Alexander Sorisky

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

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Publications (92)454.51 Total impact

  • D Felske · A Gagnon · A Sorisky ·
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    ABSTRACT: Subclinical hypothyroidism, characterized by an isolated rise in TSH serum levels with normal thyroid function, is a pro-inflammatory state associated with insulin resistance. Adipocytes express TSH receptors, but it is not known if TSH can directly inhibit insulin signaling. Using primary human differentiated adipocytes, we examined the effects of TSH on insulin-stimulated Akt phosphorylation, and whether conventional PKC (cPKC) were involved. The effect of insulin on TSH-stimulated lipolysis was also investigated. TSH inhibited insulin-stimulated Akt phosphorylation in adipocytes by 54%. TSH activated cPKC, and Gö6976, a PKCα and -β1 inhibitor, prevented the inhibitory effect of TSH on the insulin response. Insulin reduced the ability of TSH to activate cPKC and to stimulate lipolysis.Our data reveal novel interactions between TSH and insulin. TSH inhibits insulin-stimulated Akt signaling in a cPKC-dependent fashion, whereas insulin blocks TSH-stimulated cPKC activity and lipolysis. TSH and insulin act on differentiated human adipocytes to modulate their respective intracellular signals. © Georg Thieme Verlag KG Stuttgart · New York.
    Hormone and Metabolic Research 12/2014; 47(09). DOI:10.1055/s-0034-1395673 · 2.12 Impact Factor
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    ABSTRACT: Thyroid-stimulating hormone (TSH) acts on extra-thyroidal targets. When recombinant human (rh)TSH is administered to patients treated for thyroid cancer (thyroidectomy and radioablation) to screen for recurrence, metabolic and vascular stress occurs. This is indicated by elevations in levels of interleukin (IL)-6, C-reactive protein (CRP), oxidative stress, and free fatty acids (FFA), as well as a decrease in endothelium-dependent relaxationThis article is protected by copyright. All rights reserved.
    Clinical Endocrinology 12/2014; 83(2). DOI:10.1111/cen.12709 · 3.46 Impact Factor
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    Irena Druce · T C Ooi · Debbie McGuire · Alexander Sorisky · Janine Malcolm ·
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    ABSTRACT: Objective Informed consent and protection of patient confidentiality are central to the conduction of clinical research. Consent for chart review and contact (CCRC) allows a patient chart to be screened for research by persons outside the direct circle-of-care and for the patient to be contacted regarding potential studies. This study describes the process of implementation and benefits of such a consent. Design We present a descriptive report of a CCRC document that was created and presented to patients over a 3.5-year period at a tertiary care Endocrinology and Metabolism centre. To assess the potential impact of such a document on patient recruitment, the basic demographics of patients who did and did not consent were compared. In addition, we compared the recruitment rate at our centre, using our novel approach, with that at other centres for an ongoing study of patients with type 1 diabetes. Results A large proportion (6501/8025, or 81%) of patients gave their consent for chart review. Patients who denied consent were more likely to be women and older. Compared with other centres, our centre recruited at the highest rate for a known study of patients with type 1 diabetes. The majority (46/60, or 76.7%) of patients were recruited via the novel approach. Conclusions Consent for chart review and contact addresses several important ethical issues regarding the use of patient clinical information for research purposes. Our study demonstrated how such a process can be implemented.
