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Papers by Bee Tan

Research paper thumbnail of Nesfatin-1 inhibits proliferation and enhances apoptosis of human adrenocortical H295R cells

The Journal of endocrinology, Jan 13, 2015

NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexi... more NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 is expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 gen...

Research paper thumbnail of Copyright: American Diabetes Association

in Cysteine (SPARC), originally discovered in bone as osteonec-tin, is a mediator of collagen dep... more in Cysteine (SPARC), originally discovered in bone as osteonec-tin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. RESEARCH DESIGN AND METHODS—Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 3.7 kg). Another six lean subjects underwent fast-food– based hyperalimentation for 4 weeks (weight gain: 7.2 1.6 kg).

Research paper thumbnail of Chemerin induces endothelial cell inflammation: activation of nuclear factor-kappa beta and monocyte-endothelial adhesion

Oncotarget, Jan 30, 2018

Chemerin, a chemoattractant protein, acts a G-protein coupled chemokine receptor, Chemokine like ... more Chemerin, a chemoattractant protein, acts a G-protein coupled chemokine receptor, Chemokine like Receptor 1/ChemR23; levels of which are elevated in pro-inflammatory states such as obesity and type 2 diabetes mellitus (T2DM). Obesity and T2DM patients are at high risk of developing cardiovascular disorders such as atherosclerosis. We have reported that chemerin induces human endothelial cell angiogenesis and since dysregulated angiogenesis and endothelial dysfunction are hallmarks of vascular disease; we sought to determine the effects of chemerin on monocyte-endothelial adhesion, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a critical pro-inflammatory transcription factor. Human endothelial cells were transfected with pNF-kappaB-Luc plasmid. Chemerin induced NF-κB activation the MAPK and PI3K/Akt pathways. Western blot analyses and monocyte-endothelial adhesion assay showed that chemerin increased endothelial cell adhesion molecule expression and secr...

Research paper thumbnail of Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation

Health technology assessment (Winchester, England), 2017

Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight... more Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse event...

Research paper thumbnail of Insulin and glucose regulates omentin-1, a novel adipokine: relation to women with the polycyastic ovary synfrome

Research paper thumbnail of Abstract 14435: Adipolin, a Novel Adipokine, is a Novel Cardioprotective Molecule in the Ischemic Rat Heart

Circulation, Nov 26, 2013

Research paper thumbnail of The Hepatokine Fetuin-A is increased in PCOS women. Association with metabolic syndrome and regulation by metformin

Research paper thumbnail of Increased ERK activation and cellular drug accumulation in the enhanced cytotoxicity of folate receptor-targeted liposomal carboplatin

International Journal of Oncology, Mar 1, 2012

Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-posit... more Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-positive and FR-negative cell lines, KB and A549, respectively, for their cytotoxic effects. Significant enhancement in carboplatin potency and intracellular drug accumulation was observed in KB cells when treated with FRT liposomes, compared to free drug and non-targeted liposomes. No enhancement was observed in the FR-negative A549 cells. The increase in carboplatin potency was hypothesized to be associated with an increase in the formation of DNA-platinum adducts resulted from an increase in cellular accumulation of the drug. Surprisingly, FRT carboplatin liposomes showed significantly lower levels of DNA-platinum adducts in comparison to free drug. To elucidate this discrepancy, activation of extracellular signal-regulated protein kinase (ERK) was probed, which has been suggested as an alternative mechanism of carboplatin action. FRT liposomes loaded with carboplatin exhibited the highest level of ERK phosphorylation, and the cytotoxic effect of FRT carboplatin liposomes could be reversed by the MEK/ERK inhibitors, U0126 and PD98059. Importantly, empty FRT liposomes could significantly increase ERK phosphorylation in a concentration-dependent manner without causing toxicity to cells. For the first time, increased potency of carboplatin delivered by FRT liposomes was found to be associated with other molecular targets in addition to DNA-platinum adduct formation. Collectively, the current study suggests a novel mechanism by which FRT liposomes could sensitize cancer cells to drug treatment via modulation of ERK-related cell survival signals.

Research paper thumbnail of Positive correlation between serum omentin and thrombospondin-1 in gestational diabetes despite lack of correlation with insulin resistance indices

Ginekologia polska, 2010

Gestational Diabetes (GDM) is characterized by insulin resistance and a pro-inflammatory state, b... more Gestational Diabetes (GDM) is characterized by insulin resistance and a pro-inflammatory state, both factors possible related to adipokine expression. The study included 20 women with GDM, diagnosed according to the WHO criteria, and 23 matched for age and BMI women with normal glucose tolerance. Omentin and TSP-1 were measured by ELISA assays. Insulin resistance was assessed by HOMA and Insulin Resistance Index (IRI). There were no significant differences in omentin and TSP-1 levels between subjects with GDM and controls (48.0 +/- 12.0 ng/ml versus 50.2 +/- 7.9 ng/ml and 2150 +/- 1661 ng/ml versus 1569 +/- 1160 ng/ml, p = 0.64 and p = 0.29, for omentin and TSP-1 in GDM and control subjects, respectively). There was no significant correlation between either omentin or TSP-1 with HOMA or IRI, however there was a significant positive correlation between thrombospondin-1 and omentin (r = 0.49, p = 0.010). There was also a positive correlation between serum omentin and glucose levels at...

