Journal articles
Tarrant M, Khan S, Farrow C, Shah P, Daly M, Kos K (In Press). Creating and nurturing social identities in the delivery of healthcare: Patient experiences of a group-based weight-management programme for people with morbid obesity. British Journal of Health Psychology
Kos K (2020). Cardiometabolic Morbidity and Mortality with Smoking Cessation, Review of Recommendations for People with Diabetes and Obesity.
Curr Diab Rep,
20(12).
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Cardiometabolic Morbidity and Mortality with Smoking Cessation, Review of Recommendations for People with Diabetes and Obesity.
PURPOSE OF REVIEW: Obesity is closely linked with the pathogenesis of type 2 diabetes (T2DM) and cardiovascular disease (CVD), and whilst smoking cessation is associated with weight gain, there are concerns that this weight gain may offset the benefit of CVD risk reduction especially in those with considerable post-cessation weight gain. The aim of this narrative review is to evaluate recent evidence on smoking cessation and cardiometabolic outcomes and discuss limitations of current knowledge and studies. RECENT FINDINGS: Nicotine is a key player in modulating energy balance by influencing lipid storage in adipose tissue by affecting lipolysis, energy input by modulating appetite and energy output by increasing sympathetic drive and thermogenesis. It also increases insulin resistance and promotes abdominal obesity. The CVD risk and mortality associated with cigarette smoking potentiate the CVD risks in patients with diabetes. Evidence supports the benefit of quitting cigarette smoking regardless of any subsequent weight gain. Data suggests that the cardiometabolic risk is limited to the first few years and that cardiovascular health and mortality benefit of smoking cessation outweighs the harm related to weight gain. This weight gain can be limited by nicotine replacement of which e-cigarettes (vaping) are increasingly popular if it is not an alternative to cigarette smoking. However, long-term health data on e-cigarettes is needed prior to formal recommendation for its use in smoking cessation. The recommendation for cessation of cigarette smoking is justified for those at high risk of weight gain and diabetes. However, for most benefit, consideration should be given for personalized weight management to limit weight gain. Awareness of a 'lean paradox' by which lower weight is associated with increased CVD risk may help to improve motivation and insight into the bias of smoking, health and body composition otherwise known to epidemiologists as the 'obesity paradox'.
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McCulloch LJ, Bramwell LR, Knight B, Kos K (2020). Circulating and tissue specific transcription of angiopoietin-like protein 4 in human Type 2 diabetes. Metabolism, 106, 154192-154192.
Khan SS, Tarrant M, Kos K, Daly M, Gimbuta C, Farrow CV (2020). Making connections: Social identification with new treatment groups for lifestyle management of severe obesity.
Clin Psychol Psychother,
27(5), 686-696.
Abstract:
Making connections: Social identification with new treatment groups for lifestyle management of severe obesity.
Groups are regularly used to deliver healthcare services, including the management of obesity, and there is growing evidence that patients' experiences of such groups fundamentally shape treatment effects. This study investigated factors related to patients' shared social identity formed within the context of a treatment group for the management of severe obesity. A cross-sectional survey was administered to patients registered with a UK medical obesity service and enrolled on a group-based education and support programme. Patients (N = 78; MBMI = 48 on entry to the service) completed measures of group demographics (e.g. group membership continuity) and psychosocial variables (e.g. past experiences of weight discrimination) and reported their social identification with the treatment group. The results showed that patients identified with the treatment group to the extent that there was continuity in membership across the programme and they perceived themselves more centrally in terms of their weight status. Weight centrality was negatively associated with external social support and positively associated with experiences of weight discrimination. Group continuity was positively correlated with session attendance frequency. Patients presenting to clinical treatment services with severe obesity often do so after sustained weight loss failure and exposure to negative societal experiences. This study highlights that providing a treatment environment wherein these experiences can be shared with other patients may provide common ground for development of a new, positive social identity that can structure programme engagement and progression.
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Kos K (2020). Smoking cessation, weight gain, and cardiovascular risk.
Lancet Diabetes Endocrinol,
8(2), 93-95.
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Aung MM, Slade K, Freeman LAR, Kos K, Whatmore JL, Shore AC, Gooding KM (2019). Locally delivered GLP-1 analogues liraglutide and exenatide enhance microvascular perfusion in individuals with and without type 2 diabetes.
Diabetologia,
62(9), 1701-1711.