    Journal of Medical Ethics 09/2014; 41(5). DOI:10.1136/medethics-2013-101765 · 1.51 Impact Factor
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    ABSTRACT: Objective Adipose tissue is an extra-thyroidal thyroid-stimulating hormone (TSH) target. Increases in lipolysis and in expression and release of interleukin-6 occur in TSH-stimulated adipocytes, and levels of circulating free fatty acids and interleukin-6 rise following TSH administration to patients with previous thyroidectomy and radioablation for thyroid cancer. Our first objective was to compare how TSH stimulates protein kinase A and inhibitor of κB (IκB) kinase (IKK)-β. Our second objective was to investigate whether TSH induces other cytokines besides IL-6. Methods TSH stimulation of either CHO cells expressing human TSH receptor or human abdominal subcutaneous differentiated adipocytes. Results Signaling studies showed TSH increased NADPH oxidase activity, and either diphenyleneiodonium (oxidase inhibitor) or N-acetyl cysteine (scavenger of reactive oxygen species) reduced IKKβ phosphorylation. Phosphorylation of protein kinase C–δ, an upstream regulator of NADPH oxidase, was increased by TSH, and rottlerin (PKCδ inhibitor) reduced TSH-stimulated IKKβ phosphorylation. TSH upregulated monocyte chemoattractant protein-1 (MCP-1) mRNA expression and the release of MCP-1 protein in human abdominal differentiated adipocytes. H89 (PKA inhibitor) and sc-514 (IKKβ inhibitor) each blocked TSH-stimulated MCP-1 mRNA expression and protein release, suggesting protein kinase A and IKKβ participate in this pathway. Conclusions These data provide new information about TSH signaling in human differentiated adipocytes, and add to the evidence that TSH is a pro-inflammatory stimulus of adipocytes.
    Metabolism: clinical and experimental 06/2014; 63(6). DOI:10.1016/j.metabol.2014.02.015 · 3.89 Impact Factor
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    Annemarie Gagnon · Moeber Mahzari · Heather A Lochnan · Alexander Sorisky ·
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    ABSTRACT: It is now recognized that TSH can act on targets other than the thyroid, including the liver. Elevated serum TSH levels in euthyroid subjects were recently reported to correlate with high values of serum proprotein convertase subtilisin/kexin type 9 (PCSK9). This protein, expressed and secreted by hepatocytes, promotes higher LDL-cholesterol levels. We tested whether an acute increase of TSH levels following administration of TSH in vivo would raise PCSK9 levels in patients who had previously undergone total thyroidectomy and radioablation for thyroid cancer. TSH levels rose from 0.64 ± 1.02 mU/L on day 1 to 98.66 ± 4.83 mU/L on day 3, following injections of recombinant human TSH (on days 1 and 2). PCSK9 levels were 330 ± 99 ng/ml on day 1, and did not change on days 3 or 5 in response to TSH stimulation. Although a positive correlation between TSH and PCSK9 in euthyroid subjects has raised the possibility that TSH might act on the liver to raise PCSK9 values, our data show that PCSK9 levels are not affected by acute elevations of TSH levels. Whether chronic elevations of TSH are needed to upregulate PCSK9 remains to be determined.
    Thyroid Research 05/2014; 7(1):4. DOI:10.1186/1756-6614-7-4
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    ABSTRACT: Objectives Serum low density lipoprotein-cholesterol (LDL-C) correlates positively with serum PCSK9 in the general population, consistent with PCSK9 being a determinant of LDL-C levels. Patients with chronic kidney disease (CKD) on hemodialysis (HD) have lower total cholesterol (TC) and LDL-C compared to the general population. Serum PCSK9 and its relationship with serum lipids have not been reported in CKD patients on HD (CKD-HD). Methods We measured serum PCSK9 by ELISA and lipid levels in 66 CKD-HD patients and compared them to 178 non-CKD subjects. Since statins increase serum PCSK9 levels, CKD-HD patients were separated into those not on statin therapy (HD-NS, n=32) and those taking statins (HD-S, n=34). No control subjects were on statin therapy. Results Serum PCSK9, TC, LDL-C and HDL-C levels were significantly lower in the CKD-HD group (n=66) compared to the control group. HD-NS patients showed lower PCSK9, TC and LDL-C levels than control subjects and PCSK9 levels correlated with TC and LDL-C levels (r=0.35, p=0.050; r=0.423, p=0.0158 respectively) as well as TG levels (r=0.413, p=0.0188). In HD-S patients, PCSK9 levels were not significantly different from the non-CKD group. There was no correlation between PCSK9 levels and TC and LDL-C levels in the HD-S group. Conclusion Our data are the first quantitative analysis of serum PCSK9 levels in CKD-HD patients. We show that serum PCSK9 in HD-NS patients is decreased and it retains a positive correlation with LDL-C, suggesting that PCSK9 may remain a significant determinant of LDL-C in CKD-HD subjects. We also show that statin therapy disrupts the correlation between LDL-C and PCSK9 in CKD-HD patients. These data suggest that the regulation of LDL-C by PCSK9 remains intact in CKD-HD patients. PCSK9 may also play a role in the metabolism of triglyceride-rich lipoproteins in CKD-HD patients.