Research paper thumbnail of Brown adipose tissue: endocrine determinants of function and therapeutic manipulation as a novel treatment strategy for obesity

BMC Obesity, 2014

Introduction: Recent observation of brown adipose tissue (BAT) being functional in adult humans p... more Introduction: Recent observation of brown adipose tissue (BAT) being functional in adult humans provides a rationale for its stimulation to increase energy expenditure through 'adaptive thermogenesis' for an anti-obesity strategy. Many endocrine dysfunctions are associated with changes in metabolic rate that over time may result in changes in body weight. It is likely that human BAT plays a role in such processes.

Research paper thumbnail of Differential Effects of Leptin and Adiponectin in Endothelial Angiogenesis

Journal of diabetes research, 2015

Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality... more Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality. Endothelial dysfunction is pivotal to the development of cardiovascular disease (CVD). In relation to this, adipose tissue secreted factors termed "adipokines" have been reported to modulate endothelial dysfunction. In this review, we focus on two of the most abundant circulating adipokines, that is, leptin and adiponectin, in the development of endothelial dysfunction. Leptin has been documented to influence a multitude of organ systems, that is, central nervous system (appetite regulation, satiety factor) and cardiovascular system (endothelial dysfunction leading to atherosclerosis). Adiponectin, circulating at a much higher concentration, exists in different molecular weight forms, essentially made up of the collagenous fraction and a globular domain, the latter being investigated minimally for its involvement in proinflammatory processes including activation of NF-κβ and ...

Research paper thumbnail of Increased ERK activation and cellular drug accumulation in the enhanced cytotoxicity of folate receptor-targeted liposomal carboplatin

International Journal of Oncology, 2011

Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-posit... more Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-positive and FR-negative cell lines, KB and A549, respectively, for their cytotoxic effects. Significant enhancement in carboplatin potency and intracellular drug accumulation was observed in KB cells when treated with FRT liposomes, compared to free drug and non-targeted liposomes. No enhancement was observed in the FR-negative A549 cells. The increase in carboplatin potency was hypothesized to be associated with an increase in the formation of DNA-platinum adducts resulted from an increase in cellular accumulation of the drug. Surprisingly, FRT carboplatin liposomes showed significantly lower levels of DNA-platinum adducts in comparison to free drug. To elucidate this discrepancy, activation of extracellular signal-regulated protein kinase (ERK) was probed, which has been suggested as an alternative mechanism of carboplatin action. FRT liposomes loaded with carboplatin exhibited the highest level of ERK phosphorylation, and the cytotoxic effect of FRT carboplatin liposomes could be reversed by the MEK/ERK inhibitors, U0126 and PD98059. Importantly, empty FRT liposomes could significantly increase ERK phosphorylation in a concentration-dependent manner without causing toxicity to cells. For the first time, increased potency of carboplatin delivered by FRT liposomes was found to be associated with other molecular targets in addition to DNA-platinum adduct formation. Collectively, the current study suggests a novel mechanism by which FRT liposomes could sensitize cancer cells to drug treatment via modulation of ERK-related cell survival signals.

Research paper thumbnail of Decidualization Induces a Secretome Switch in Perivascular Niche Cells of the Human Endometrium

The endometrial perivascular microenvironment is rich in mesenchymal stem-like cells that express... more The endometrial perivascular microenvironment is rich in mesenchymal stem-like cells that express type 1 integral membrane protein Sushi domain containing 2 (SUSD2) but the role of these cells in the decidual transformation of this tissue in pregnancy is unknown. We used an antibody directed against SUSD2 (W5C5) to isolate perivascular (W5C5 ϩ ) and non-perivascular (W5C5 -) fibroblasts from mid-luteal biopsies. We show that SUSD2 expression, and hence the ratio of W5C5 ϩ to W5C5cells, changes in culture depending on cell-cell contact and activation of the Notch signaling pathway. RNA sequencing revealed that cultures derived from W5C5 ϩ progenitor cells remain phenotypically distinct by the enrichment of novel and established endometrial perivascular signature genes. In an undifferentiated state, W5C5 ϩ -derived cells produced lower levels of various chemokines and inflammatory modulators when compared to their W5C5counterparts. This divergence in secretomes was switched and became more pronounced upon decidualization, which transformed perivascular W5C5 ϩ cells into the dominant source of a range of chemokines and cytokines, including leukemia inhibitory factor and chemokine (C-C motif) ligand 7. Our findings indicate that the decidual response is spatially organized at the embryo-maternal interface with differentiating perivascular cells establishing distinct cytokine and chemokine profiles that could potentially direct trophoblast towards maternal vessels and govern local immune responses in pregnancy.

Research paper thumbnail of Direct inhibitors of InhA are active against Mycobacterium tuberculosis

Science translational medicine, Jan 7, 2015

New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resist... more New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)-dependent manner and blocked the enoyl substrate-binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rat...