Abstract:
Locally delivered GLP-1 analogues liraglutide and exenatide enhance microvascular perfusion in individuals with and without type 2 diabetes.
AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) analogues reduce the risk of macrovascular disease in diabetes; however, little is known about their microvascular effects. This research examined the microvascular actions of the GLP-1 analogues liraglutide and exenatide in individuals with and without type 2 diabetes (study 1). It also explored the involvement of the GLP-1 receptor (study 2) and the nitric oxide pathway in mediating the microvascular effects of the analogues. METHODS: Trial design: Studies 1 and 2 had a randomised, controlled, double-blind study design. Study 1 participants, intervention and methods: three participant groups were recruited: individuals with well-controlled type 2 diabetes, and obese and lean individuals without diabetes (21 participants per group). Liraglutide (0.06 mg), exenatide (0.5 μg) and saline (154 mmol/l NaCl; 0.9%) control were microinjected into separate sites in the dermis (forearm) in a randomised order, blinded to operator and participant. Skin microvascular perfusion was assessed by laser Doppler perfusion imaging. Outcomes were stabilised response (mean skin perfusion between 7.5 and 10 min post microinjection) and total response (AUC, normalised for baseline perfusion). Perfusion response to GLP-1 analogues was compared with saline within each group as well as between groups. Study 2 participants, intervention and methods: in healthy individuals (N = 16), liraglutide (0.06 mg) and saline microinjected sites were pretreated with saline or the GLP-1 receptor blocker, exendin-(9,39), in a randomised order, blinded to participant and operator. Outcomes were as above (stabilised response and total perfusion response). Perfusion response to liraglutide was compared between the saline and the exendin-(9,39) pretreated sites. In vitro study: the effects of liraglutide and exenatide on nitrate levels and endothelial nitric oxide synthase phosphorylation (activation) were examined using human microvascular endothelial cells. RESULTS: Study 1 results: both analogues increased skin perfusion (stabilised response and total response) in all groups (n = 21 per group, p
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Pastel E, Price E, Sjöholm K, McCulloch LJ, Rittig N, Liversedge N, Knight B, Møller N, Svensson P-A, Kos K, et al (2018). Lysyl oxidase and adipose tissue dysfunction.
Metabolism,
78, 118-127.
Abstract:
Lysyl oxidase and adipose tissue dysfunction.
BACKGROUND/OBJECTIVES: Lysyl oxidase (LOX) is an enzyme crucial for collagen fibre crosslinking and thus for fibrosis development. Fibrosis is characterised by a surplus of collagen fibre accumulation and is amongst others also a feature of obesity-associated dysfunctional adipose tissue (AT) which has been linked with type 2 diabetes. We hypothesised that in type 2 diabetes and obesity LOX expression and activity will be increased as a consequence of worsening AT dysfunction. This study aimed to provide a comprehensive characterisation of LOX in human AT. METHODS: LOX mRNA expression was analysed in omental and abdominal subcutaneous AT obtained during elective surgery from subjects with a wide range of BMI, with and without diabetes. In addition, LOX expression was studied in subcutaneous AT before and 9.5months after bariatric surgery. To study the mechanism of LOX changes, its expression and activity were assessed after either hypoxia, recombinant human leptin or glucose treatment of AT explants. In addition, LOX response to acute inflammation was tested after stimulation by a single injection of lipopolysaccharide versus saline solution (control) in healthy men, in vivo. Quantity of mRNA was measured by RT-qPCR. RESULTS: LOX expression was higher in obesity and correlated with BMI whilst, in vitro, leptin at high concentrations, as a potential feedback mechanism, suppressed its expression. Neither diabetes status, nor hyperglycaemia affected LOX. Hypoxia and lipopolysaccharide-induced acute inflammation increased LOX AT expression, latter was independent of macrophage infiltration. CONCLUSIONS: Whilst LOX may not be affected by obesity-associated complications such as diabetes, our results confirm that LOX is increased by hypoxia and inflammation as underlying mechanism for its upregulation in adipose tissue with obesity.
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Thorn CE, Knight B, Pastel E, McCulloch LJ, Patel B, Shore AC, Kos K (2017). Adipose tissue is influenced by hypoxia of obstructive sleep apnea syndrome independent of obesity.
Diabetes Metab,
43(3), 240-247.