    Atherosclerosis 03/2014; 233(1). DOI:10.1016/j.atherosclerosis.2013.12.030 · 3.99 Impact Factor
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    ABSTRACT: Purpose: Fetuin-A is a hepatokine that is linked to lipid metabolism, obesity, insulin resistance, type 2 diabetes and cardiovascular disease. Elevated thyroid-stimulating hormone (TSH) levels are associated with metabolic and cardiovascular disturbances. Our aim was to determine if TSH can regulate fetuin-A levels. Methods: Fetuin-A serum levels were examined in 26 subjects (19 women; previous thyroidectomy and radioactive iodine ablation) undergoing recombinant human TSH (rhTSH) stimulation to screen for thyroid cancer recurrence. Their age was 49±10 years, and body mass index (BMI) was 28±6 (both expressed as mean±SD). The patients received two doses of rhTSH (0.9 mg), administered 24 hours apart on days 1 and 2, without discontinuation of ongoing L-thyroxine therapy. Morning blood samples were obtained on days 1 (prior to the first dose of rhTSH), 3 and 5. Results: The baseline value of fetuin-A (mean±SD) for all participants was 527±186 mg/L. Values of fetuin-A did not change in response to rhTSH administration. The lack of response was not dependent on gender, age, baseline free thyroxine level or BMI. Conclusion: Fetuin-A has been implicated in metabolic and inflammatory conditions, but there have been no reports on whether fetuin-A is influenced by TSH. Within the context of rhTSH administration for surveillance of thyroid cancer recurrence, there was no effect on serum levels of fetuin-A.
    Clinical and investigative medicine. Medecine clinique et experimentale 10/2013; 36(5):E264. · 1.23 Impact Factor
  • Amanda Biernacka-Larocque · Annemarie Gagnon · Alexander Sorisky ·

    Canadian Journal of Diabetes 10/2013; 37S4:S67. DOI:10.1016/j.jcjd.2013.08.203 · 2.00 Impact Factor
  • H Abujrad · J Mayne · M Ruzicka · M Cousins · R Angela · J Cheesman · A Sorisky · K Burns · T Ooi ·

    The Canadian journal of cardiology 10/2013; 29(10):S179. DOI:10.1016/j.cjca.2013.07.280 · 3.71 Impact Factor
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    ABSTRACT: Macrophage infiltration into adipose tissue is associated with obesity and the crosstalk between adipocytes and infiltrated macrophages has been investigated as an important pathological phenomenon during adipose tissue inflammation. Here, we sought to identify adipocyte mRNAs that are regulated by interaction with infiltrated macrophages in vivo. An anti-inflammatory vitamin, vitamin B6, suppressed macrophage infiltration into white adipose tissue and altered mRNA expression. We identified >3500 genes whose expression is significantly altered during the development of obesity in db/db mice, and compared them to the adipose tissue mRNA expression profile of mice supplemented with vitamin B6. We identified PTX3 and MMP3 as candidate genes regulated by macrophage infiltration. PTX3 and MMP3 mRNA expression in 3T3-L1 adipocytes was up-regulated by activated RAW264.7 cells and these mRNA levels were positively correlated with macrophage number in adipose tissue in vivo. Next, we screened adipose genes down-regulated by the interaction with macrophages, and isolated RASSF6 (Ras association domain family 6). RASSF6 mRNA in adipocytes was decreased by culture medium conditioned by activated RAW264.7 cells, and RASSF6 mRNA level was negatively correlated with macrophage number in adipose tissue, suggesting that adipocyte RASSF6 mRNA expression is down-regulated by infiltrated macrophages in vivo. Finally, this study also showed that decreased RASSF6 expression up-regulates mRNA expression of several genes, such as CD44 and high mobility group protein HMGA2. These data provide novel insights into the biological significance of interactions between adipocytes and macrophages in adipose tissue during the development of obesity.