Research paper thumbnail of Omentin: A Novel Link Between Inflammation, Diabesity, and Cardiovascular Disease

Trends in Cardiovascular Medicine, 2010

Obesity has reached pandemic proportions and is associated with serious cardiometabolic sequelae ... more Obesity has reached pandemic proportions and is associated with serious cardiometabolic sequelae including insulin resistance, diabetes, dyslipidemia, hypertension, and cardiovascular disease, where adipose tissue-secreted cytokines, that is, adipokines, have been implicated in these processes. Omentin is a novel adipokine preferentially produced by visceral adipose tissue with insulin-sensitizing effects, where circulating levels are decreased in insulin-resistant states, for example, obesity and diabetes. With respect to vascular biology, omentin causes vasodilatation of blood vessels and attenuates C-reactive protein-induced angiogenesis potentially via the nuclear factor B signaling pathway, a potent proinflammatory signaling pathway. Thus, omentin may have beneficial effects on the metabolic syndrome and could potentially be used as a biologic marker and/or pharmacologic agent in this respect.

Research paper thumbnail of A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy

Nature Communications, 2010

Candidate antibacterials are usually identifi ed on the basis of their in vitro activity. However... more Candidate antibacterials are usually identifi ed on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo . In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine -imidazoles (PIs) were identifi ed in a whole-cell screen against Mycobacterium tuberculosis . Lead optimization generated in vitro potent derivatives with desirable pharmacokinetic properties, yet without in vivo effi cacy. Mechanism of action studies linked the PI activity to glycerol metabolism, which is not relevant for M. tuberculosis during infection. PIs induced self-poisoning of M. tuberculosis by promoting the accumulation of glycerol phosphate and rapid ATP depletion. This study underlines the importance of understanding central bacterial metabolism in vivo and of developing predictive in vitro culture conditions as a prerequisite for the rational discovery of new antibiotics.

Research paper thumbnail of Adiponectin and resistin serum levels in women with polycystic ovary syndrome during oral glucose tolerance test: A significant reciprocal correlation between adiponectin and resistin independent of insulin resistance indices

Molecular Genetics and Metabolism, 2005

Polycystic ovary syndrome (PCOS) is associated with an increased incidence of insulin resistance ... more Polycystic ovary syndrome (PCOS) is associated with an increased incidence of insulin resistance (IR), obesity, and type 2 diabetes. Resistin, an adipocytokine, may represent a link between obesity, and these metabolic disorders. There is also evidence that inXammation is a hyperresistinemic state in humans, and cytokine induction of resistin may contribute to insulin resistance in endotoxemia, obesity, and other inXammatory states. In contrast, adiponectin, increases insulin sensitivity, improves glucose tolerance, inhibits inXammatory pathways, while adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis. We aimed to assess, in women with PCOS, whether there is a relationship between adiponectin and resistin and the indices of IR, and whether serum levels of these adipocytokines are altered by glucose-induced hyperinsulinaemia. Serum levels of resistin and adiponectin were measured at 0, 60, and 120 min during 75 g oral glucose tolerance test (OGTT), in 19 women with PCOS, age 36.3 § 11.4 years (mean § SD), body mass index (BMI) 29.3 § 7.7 kg/m 2 , and correlated with the indices of IR, such as HOMA-IR, QUICKI, and the insulin resistance index calculated from glucose and insulin levels obtained during OGTT. There was no change in resistin concentrations (7.31 § 4.58, 7.47 § 5.40, 7.22 § 5.12 pg/ml, at 0, 60, and 120 min of OGTT, respectively, P D 0.77), but there was an increase in adiponectin from 11.32 § 4.64 g/ml at baseline to 14.78 § 7.41 g/ml, at 120 min of OGTT (P < 0.01). The magnitude of the overall rise in adiponectin was greater from 60 to 120 min (from 12.31 § 5.72 to 14.78 § 7.41 g/ml, P < 0.006). Neither resistin, nor adiponectin correlated with the indices of IR, lipids, or other hormonal parameters of the PCOS. There was, however, a signiWcant negative correlation between serum resistin and adiponectin (P D 0.001). In conclusion, we observed a strong negative correlation between serum adiponectin and resistin, despite the lack of direct correlation with the indices of IR. Given the opposite eVects of resistin and adiponectin on the inXammatory process, we speculate that relative proportion of adiponectin-to-resistin might potentially inXuence cardiometabolic risk in women with the PCOS independently of IR parameters. The observed increase in adiponectin during OGTT requires further study. 