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Adipose tissue is influenced by hypoxia of obstructive sleep apnea syndrome independent of obesity.
AIMS: Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular risk and diabetes independent of obesity. We investigated whether adipose tissue dysfunction is exacerbated due to increased tissue hypoxia. METHODS: Adipose tissue (AT) oxygenation was measured with a Clarke-type electrode (pATO2) in 16 men with OSAS before and after 4 months of continuous positive airway pressure therapy (CPAP) and in BMI-matched controls. Oxygenation was simultaneously monitored in arterial blood by pulse oximetry (SaO2); mixed blood in AT microcirculation by reflectance spectroscopy (SATO2) along with blood flow. Markers of hypoxia, adipo- and angiogenesis, inflammation and fibrosis were analysed in AT and serum. RESULTS: OSAS subjects were more insulin resistant. Despite lower arterial SaO2 (95.4±1.3% vs. 97.1±1.6%, P=0.013) in subjects with OSAS, there was no difference in the oxygen content of AT microcirculation (61.6±18.4 vs. 72.2±7.0%, P=0.07) or pATO2 (49.2±7.5 vs. 50.4±14.7mmHg, P=0.83) between groups. Resting AT blood flow was higher in OSAS compared to controls (108.5±22.7 vs. 78.9±24.9au, P
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Bowman K, Atkins JL, Delgado J, Kos K, Kuchel GA, Ble A, Ferrucci L, Melzer D (2017). Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants.
Am J Clin Nutr,
106(1), 130-135.
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Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants.
Background: for older groups, being overweight [body mass index (BMI; in kg/m2): 25 to
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Pastel E, McCulloch LJ, Ward R, Joshi S, Gooding KM, Shore AC, Kos K (2017). GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction.
Clin Sci (Lond),
131(5), 343-353.
Abstract:
GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction.
Glucagon-like peptide-1 (GLP-1) analogues aid weight loss that improves obesity-associated adipose tissue (AT) dysfunction. GLP-1 treatment may however also directly influence AT that expresses the GLP-1 receptor (GLP-1R). The present study aimed to assess the impact of GLP-1 analogue treatment on subcutaneous AT (SCAT) inflammatory and fibrotic responses, compared with weight loss by calorie reduction (control). Among the 39 participants with Type 2 diabetes recruited, 30 age-matched participants were randomized to 4 months treatment with Liraglutide (n=22) or calorie restriction based on dietetic counselling (n=8). Assessments included clinical characteristics and repeated subcutaneous abdominal AT biopsies. Liraglutide resulted in weight loss in most participants (-3.12±1.72 kg, P=0.007) and significant reduction in visceral AT (VAT). It was more effective in lowering fasting glucose, in comparison with weight loss by dieting. However, tumour necrosis factor-α (TNFA) AT-expression (P=0.0005), macrophage chemoattractant protein-1 (MCP-1) expression (P=0.027) and its serum levels (P=0.048) increased with Liraglutide, suggestive of an inflammatory response unlike in the diet arm in which a trend of lower cluster of differentiation 14 (CD14) expression (P=0.09) was found. Liraglutide treatment also increased expression of factors involved in extracellular matrix (ECM) deposition, transforming growth factor-β (TGFB) and collagen type 1 alpha 1 chain (COL1A1) (TGFB1: before 0.73±0.09 arbitrary units (AU), after 1.00±0.13 AU, P=0.006; COL1A1: 0.84±0.09 AU compared with 1.49±0.26 AU, P=0.026). Liraglutide thus appears to induce an inflammatory response in AT and influences ECM remodelling. Despite its superior effect on glycaemia, Liraglutide does not improve obesity-associated AT dysfunction in subcutaneous tissue. It is yet unclear whether this limits AT storage capacity for lipids. This may be of importance in patients being re-exposed to positive energy balance such as post GLP-1 discontinuation.
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Pulsford R, Blackwell J, Hillsdon M, Kos K (2017). Intermittent walking, but not standing, improves postprandial insulin and glucose relative to sustained sitting: a randomised cross-over study in inactive middle-aged men.
JOURNAL OF SCIENCE AND MEDICINE IN SPORT,
20(3), 278-283.
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Tarrant M, Khan SS, Farrow CV, Shah P, Daly M, Kos K (2017). Patient experiences of a bariatric group programme for managing obesity: a qualitative interview study.