    PLoS ONE 04/2013; 8(4):e61931. DOI:10.1371/journal.pone.0061931 · 3.23 Impact Factor
  • Annemarie Gagnon · Charlie Foster · Anne Landry · Alexander Sorisky ·
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    ABSTRACT: When adipose tissue accumulates in obesity, the ability of preadipocytes to differentiate permits a hyperplastic expansion of functional adipocytes that preserves insulin sensitivity. Adipose infiltration by macrophages is associated with an adipogenic deficit and the appearance of inflamed, insulin-resistant hypertrophied adipocytes. Interleukin (IL)-1β has been reported to account for the anti-adipogenic action of macrophages in a mouse model. Using the THP-1 human macrophage cell line and human primary preadipocytes, our objective was to determine if IL-1β was necessary for the ability of conditioned medium from THP-1 macrophages (THP-1-MacCM) to 1) stimulate human preadipocyte inhibitor of κB kinase (IKK) β and 2) inhibit human adipocye differentiation. IL-1β is present in THP-1-MacCM, and THP-1-MacCM or IL-1β (500 pg/ml; its concentration in THP-1-MacCM) acutely stimulated IKKβ phosphorylation and inhibitor of κB (IκB) degradation in preadipocytes. IL-1β was sufficient to inhibit adipogenesis on its own, and this was blocked by sc-514, an inhibitor of IKKβ, as has been reported for THP-1-MacCM. IκB degradation by IL-1β-immunodepleted THP-1-MacCM was attenuated, whereas IKKβ phosphorylation and inhibition of adipocyte differentiation was unchanged. Therefore, in contrast to what has been suggested for mouse cell models, IL-1β is not required for the ability of MacCM to inhibit adipogenesis in human cell models.
    Journal of Endocrinology 03/2013; 217(2). DOI:10.1530/JOE-12-0565 · 3.72 Impact Factor
  • Alexander Sorisky · André S D Molgat · Annemarie Gagnon ·
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    ABSTRACT: Adipose tissue can be regarded as a multidepot organ responsible for metabolic homeostasis by managing sophisticated energy transactions as well as by producing bioactive molecules that regulate insulin sensitivity and immune and vascular responses. Chronic nutrient excess expands adipose tissue, and concomitant variations in its cellular and matrix remodeling can affect the extent of the metabolic dysfunction that is associated with obesity. Preadipocytes, also termed adipose progenitor cells, play a pivotal role in determining whether a dysfunctional hypertrophic state arises as opposed to a hyperplastic process in which mature adipocytes remain relatively responsive. Obesity is associated with infiltration of macrophages, and these immune cells have been shown to communicate with preadipocytes to influence how they differentiate, survive, and proliferate. Understanding macrophage-preadipocyte interactions and their effect on adipose remodeling mechanisms may identify potential therapeutic molecular targets to improve adipose tissue function, even in the face of obesity.