Research paper thumbnail of Striatin-3  inhibits estrogen receptor activity by recruiting a protein phosphatase

Journal of Molecular Endocrinology, 2008

A splicing variant of rat striatin-3 (rSTRN3g) was found to associate with estrogen receptor-a (E... more A splicing variant of rat striatin-3 (rSTRN3g) was found to associate with estrogen receptor-a (ERa) in a ligand-dependent manner. In two-hybrid and pull-down analyses, estradiol induced an interaction between rSTRN3g and ERa. STRN3g protein was found in nuclear extracts from rat uterus and human cell lines. Overexpression of rSTRN3g induced a decrease in ERa transcriptional activity but had no effect on ERb activity. Immunoprecipitation analyses showed that rSTRN3g interacts with both the ERa and the catalytic subunit of protein phosphatase 2A (PP2A(C)). The transrepressor action of rSTRN3g was overcome by okadaic acid, an inhibitor of PP2A(C), and by cotransfection of PP2A(C) siRNA. rSTRN3g caused dephosphorylation of ERa at serine 118 and this was abrogated by okadaic acid. ERa lacking phosphorylation sites at either serine 118 or 167 was insensitive to the corepressor action of rSTRN3g. These observations suggest that an rSTRN3g-PP2A(C) complex is recruited to agonist-activated ERa, thereby leading to its dephosphorylation and inhibiting transcription. caused a significant (*P!0 . 05) decrease in E 2 -induced transcription only in the cells transfected with the ERa (S102, 104, 106A) mutant.

Research paper thumbnail of Insulin regulates the novel adipokine adipolin/CTRP12: in vivo and ex vivo effects

Journal of Endocrinology, 2014

There has been intense interest in the adipokines of the C1q complement/TNF-related protein (CTRP... more There has been intense interest in the adipokines of the C1q complement/TNF-related protein (CTRP) superfamily. Adipolin (CTRP12) has been described as a novel adipokine, abundantly expressed in adipose tissue with insulin-sensitising and anti-inflammatory effects. We wanted to investigate the effects of acute and chronic hyperinsulinaemia on circulating adipolin concentrations (ELISA) via a prolonged insulin-glucose infusion in humans. We also examined the effects of insulin and the insulin sensitiser, rosiglitazone, on adipolin concentrations (western blotting) in human adipose tissue explants. We found that hyperinsulinaemic induction in healthy lean human subjects significantly increased circulating levels of adipolin (P!0.05 and P!0.01). Furthermore, in subcutaneous adipose tissue explants, insulin significantly increased adipolin protein expression and secretion (P!0.05 and P!0.01). This effect was attenuated by the phosphatidylinositol 3-kinase inhibitor, LY294002 (P!0.05). Moreover, the insulin-sensitising peroxisome proliferator-activated receptor g (PPARg) agonist, rosiglitazone, significantly increased adipolin protein expression and secretion in subcutaneous adipose tissue explants (P!0.05 and P!0.01). This effect was inhibited by the PPARg antagonist, GW9662 (P!0.05). Our data provide novel insights into adipolin physiology in human subjects. Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 112 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 113 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 114 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 115 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 116 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 117 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 118 Journal of Endocrinology Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 119

Research paper thumbnail of Decreased Cerebrospinal Fluid/Plasma Ratio of the Novel Satiety Molecule, Nesfatin-1/NUCB-2, in Obese Humans: Evidence of Nesfatin-1/NUCB-2 Resistance and Implications for Obesity Treatment

The Journal of Clinical Endocrinology & Metabolism, 2011

The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in over... more The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in overweight individuals. The aim of the study was to investigate the mechanisms underlying brain nesfatin-1/NUCB-2 uptake and to determine whether reduced uptake may contribute to nesfatin-1/NUCB-2 resistance. Cerebrospinal fluid (CSF) and corresponding plasma nesfatin-1/NUCB-2 were measured by ELISA [18 men and 20 women; age, 19-80 yr; body mass index (BMI), 16.2-38.1 kg/m(2)] and correlated to body adiposity and metabolic parameters. CSF/plasma nesfatin-1/NUCB-2 ratio was significantly negatively associated with BMI, body weight, fat mass, and CSF glucose. BMI was predictive of CSF/plasma nesfatin-1/NUCB-2 ratio (β = -0.786; P = 0.045). CSF nesfatin-1/NUCB-2 was significantly positively associated with plasma nesfatin-1/NUCB-2 (R = 0.706; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). There was a significant linear relation between CSF and plasma nesfatin-1/NUCB-2 in lean (BMI &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;25 kg/m(2); R = 0.744; P = 0.002) and obese (BMI ≥ 30 kg/m(2); R = 0.693; P = 0.026) subjects. Subjects in the highest plasma nesfatin-1/NUCB-2 quintile had lower CSF/plasma nesfatin-1/NUCB-2 ratio [26.5% (26.0-29.5%)] compared to the lowest plasma nesfatin-1/NUCB-2 quintile [38.5% (34.0-42.0%)] (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), corresponding BMI [32.4 (31.0-35.0) vs. 23.3 (19.7-23.5) kg/m(2); P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01], and fat mass [32.8 (29.5-40.6) vs. 30.7 (8.2-20.1) kg/m(2); P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01]. Our observations have important implications with respect to the potential weight-reducing actions of nesfatin-1/NUCB-2 treatment. Future research should seek to clarify whether nesfatin-1/NUCB-2 would be beneficial in the management of obesity.

