity of the cyclin A promoter. Thus, FBI-1, a POZ zinc finger transcription factor, is induced during the early phases of human and murine preadipocyte differentiation where it may contribute to adipogenesis through influencing the switch from cellular proliferation to terminal differentiation.

Semple RK, Crowley VC, Sewter CP, Laudes M, Christodoulides C, Considine RV, Vidal-Puig A, O'Rahilly S. 2004. Expression of the thermogenic nuclear hormone receptor coactivator PGC-1alpha is reduced in the adipose tissue of morbidly obese subjects. Int J Obes Relat Metab Disord, 28 (1), pp. 176-179. | Show Abstract | Read more

Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha) is an accessory protein which can potentiate the transcriptional activation function of many nuclear hormone receptors. Its tissue distribution and physiological studies suggest that its principal in vivo roles are to promote cold-induced thermogenesis, mitochondrial biogenesis, hepatic gluconeogenesis, and fatty acid beta-oxidation. It is expressed in the white adipose tissue of both humans and rodents, and in rodents it has been suggested to mediate in part the leptin-induced conversion of white adipocytes from fat storing to fat oxidising cells. In this study, quantitative real-time PCR has been used in human tissue to demonstrate that (1) PGC1alpha mRNA levels in subcutaneous fat are three-fold lower in morbidly obese than in slim subjects; (2) there are no differences in PGC1alpha mRNA between omental and subcutaneous mature adipocytes; (3) there is a robust induction of PGC1alpha expression during subcutaneous human preadipocyte differentiation ex vivo. Whether low PGC1alpha expression is a prelude to the development of obesity, or a consequence of that obesity, attempts to upregulate endogenous white adipose tissue expression may prove a valuable new avenue to explore in obesity therapy.

Bhattacharyya A, Christodoulides C, Kaushal K, New JP, Young RJ. 2002. In-patient management of diabetes mellitus and patient satisfaction (vol 19, pg 412, 2002) DIABETIC MEDICINE, 19 (9), pp. 797-797.

Bhattacharyya A, Christodoulides C, Kaushal K, New JP, Young RJ. 2002. In-patient management of diabetes mellitus and patient satisfaction. Diabet Med, 19 (5), pp. 412-416. | Show Abstract | Read more

AIMS: To devise a system for assessing in-patient glycaemic control and care satisfaction in diabetic patients admitted to hospital for reasons other than their diabetes. METHODS: Consecutive January to March 2001 case-notes were reviewed. Admissions with acute metabolic complications, acute myocardial infarction and pregestational or gestational diabetes were excluded. Glycaemic control, frequency of blood monitoring and management of hyperglycaemia were recorded. The diabetes treatment satisfaction questionnaire was used to assess preadmission satisfaction with care. Post-admission a 12-stem questionnaire was used to assess satisfaction with in-patient diabetes management. RESULTS: Hypoglycaemia was common. Although none developed a hyperglycaemic emergency, high blood glucose was prevalent and, frequently, persistent hyperglycaemia or recurrent hypoglycaemia was not acted on appropriately. The overall score for in-patient satisfaction with treatment was fair (4.1 +/- 1.8 on a six-point scale; 6 = very satisfied and 1 = very dissatisfied). Scores were higher among patients on surgical wards than on medical wards (P = 0.008), but satisfaction did not vary when patients were stratified according to sex, age and mode of treatment. CONCLUSION: Current systems are not achieving satisfactory in-patient glycaemic control and there is poor satisfaction with medical in-patient diabetes care. Following changes intended to produce improvements, this assessment system can be used recurrently to monitor in-patient care and satisfaction.

Bhattacharyya A, Christodoulides C, Kaushal K, New JP, Young RJ. 2002. Errata Diabetic Medicine, 19 (9), pp. 797-797. | Read more

Loh NY, Neville MJ, Marinou K, Hardcastle SA, Fielding BA, Duncan EL, McCarthy MI, Tobias JH, Gregson CL, Karpe F, Christodoulides C. 2015. LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion. Cell Metab, 21 (2), pp. 262-272. | Show Abstract | Read more

Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.

Lagathu C, Christodoulides C, Tan CY, Virtue S, Laudes M, Campbell M, Ishikawa K, Ortega F, Tinahones FJ, Fernández-Real JM et al. 2010. Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity. Int J Obes (Lond), 34 (12), pp. 1695-1705. | Show Abstract | Read more