    Advances in Nutrition 01/2013; 4(1):67-75. DOI:10.3945/an.112.003020 · 4.71 Impact Factor
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    ABSTRACT: Impaired glucose tolerance and impaired fasting glucose, referred to as prediabetes, are predisease states that may progress to type 2 diabetes mellitus. The value of intervening in these states, especially with respect to cardiovascular outcomes, is unclear. The purpose of this study was to develop a broad synopsis of the available literature through an evidence map of systematic reviews about interventions in adults with prediabetes. The Cochrane Library Issue 4, 2011, Ovid MEDLINE (1946-January 4, 2012) and grey literature were searched. Studies were selected according to defined eligibility criteria. Fourteen relevant systematic reviews, of mostly high quality, were retrieved. The majority of reviews evaluated pharmacotherapeutic interventions or diet/exercise/lifestyle. A few reviews assessed complementary alternative medicine, behavioural strategies, standard prevention education or gastric bypass surgery. Very few reviews reported data on clinical cardiovascular endpoints. Most reviews reported either shorter-term surrogate markers of cardiovascular outcomes or progression to type 2 diabetes mellitus. Based on an assessment of authors' overall conclusions, the value of pharmacotherapeutic interventions and diet/exercise/lifestyle ranged from beneficial to inconclusive, behavioural strategies were beneficial, and gastric bypass surgery was probably beneficial. The value of complementary alternative medicine was inconclusive. A considerable amount of evidence pertaining to interventions in prediabetes exists. Future research should synthesize the available systematic review evidence base in an overview of reviews. In addition, more primary research should be conducted to assess clinical cardiovascular endpoints. (C) 2012 Canadian Diabetes Association
    Canadian Journal of Diabetes 10/2012; 36(5):281–291. DOI:10.1016/j.jcjd.2012.06.004 · 2.00 Impact Factor
  • Annemarie Gagnon · Michelle N Yarmo · Anne Landry · Alexander Sorisky ·
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    ABSTRACT: Adipose tissue of obese individuals is characterized by increased fibrosis and macrophage infiltration. Extensive remodeling of the extracellular matrix (ECM) that occurs during adipogenesis can be influenced by macrophages, but it remains unclear how macrophage-secreted factors alter preadipocyte ECM protein expression under non-adipogenic versus adipogenic conditions. Confluent human subcutaneous abdominal preadipocytes were cultured for 14 days, with or without adipogenic inducers, in either control medium, medium conditioned by THP-1 monocytes (THP-1-MonCM), or medium conditioned by THP-1 macrophages (THP-1-MacCM). Under non-adipogenic conditions in THP-1-MacCM, collagen I/III and fibronectin protein levels rose by 40 and 70 %, respectively (p < 0.05, n = 3; compared to control non-adipogenic medium). When preadipocytes were exposed to adipogenic inducers in THP-1-MacCM, collagen I/III levels increased by 50 %, but those of fibronectin fell by 48 %, both compared to non-adipogenic THP-1-MacCM conditions. The rise in collagen I/III levels contrasts with the 51 % decrease in collagen I/III that occurs with induction of differentiation in control medium, whereas, the decrease in fibronectin is more modest, but consistent in THP-1-MacCM (48 %) and control medium (92 %). A similar effect on fibronectin levels occurred using medium conditioned by LPS-treated human monocyte-derived macrophages (MD-MacCM). Our data indicate macrophage-derived factors regulate levels of collagen I/III and fibronectin in preadipocytes under non-adipogenic and adipogenic conditions. Further studies are needed to determine if these changes in these ECM proteins contribute to the anti-adipogenic action of MacCM.
    Lipids 07/2012; 47(9):873-80. DOI:10.1007/s11745-012-3696-8 · 1.85 Impact Factor
  • A B Thrush · A Gagnon · A Sorisky ·
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    ABSTRACT: Adipocytes express TSH receptors, and TSH can stimulate cAMP-dependent protein kinase, perilipin phosphorylation, and lipolysis in human and mouse 3T3-L1 adipocytes. TSH activates PKC in thyrocytes. Since PKC has been implicated in lipolysis in adipocytes, we examined whether the family of conventional isoforms of PKC (cPKC) is a target of TSH in adipocytes, and whether cPKC is required for TSH-stimulated lipolysis. Differentiated 3T3-L1 and subcutaneous abdominal human adipocytes in culture were treated with TSH in the presence or absence of either PKC inhibitor Gö6976 (inhibits PKCα, βI) or Gö6983 (inhibits PKCα, βI, βII, γ, δ). Activation of cPKC was assessed by phospho-(ser) PKC substrate antibody immunoblot analysis. Perilipin phosphorylation was measured by SDS-PAGE electromobility shift followed by anti-perilipin immunoblot analysis. Lipolysis was quantified by the amount of nonesterified fatty acids (NEFAs) released into the medium. TSH strongly and significantly activated cPKC in differentiated human and 3T3-L1 adipocytes from undetectable levels in control conditions. This cPKC stimulation in human adipocytes by TSH was reduced significantly by 40% or 48% in the presence of PKC inhibitor Gö6983 or Gö6976, respectively. Gö6976 inhibited TSH-stimulated human adipocyte perilipin phosphorylation and NEFA release by 80% and 50%, respectively. We conclude that cPKC is activated by TSH in human differentiated adipocytes. Based on the effects of cPKC inhibition, cPKC activation is required for TSH-stimulated perilipin phosphorylation and lipolysis in human differentiated adipocytes.