Research paper thumbnail of Nesfatin-1 inhibits proliferation and enhances apoptosis of human adrenocortical H295R cells

The Journal of endocrinology, Jan 13, 2015

NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexi... more NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 is expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 gen...

Research paper thumbnail of Copyright: American Diabetes Association

in Cysteine (SPARC), originally discovered in bone as osteonec-tin, is a mediator of collagen dep... more in Cysteine (SPARC), originally discovered in bone as osteonec-tin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. RESEARCH DESIGN AND METHODS—Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 3.7 kg). Another six lean subjects underwent fast-food– based hyperalimentation for 4 weeks (weight gain: 7.2 1.6 kg).

Research paper thumbnail of Chemerin induces endothelial cell inflammation: activation of nuclear factor-kappa beta and monocyte-endothelial adhesion

Oncotarget, Jan 30, 2018

Chemerin, a chemoattractant protein, acts a G-protein coupled chemokine receptor, Chemokine like ... more Chemerin, a chemoattractant protein, acts a G-protein coupled chemokine receptor, Chemokine like Receptor 1/ChemR23; levels of which are elevated in pro-inflammatory states such as obesity and type 2 diabetes mellitus (T2DM). Obesity and T2DM patients are at high risk of developing cardiovascular disorders such as atherosclerosis. We have reported that chemerin induces human endothelial cell angiogenesis and since dysregulated angiogenesis and endothelial dysfunction are hallmarks of vascular disease; we sought to determine the effects of chemerin on monocyte-endothelial adhesion, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a critical pro-inflammatory transcription factor. Human endothelial cells were transfected with pNF-kappaB-Luc plasmid. Chemerin induced NF-κB activation the MAPK and PI3K/Akt pathways. Western blot analyses and monocyte-endothelial adhesion assay showed that chemerin increased endothelial cell adhesion molecule expression and secr...

Research paper thumbnail of Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation

Health technology assessment (Winchester, England), 2017

Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight... more Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse event...

Research paper thumbnail of Insulin and glucose regulates omentin-1, a novel adipokine: relation to women with the polycyastic ovary synfrome

Research paper thumbnail of Abstract 14435: Adipolin, a Novel Adipokine, is a Novel Cardioprotective Molecule in the Ischemic Rat Heart

Circulation, Nov 26, 2013

Research paper thumbnail of The Hepatokine Fetuin-A is increased in PCOS women. Association with metabolic syndrome and regulation by metformin

Research paper thumbnail of Increased ERK activation and cellular drug accumulation in the enhanced cytotoxicity of folate receptor-targeted liposomal carboplatin

International Journal of Oncology, Mar 1, 2012

Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-posit... more Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-positive and FR-negative cell lines, KB and A549, respectively, for their cytotoxic effects. Significant enhancement in carboplatin potency and intracellular drug accumulation was observed in KB cells when treated with FRT liposomes, compared to free drug and non-targeted liposomes. No enhancement was observed in the FR-negative A549 cells. The increase in carboplatin potency was hypothesized to be associated with an increase in the formation of DNA-platinum adducts resulted from an increase in cellular accumulation of the drug. Surprisingly, FRT carboplatin liposomes showed significantly lower levels of DNA-platinum adducts in comparison to free drug. To elucidate this discrepancy, activation of extracellular signal-regulated protein kinase (ERK) was probed, which has been suggested as an alternative mechanism of carboplatin action. FRT liposomes loaded with carboplatin exhibited the highest level of ERK phosphorylation, and the cytotoxic effect of FRT carboplatin liposomes could be reversed by the MEK/ERK inhibitors, U0126 and PD98059. Importantly, empty FRT liposomes could significantly increase ERK phosphorylation in a concentration-dependent manner without causing toxicity to cells. For the first time, increased potency of carboplatin delivered by FRT liposomes was found to be associated with other molecular targets in addition to DNA-platinum adduct formation. Collectively, the current study suggests a novel mechanism by which FRT liposomes could sensitize cancer cells to drug treatment via modulation of ERK-related cell survival signals.

Research paper thumbnail of Positive correlation between serum omentin and thrombospondin-1 in gestational diabetes despite lack of correlation with insulin resistance indices

Ginekologia polska, 2010

Gestational Diabetes (GDM) is characterized by insulin resistance and a pro-inflammatory state, b... more Gestational Diabetes (GDM) is characterized by insulin resistance and a pro-inflammatory state, both factors possible related to adipokine expression. The study included 20 women with GDM, diagnosed according to the WHO criteria, and 23 matched for age and BMI women with normal glucose tolerance. Omentin and TSP-1 were measured by ELISA assays. Insulin resistance was assessed by HOMA and Insulin Resistance Index (IRI). There were no significant differences in omentin and TSP-1 levels between subjects with GDM and controls (48.0 +/- 12.0 ng/ml versus 50.2 +/- 7.9 ng/ml and 2150 +/- 1661 ng/ml versus 1569 +/- 1160 ng/ml, p = 0.64 and p = 0.29, for omentin and TSP-1 in GDM and control subjects, respectively). There was no significant correlation between either omentin or TSP-1 with HOMA or IRI, however there was a significant positive correlation between thrombospondin-1 and omentin (r = 0.49, p = 0.010). There was also a positive correlation between serum omentin and glucose levels at...