AIM: The Wnt/β-catenin signaling network offers potential targets to diagnose and uncouple obesity from its metabolic complications. In this study, we investigate the role of the Wnt antagonist, secreted frizzled-related protein 1 (SFRP1), in promoting adipogenesis in vitro and adipose tissue expansion in vivo. METHODS: We use a combination of human and murine, in vivo and in vitro models of adipogenesis, adipose tissue expansion and obesity-related metabolic syndrome to profile the involvement of SFRP1. RESULTS: SFRP1 is expressed in both murine and human mature adipocytes. The expression of SFRP1 is induced during in vitro adipogenesis, and SFRP1 is preferentially expressed in mature adipocytes in human adipose tissue. Constitutive ectopic expression of SFRP1 is proadipogenic and inhibits the Wnt/β-catenin signaling pathway. In vivo endogenous levels of adipose SFRP1 are regulated in line with proadipogenic states. However, in longitudinal studies of high-fat-diet-fed mice, we observed a dynamic temporal but biphasic regulation of endogenous SFRP1. In agreement with this profile, we observed that SFRP1 expression in human tissues peaks in patients with mild obesity and gradually falls in morbidly obese subjects. CONCLUSIONS: Our results suggest that SFRP1 is an endogenous modulator of Wnt/β-catenin signaling and participates in the paracrine regulation of human adipogenesis. The reduced adipose expression of SFRP1 in morbid obesity and its knock-on effect to prevent further adipose tissue expansion may contribute to the development of metabolic complications in these individuals.

Christodoulides C, Dyson P, Sprecher D, Tsintzas K, Karpe F. 2009. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man. J Clin Endocrinol Metab, 94 (9), pp. 3594-3601. | Show Abstract | Read more

CONTEXT: Murine fibroblast growth factor (FGF) 21 is a nutritionally regulated hormone secreted by the liver principally in response to peroxisome proliferator-activated receptor-alpha (PPAR alpha) activation, which plays a critical role in regulating metabolism during ketosis. FGF21 is also a PPAR gamma target gene in mouse adipose tissue. Little information is available on FGF21 functions in humans. OBJECTIVE: The aim of the study was to measure plasma FGF21 during fasting, ketogenic diet, and PPAR agonist treatment in humans. DESIGN AND SETTING: We conducted a prospective study involving three patient groups at two university hospitals. PATIENTS: Eight healthy male volunteers underwent a 48-h period of starvation followed by 24-h refeeding (group 1); seven obese individuals were allocated to a low-carbohydrate diet for 3 months (group 2); and three groups of healthy, overweight or obese male volunteers received treatment with a PPAR alpha (20 microg/d GW590735) (n=6), PPAR delta (10 mg/d GW501516) (n=6), or PPAR gamma agonist (rosiglitazone) (n=10) for 2 wk (group 3). MAIN OUTCOME MEASURES: Fasting plasma FGF21 and serum 3-hydroxybutyrate were measured. RESULTS: There was no significant variation in human plasma FGF21 during fasting and refeeding. A 3-month ketogenic diet was associated with a 42% decline in plasma FGF21 levels. Circulating FGF21 increased significantly in response to treatment with PPAR alpha (39%) and PPAR delta (32%), but not PPAR gamma agonists. CONCLUSION: FGF21 does not play a major role in regulating the fasting response or ketosis in man. However, plasma FGF21 is elevated in response to pharmacological activation of PPAR alpha and PPAR delta and may contribute to the beneficial metabolic effects observed in response to pharmacotherapy with these compounds.

Lagathu C, Christodoulides C, Virtue S, Cawthorn WP, Franzin C, Kimber WA, Nora ED, Campbell M, Medina-Gomez G, Cheyette BN et al. 2009. Dact1, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the Wnt/beta-catenin signaling network. Diabetes, 58 (3), pp. 609-619. | Show Abstract | Read more

OBJECTIVE: Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Wnt modulator Dapper1/Frodo1 (Dact1) as a new preadipocyte gene involved in the regulation of murine and human adipogenesis. RESEARCH DESIGN AND METHODS: Changes in Dact1 expression were investigated in three in vitro models of adipogenesis. In vitro gain- and loss-of-function studies were used to investigate the mechanism of Dact1 action during adipogenesis. The in vivo regulation of Dact1 and Wnt/beta-catenin signaling were investigated in murine models of altered nutritional status, of pharmacological stimulation of in vivo adipogenesis, and during the development of dietary and genetic obesity. RESULTS: Dact1 is a preadipocyte gene that decreases during adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation of the Wnt/beta-catenin signaling pathway, and this is reversed by treatment with the secreted Wnt antagonist, secreted Frizzled-related protein 1 (Sfrp1). In contrast, constitutive Dact1 overexpression promotes adipogenesis and confers resistance to Wnt ligand-induced antiadipogenesis through increased expression of endogenous Sfrps and reduced expression of Wnts. In vivo, in white adipose tissue, Dact1 and Wnt/beta-catenin signaling also exhibit coordinated expression profiles in response to altered nutritional status, in response to pharmacological stimulation of in vivo adipogenesis, and during the development of dietary and genetic obesity. CONCLUSIONS: Dact1 regulates adipogenesis through coordinated effects on gene expression that selectively alter intracellular and paracrine/autocrine components of the Wnt/beta-catenin signaling pathway. These novel insights into the molecular mechanisms controlling adipose tissue plasticity provide a functional network with therapeutic potential against diseases, such as obesity and associated metabolic disorders.

Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A. 2009. Adipogenesis and WNT signalling. Trends Endocrinol Metab, 20 (1), pp. 16-24. | Show Abstract | Read more

An inability of adipose tissue to expand consequent to exhausted capacity to recruit new adipocytes might underlie the association between obesity and insulin resistance. Adipocytes arise from mesenchymal precursors whose commitment and differentiation along the adipocytic lineage is tightly regulated. These regulatory factors mediate cross-talk between adipose cells, ensuring that adipocyte growth and differentiation are coupled to energy storage demands. The WNT family of autocrine and paracrine growth factors regulates adult tissue maintenance and remodelling and, consequently, is well suited to mediate adipose cell communication. Indeed, several recent reports, summarized in this review, implicate WNT signalling in regulating adipogenesis. Manipulating the WNT pathway to alter adipose cellular makeup, therefore, constitutes an attractive drug-development target to combat obesity-associated metabolic complications.

Christodoulides C, Laudes M, Cawthorn WP, Schinner S, Soos M, O'Rahilly S, Sethi JK, Vidal-Puig A. 2006. The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis. J Cell Sci, 119 (Pt 12), pp. 2613-2620. | Show Abstract | Read more

Secretion of Wnts by adipose cells has an important role in the control of murine adipogenesis. We present the first evidence that a Wnt antagonist, Dickkopf 1 (Dkk1), is secreted by human preadipocytes and promotes adipogenesis. DKK1 mRNA increases six hours after onset of human adipogenesis and this is followed by an increase in Dkk1 protein. With further differentiation, the mRNA and protein levels progressively decline such that they are undetectable in mature adipocytes. The transient induction in DKK1 correlates with downregulation of cytoplasmic and nuclear beta-catenin levels, this being a surrogate marker of canonical Wnt signalling, and Wnt/beta-catenin transcriptional activity. In addition, constitutive expression of Dkk1 in 3T3-L1 preadipocytes promotes their differentiation, further supporting the functional significance of increased Dkk1 levels during human adipogenesis. Concomitant downregulation of the Dkk1 receptors LRP5 and LRP6 is likely to potentiate the ability of Dkk1 to inhibit Wnt signalling and promote differentiation. Notably, Dkk1 is not expressed in primary murine preadipocytes or cell lines. The involvement of Dkk1 in human but not murine adipogenesis indicates that inter-species differences exist in the molecular control of this process. Given the public health importance of disorders of adipose mass, further knowledge of the pathways involved specifically in human adipocyte differentiation might ultimately be of clinical relevance.

Christodoulides C, Scarda A, Granzotto M, Milan G, Dalla Nora E, Keogh J, De Pergola G, Stirling H, Pannacciulli N, Sethi JK et al. 2006. WNT10B mutations in human obesity. Diabetologia, 49 (4), pp. 678-684. | Show Abstract | Read more

AIMS/HYPOTHESIS: Recent studies suggest that wingless-type MMTV integration site family, member 10B (WNT10B) may play a role in the negative regulation of adipocyte differentiation in vitro and in vivo. In order to determine whether mutations in WNT10B contribute to human obesity, we screened two independent populations of obese subjects for mutations in this gene. SUBJECTS AND METHODS: We studied 96 subjects with severe obesity of early onset (less than 10 years of age) from the UK Genetics of Obesity Study and 115 obese Italian subjects of European origin. RESULTS: One proband with early-onset obesity was found to be heterozygous for a C256Y mutation, which abrogated the ability of WNT10B to activate canonical WNT signalling and block adipogenesis and was not found in 600 control alleles. All relatives of the proband who carried this allele were either overweight or obese. Three other rare missense variants were found in obese probands, but these did not clearly cosegregate with obesity in family studies and one (P301S), which was found in three unrelated subjects with early-onset obesity, had normal functional properties. CONCLUSIONS/INTERPRETATION: These mutations represent the first naturally occurring missense variants of WNT10B. While the pedigree analysis in the case of C256Y WNT10B does not provide definitive proof of a causal link of this variant with obesity, the finding of a non-functioning WNT10B allele in a human family affected by obesity should encourage further study of this gene in other obese populations.

Identifying new molecular players governing fat distribution and susceptibility to osteoporosis

Osteoporosis and obesity are 2 major public health problems arising from dysregulation of MSCs which give rise to both osteoblasts and adipocytes. Osteoporosis results from disordered bone remodelling where the bone-resorbing activity of osteoclasts exceeds the bone-forming activity of an insufficient osteoblast pool. Similarly, an inability of subcutaneous (SC) white adipose tissue (WAT) to adequately expand - by recruiting new adipocytes from MSCs - and safely store lipid in the face of ...

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