    Hormone and Metabolic Research 06/2012; 44(11):825-31. DOI:10.1055/s-0032-1316332 · 2.12 Impact Factor
  • André S D Molgat · AnneMarie Gagnon · Charlie Foster · Alexander Sorisky ·
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    ABSTRACT: Adipose tissue contains macrophages whose state of activation is regulated as obesity develops. Macrophage-secreted factors influence critical processes involved in adipose tissue homeostasis, including preadipocyte proliferation and differentiation into adipocytes. Macrophage-conditioned medium (MacCM) from J774A.1 macrophages protects 3T3-L1 preadipocytes from apoptosis through platelet-derived growth factor (PDGF) signaling. Here, we investigated the effect of macrophage activation on MacCM-dependent preadipocyte survival. MacCM was prepared following activation of either J774A.1 macrophages with lipopolysaccharide (LPS) or human primary monocyte-derived macrophages (MD-macrophages) with LPS or interleukin 4 (IL4). 3T3-L1 and human primary preadipocytes were induced to undergo apoptosis in MacCM, and apoptosis was quantified by cell enumeration or Hoechst nuclear staining. Preadipocyte PDGF signaling was assessed by immunoblot analysis of phosphorylated PDGF receptor, Akt, and ERK1/2. Pro-inflammatory activation of J774A.1 macrophages with LPS inhibited the pro-survival activity of MacCM on 3T3-L1 preadipocytes, despite intact PDGF signaling. Upregulation of macrophage tumor necrosis factor a (TNFα) expression occurred in response to LPS, and TNFα was demonstrated to be responsible for the inability of LPS-J774A.1-MacCM to inhibit preadipocyte apoptosis. Furthermore, MacCM from human MD-macrophages (MD-MacCM) inhibited apoptosis of primary human preadipocytes. MD-MacCM from LPS-treated macrophages, but not IL4-treated anti-inflammatory macrophages, was unable to protect human preadipocytes from cell death. In both murine cell lines and human primary cells, pro-inflammatory activation of macrophages inhibits their pro-survival activity, favoring preadipocyte death. These findings may be relevant to preadipocyte fate and adipose tissue remodeling in obesity.
    Journal of Endocrinology 05/2012; 214(1):21-9. DOI:10.1530/JOE-12-0114 · 3.72 Impact Factor
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    ABSTRACT: We reported aldosterone as a novel adipocyte-derived factor that regulates vascular function. We aimed to investigate molecular mechanisms, signaling pathways, and functional significance of adipocyte-derived aldosterone and to test whether adipocyte-derived aldosterone is increased in diabetes mellitus-associated obesity, which contributes to vascular dysfunction. Studies were performed in the 3T3-L1 adipocyte cell line and mature adipocytes isolated from human and mouse (C57BL/6J) adipose tissue. Mesenteric arteries with and without perivascular fat and mature adipocytes were obtained from obese diabetic db/db and control db/+ mice. Aldosterone synthase (CYP11B2; mRNA and protein) was detected in 3T3-L1 and mature adipocytes, which secrete aldosterone basally and in response to angiotensin II (Ang II). In 3T3-L1 adipocytes, Ang II stimulation increased aldosterone secretion and CYP11B2 expression. Ang II effects were blunted by an Ang II type 1 receptor antagonist (candesartan) and inhibitors of calcineurin (cyclosporine A and FK506) and nuclear factor of activated T-cells (VIVIT). FAD286 (aldosterone synthase inhibitor) blunted adipocyte differentiation. In candesartan-treated db/db mice (1 mg/kg per day, 4 weeks) increased plasma aldosterone, CYP11B2 expression, and aldosterone secretion were reduced. Acetylcholine-induced relaxation in db/db mesenteric arteries containing perivascular fat was improved by eplerenone (mineralocorticoid receptor antagonist) without effect in db/+ mice. Adipocytes possess aldosterone synthase and produce aldosterone in an Ang II/Ang II type 1 receptor/calcineurin/nuclear factor of activated T-cells-dependent manner. Functionally adipocyte-derived aldosterone regulates adipocyte differentiation and vascular function in an autocrine and paracrine manner, respectively. These novel findings identify adipocytes as a putative link between aldosterone and vascular dysfunction in diabetes mellitus-associated obesity.