Research paper thumbnail of Brown adipose tissue: endocrine determinants of function and therapeutic manipulation as a novel treatment strategy for obesity

BMC Obesity, 2014

Introduction: Recent observation of brown adipose tissue (BAT) being functional in adult humans p... more Introduction: Recent observation of brown adipose tissue (BAT) being functional in adult humans provides a rationale for its stimulation to increase energy expenditure through 'adaptive thermogenesis' for an anti-obesity strategy. Many endocrine dysfunctions are associated with changes in metabolic rate that over time may result in changes in body weight. It is likely that human BAT plays a role in such processes.

Research paper thumbnail of Differential Effects of Leptin and Adiponectin in Endothelial Angiogenesis

Journal of diabetes research, 2015

Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality... more Obesity is a major health burden with an increased risk of cardiovascular morbidity and mortality. Endothelial dysfunction is pivotal to the development of cardiovascular disease (CVD). In relation to this, adipose tissue secreted factors termed "adipokines" have been reported to modulate endothelial dysfunction. In this review, we focus on two of the most abundant circulating adipokines, that is, leptin and adiponectin, in the development of endothelial dysfunction. Leptin has been documented to influence a multitude of organ systems, that is, central nervous system (appetite regulation, satiety factor) and cardiovascular system (endothelial dysfunction leading to atherosclerosis). Adiponectin, circulating at a much higher concentration, exists in different molecular weight forms, essentially made up of the collagenous fraction and a globular domain, the latter being investigated minimally for its involvement in proinflammatory processes including activation of NF-κβ and ...

Research paper thumbnail of Increased ERK activation and cellular drug accumulation in the enhanced cytotoxicity of folate receptor-targeted liposomal carboplatin

International Journal of Oncology, 2011

Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-posit... more Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-positive and FR-negative cell lines, KB and A549, respectively, for their cytotoxic effects. Significant enhancement in carboplatin potency and intracellular drug accumulation was observed in KB cells when treated with FRT liposomes, compared to free drug and non-targeted liposomes. No enhancement was observed in the FR-negative A549 cells. The increase in carboplatin potency was hypothesized to be associated with an increase in the formation of DNA-platinum adducts resulted from an increase in cellular accumulation of the drug. Surprisingly, FRT carboplatin liposomes showed significantly lower levels of DNA-platinum adducts in comparison to free drug. To elucidate this discrepancy, activation of extracellular signal-regulated protein kinase (ERK) was probed, which has been suggested as an alternative mechanism of carboplatin action. FRT liposomes loaded with carboplatin exhibited the highest level of ERK phosphorylation, and the cytotoxic effect of FRT carboplatin liposomes could be reversed by the MEK/ERK inhibitors, U0126 and PD98059. Importantly, empty FRT liposomes could significantly increase ERK phosphorylation in a concentration-dependent manner without causing toxicity to cells. For the first time, increased potency of carboplatin delivered by FRT liposomes was found to be associated with other molecular targets in addition to DNA-platinum adduct formation. Collectively, the current study suggests a novel mechanism by which FRT liposomes could sensitize cancer cells to drug treatment via modulation of ERK-related cell survival signals.

Research paper thumbnail of Decidualization Induces a Secretome Switch in Perivascular Niche Cells of the Human Endometrium

The endometrial perivascular microenvironment is rich in mesenchymal stem-like cells that express... more The endometrial perivascular microenvironment is rich in mesenchymal stem-like cells that express type 1 integral membrane protein Sushi domain containing 2 (SUSD2) but the role of these cells in the decidual transformation of this tissue in pregnancy is unknown. We used an antibody directed against SUSD2 (W5C5) to isolate perivascular (W5C5 ϩ ) and non-perivascular (W5C5 -) fibroblasts from mid-luteal biopsies. We show that SUSD2 expression, and hence the ratio of W5C5 ϩ to W5C5cells, changes in culture depending on cell-cell contact and activation of the Notch signaling pathway. RNA sequencing revealed that cultures derived from W5C5 ϩ progenitor cells remain phenotypically distinct by the enrichment of novel and established endometrial perivascular signature genes. In an undifferentiated state, W5C5 ϩ -derived cells produced lower levels of various chemokines and inflammatory modulators when compared to their W5C5counterparts. This divergence in secretomes was switched and became more pronounced upon decidualization, which transformed perivascular W5C5 ϩ cells into the dominant source of a range of chemokines and cytokines, including leukemia inhibitory factor and chemokine (C-C motif) ligand 7. Our findings indicate that the decidual response is spatially organized at the embryo-maternal interface with differentiating perivascular cells establishing distinct cytokine and chemokine profiles that could potentially direct trophoblast towards maternal vessels and govern local immune responses in pregnancy.

Research paper thumbnail of Direct inhibitors of InhA are active against Mycobacterium tuberculosis

Science translational medicine, Jan 7, 2015

New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resist... more New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)-dependent manner and blocked the enoyl substrate-binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rat...

Research paper thumbnail of Omentin: A Novel Link Between Inflammation, Diabesity, and Cardiovascular Disease

Trends in Cardiovascular Medicine, 2010

Obesity has reached pandemic proportions and is associated with serious cardiometabolic sequelae ... more Obesity has reached pandemic proportions and is associated with serious cardiometabolic sequelae including insulin resistance, diabetes, dyslipidemia, hypertension, and cardiovascular disease, where adipose tissue-secreted cytokines, that is, adipokines, have been implicated in these processes. Omentin is a novel adipokine preferentially produced by visceral adipose tissue with insulin-sensitizing effects, where circulating levels are decreased in insulin-resistant states, for example, obesity and diabetes. With respect to vascular biology, omentin causes vasodilatation of blood vessels and attenuates C-reactive protein-induced angiogenesis potentially via the nuclear factor B signaling pathway, a potent proinflammatory signaling pathway. Thus, omentin may have beneficial effects on the metabolic syndrome and could potentially be used as a biologic marker and/or pharmacologic agent in this respect.

Research paper thumbnail of A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy

Nature Communications, 2010

Candidate antibacterials are usually identifi ed on the basis of their in vitro activity. However... more Candidate antibacterials are usually identifi ed on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo . In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine -imidazoles (PIs) were identifi ed in a whole-cell screen against Mycobacterium tuberculosis . Lead optimization generated in vitro potent derivatives with desirable pharmacokinetic properties, yet without in vivo effi cacy. Mechanism of action studies linked the PI activity to glycerol metabolism, which is not relevant for M. tuberculosis during infection. PIs induced self-poisoning of M. tuberculosis by promoting the accumulation of glycerol phosphate and rapid ATP depletion. This study underlines the importance of understanding central bacterial metabolism in vivo and of developing predictive in vitro culture conditions as a prerequisite for the rational discovery of new antibiotics.

Research paper thumbnail of Adiponectin and resistin serum levels in women with polycystic ovary syndrome during oral glucose tolerance test: A significant reciprocal correlation between adiponectin and resistin independent of insulin resistance indices

Molecular Genetics and Metabolism, 2005

Polycystic ovary syndrome (PCOS) is associated with an increased incidence of insulin resistance ... more Polycystic ovary syndrome (PCOS) is associated with an increased incidence of insulin resistance (IR), obesity, and type 2 diabetes. Resistin, an adipocytokine, may represent a link between obesity, and these metabolic disorders. There is also evidence that inXammation is a hyperresistinemic state in humans, and cytokine induction of resistin may contribute to insulin resistance in endotoxemia, obesity, and other inXammatory states. In contrast, adiponectin, increases insulin sensitivity, improves glucose tolerance, inhibits inXammatory pathways, while adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis. We aimed to assess, in women with PCOS, whether there is a relationship between adiponectin and resistin and the indices of IR, and whether serum levels of these adipocytokines are altered by glucose-induced hyperinsulinaemia. Serum levels of resistin and adiponectin were measured at 0, 60, and 120 min during 75 g oral glucose tolerance test (OGTT), in 19 women with PCOS, age 36.3 § 11.4 years (mean § SD), body mass index (BMI) 29.3 § 7.7 kg/m 2 , and correlated with the indices of IR, such as HOMA-IR, QUICKI, and the insulin resistance index calculated from glucose and insulin levels obtained during OGTT. There was no change in resistin concentrations (7.31 § 4.58, 7.47 § 5.40, 7.22 § 5.12 pg/ml, at 0, 60, and 120 min of OGTT, respectively, P D 0.77), but there was an increase in adiponectin from 11.32 § 4.64 g/ml at baseline to 14.78 § 7.41 g/ml, at 120 min of OGTT (P < 0.01). The magnitude of the overall rise in adiponectin was greater from 60 to 120 min (from 12.31 § 5.72 to 14.78 § 7.41 g/ml, P < 0.006). Neither resistin, nor adiponectin correlated with the indices of IR, lipids, or other hormonal parameters of the PCOS. There was, however, a signiWcant negative correlation between serum resistin and adiponectin (P D 0.001). In conclusion, we observed a strong negative correlation between serum adiponectin and resistin, despite the lack of direct correlation with the indices of IR. Given the opposite eVects of resistin and adiponectin on the inXammatory process, we speculate that relative proportion of adiponectin-to-resistin might potentially inXuence cardiometabolic risk in women with the PCOS independently of IR parameters. The observed increase in adiponectin during OGTT requires further study. 