    Hypertension 04/2012; 59(5):1069-78. DOI:10.1161/HYPERTENSIONAHA.111.190223 · 6.48 Impact Factor
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    Scientific Sessions of High Blood Pressure Research; 11/2011
  • Chetna Tailor · Iris Teo · Alexander Sorisky ·

    Clinical neurology and neurosurgery 09/2011; 113(9):810-2. DOI:10.1016/j.clineuro.2011.08.015 · 1.13 Impact Factor
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    ABSTRACT: Macrophage infiltration into adipose tissue, associated with obesity, is thought to contribute to abnormal adipose tissue remodeling, low-grade inflammation, and insulin resistance. Medium conditioned by macrophages (MacCM) inhibits 3T3-L1 and human adipocyte differentiation, as well as early adipogenic cell cycle events including MCE and retinoblastoma protein (Rb) phosphorylation. Our objective was to determine if the inhibition of Rb phosphorylation was linked to changes in cell cycle-related proteins. We treated 3T3-L1 preadipocytes with adipogenic inducers for 24 h in control medium versus J774A.1-MacCM. The differentiation-induced mRNA and protein expression of cyclin A, an activator of cyclin-dependent kinase (cdk) 2 which phosphorylates Rb, was inhibited by 82% and 73%, respectively, by J774A.1-MacCM; adipogenic expression of Myc, a transcriptional regulator of cyclin A, was also suppressed significantly. Consistent with the reduction in cyclin A levels, the activation of cdk2 by adipogenic inducers was inhibited by 75% by J774A.1-MacCM. J774A.1-MacCM also lowered levels of cyclins D1 and D2. Inhibition studies demonstrated that platelet-derived growth factor, an anti-adipogenic factor found in J774A.1-MacCM, was not responsible for the inhibitory effect on differentiation. The anti-adipogenic effect of J774A.1-MacCM was resistant to proteinase K and heat treatment, and was present in a <3 kDa fraction. Our data indicate that J774A.1-MacCM interferes with the upregulation of cyclin A levels and cdk2 activity that are required for Rb phosphorylation and MCE in 3T3-L1 adipogenesis.
    Journal of Cellular Physiology 09/2011; 226(9):2297-306. DOI:10.1002/jcp.22566 · 3.84 Impact Factor

Publication Stats

2k Citations
454.51 Total Impact Points


  • 2005-2014
    • Ottawa Hospital Research Institute
      • Chronic Disease Program
      Ottawa, Ontario, Canada
  • 1996-2014
    • University of Ottawa
      • • Department of Medicine
      • • Department of Biochemistry, Microbiology and Immunology
      Ottawa, Ontario, Canada
  • 1995-2013
    • The Ottawa Hospital
      • Department of Medicine
      Ottawa, Ontario, Canada
  • 2002
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1992
    • University of Vermont Medical Center
      Burlington, Vermont, United States
    • Thomas Jefferson University
      • Division of Clinical Pharmacology
      Filadelfia, Pennsylvania, United States
  • 1991
    • University of Vermont
      • Department of Biochemistry
      Burlington, Vermont, United States