Research paper thumbnail of Striatin-3  inhibits estrogen receptor activity by recruiting a protein phosphatase

Journal of Molecular Endocrinology, 2008

A splicing variant of rat striatin-3 (rSTRN3g) was found to associate with estrogen receptor-a (E... more A splicing variant of rat striatin-3 (rSTRN3g) was found to associate with estrogen receptor-a (ERa) in a ligand-dependent manner. In two-hybrid and pull-down analyses, estradiol induced an interaction between rSTRN3g and ERa. STRN3g protein was found in nuclear extracts from rat uterus and human cell lines. Overexpression of rSTRN3g induced a decrease in ERa transcriptional activity but had no effect on ERb activity. Immunoprecipitation analyses showed that rSTRN3g interacts with both the ERa and the catalytic subunit of protein phosphatase 2A (PP2A(C)). The transrepressor action of rSTRN3g was overcome by okadaic acid, an inhibitor of PP2A(C), and by cotransfection of PP2A(C) siRNA. rSTRN3g caused dephosphorylation of ERa at serine 118 and this was abrogated by okadaic acid. ERa lacking phosphorylation sites at either serine 118 or 167 was insensitive to the corepressor action of rSTRN3g. These observations suggest that an rSTRN3g-PP2A(C) complex is recruited to agonist-activated ERa, thereby leading to its dephosphorylation and inhibiting transcription. caused a significant (*P!0 . 05) decrease in E 2 -induced transcription only in the cells transfected with the ERa (S102, 104, 106A) mutant.

Research paper thumbnail of Insulin regulates the novel adipokine adipolin/CTRP12: in vivo and ex vivo effects

Journal of Endocrinology, 2014

There has been intense interest in the adipokines of the C1q complement/TNF-related protein (CTRP... more There has been intense interest in the adipokines of the C1q complement/TNF-related protein (CTRP) superfamily. Adipolin (CTRP12) has been described as a novel adipokine, abundantly expressed in adipose tissue with insulin-sensitising and anti-inflammatory effects. We wanted to investigate the effects of acute and chronic hyperinsulinaemia on circulating adipolin concentrations (ELISA) via a prolonged insulin-glucose infusion in humans. We also examined the effects of insulin and the insulin sensitiser, rosiglitazone, on adipolin concentrations (western blotting) in human adipose tissue explants. We found that hyperinsulinaemic induction in healthy lean human subjects significantly increased circulating levels of adipolin (P!0.05 and P!0.01). Furthermore, in subcutaneous adipose tissue explants, insulin significantly increased adipolin protein expression and secretion (P!0.05 and P!0.01). This effect was attenuated by the phosphatidylinositol 3-kinase inhibitor, LY294002 (P!0.05). Moreover, the insulin-sensitising peroxisome proliferator-activated receptor g (PPARg) agonist, rosiglitazone, significantly increased adipolin protein expression and secretion in subcutaneous adipose tissue explants (P!0.05 and P!0.01). This effect was inhibited by the PPARg antagonist, GW9662 (P!0.05). Our data provide novel insights into adipolin physiology in human subjects. Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 112 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 113 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 114 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 115 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 116 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 117 Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 118 Journal of Endocrinology Research B K TAN and others Insulin and rosiglitazone increase adipolin 221:1 119

Research paper thumbnail of Decreased Cerebrospinal Fluid/Plasma Ratio of the Novel Satiety Molecule, Nesfatin-1/NUCB-2, in Obese Humans: Evidence of Nesfatin-1/NUCB-2 Resistance and Implications for Obesity Treatment

The Journal of Clinical Endocrinology & Metabolism, 2011

The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in over... more The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in overweight individuals. The aim of the study was to investigate the mechanisms underlying brain nesfatin-1/NUCB-2 uptake and to determine whether reduced uptake may contribute to nesfatin-1/NUCB-2 resistance. Cerebrospinal fluid (CSF) and corresponding plasma nesfatin-1/NUCB-2 were measured by ELISA [18 men and 20 women; age, 19-80 yr; body mass index (BMI), 16.2-38.1 kg/m(2)] and correlated to body adiposity and metabolic parameters. CSF/plasma nesfatin-1/NUCB-2 ratio was significantly negatively associated with BMI, body weight, fat mass, and CSF glucose. BMI was predictive of CSF/plasma nesfatin-1/NUCB-2 ratio (β = -0.786; P = 0.045). CSF nesfatin-1/NUCB-2 was significantly positively associated with plasma nesfatin-1/NUCB-2 (R = 0.706; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). There was a significant linear relation between CSF and plasma nesfatin-1/NUCB-2 in lean (BMI &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;25 kg/m(2); R = 0.744; P = 0.002) and obese (BMI ≥ 30 kg/m(2); R = 0.693; P = 0.026) subjects. Subjects in the highest plasma nesfatin-1/NUCB-2 quintile had lower CSF/plasma nesfatin-1/NUCB-2 ratio [26.5% (26.0-29.5%)] compared to the lowest plasma nesfatin-1/NUCB-2 quintile [38.5% (34.0-42.0%)] (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), corresponding BMI [32.4 (31.0-35.0) vs. 23.3 (19.7-23.5) kg/m(2); P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01], and fat mass [32.8 (29.5-40.6) vs. 30.7 (8.2-20.1) kg/m(2); P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01]. Our observations have important implications with respect to the potential weight-reducing actions of nesfatin-1/NUCB-2 treatment. Future research should seek to clarify whether nesfatin-1/NUCB-2 would be beneficial in the management of obesity.