Br J Health Psychol,
22(1), 77-93.
Abstract:
Patient experiences of a bariatric group programme for managing obesity: a qualitative interview study.
OBJECTIVES: People with obesity experience a range of physical and psychological ill-health outcomes. This study examined patients' experiences of a group-based programme for the management of morbid obesity delivered within the UK National Health Service. The focus of the study was on the emerging dynamic of the group and patients' perceptions of its impact on health outcomes. DESIGN: a qualitative interview study was conducted and involved patients recruited from a Tier 3 bariatric service in South West England. Verbatim transcripts were analysed using thematic analysis. METHODS: Twenty patients (12 females) with a BMI ≥ 35 kg/m2 participated in a semi-structured one-to-one interview. Participants had been registered with the bariatric service for at least 6 months. None of the participants had had bariatric surgery. RESULTS: Most participants felt that they had benefited from participating in the group programme and talked about the group as a resource for lifestyle change. Participants' narratives centred on the emergence of a sense of self based upon their participation in the group: establishing psychological connections to other patients, or shared social identity, was regarded as a key mechanism through which the programme's educational material was accessed, and underpinned the experience of social support within the group. Through interaction with other patients, involving the sharing of personal experiences and challenges, participants came to experience their weight 'problem' through a collective lens that they felt empowered them to initiate and sustain individual lifestyle change. DISCUSSION: Bariatric care groups have the potential to support lifestyle change and weight loss and may help address the psychological needs of patients. Nurturing a sense of shared social identity amongst patients with morbid obesity should be a core aim of the care pathway and may provide the foundation for successful translation of dietetic content in group programmes. Statement of contribution What is already known on this subject? Services for people with obesity who require specialist care are often supported by group-based bariatric programmes. There are no specific guidelines for the organization of bariatric groups beyond the recommendation for lifestyle interventions delivered by a multidisciplinary care team. Research with other health conditions suggests that the psychological connections formed between participants in bariatric programmes may play an important role in structuring programme effectiveness. What does this study add? Establishing psychological connections with other patients underpins bariatric patients' group experience. Shared social identity structures behaviour change in patients on bariatric programmes. Nurturing shared social identity should be a core aim of the bariatric care pathway.
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Pastel E, Joshi S, Knight B, Liversedge N, Ward R, Kos K (2016). Effects of Exendin-4 on human adipose tissue inflammation and ECM remodelling.
Nutr Diabetes,
6(12).
Abstract:
Effects of Exendin-4 on human adipose tissue inflammation and ECM remodelling.
BACKGROUND/OBJECTIVES: Subjects with type-2 diabetes are typically obese with dysfunctional adipose tissue (AT). Glucagon-like peptide-1 (GLP-1) analogues are routinely used to improve glycaemia. Although, they also aid weight loss that improves AT function, their direct effect on AT function is unclear. To explore GLP-1 analogues' influence on human AT's cytokine and extracellular matrix (ECM) regulation, we therefore obtained and treated omental (OMAT) and subcutaneous (SCAT) AT samples with Exendin-4, an agonist of the GLP-1 receptor (GLP-1R). SUBJECTS/METHODS: OMAT and abdominal SCAT samples obtained from women during elective surgery at the Royal Devon & Exeter Hospital (UK) were treated with increasing doses of Exendin-4. Changes in RNA expression of adipokines, inflammatory cytokines, ECM components and their regulators were assessed and protein secretion analysed by ELISA. GLP-1R protein accumulation was compared in paired AT depot samples. RESULTS: Exendin-4 induced an increase in OMAT adiponectin (P=0.02) and decrease in elastin expression (P=0.03) in parallel with reduced elastin secretion (P=0.04). In contrast to OMAT, we did not observe an effect on SCAT. There was no change in the expression of inflammatory markers (CD14, TNFA, MCP-1), collagens, TGFB1 or CTGF. GLP-1R accumulation was higher in SCAT. CONCLUSIONS: Independently of weight loss, which may bias findings of in vivo studies, GLP-1 analogues modify human OMAT physiology favourably by increasing the insulin-sensitising cytokine adiponectin. However, the reduction of elastin and no apparent effect on AT's inflammatory cytokines suggest that GLP-1 analogues may be less beneficial to AT function, especially if there is no associated weight loss.
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Lee BP, Lloyd-Laney HO, Locke JM, McCulloch LJ, Knight B, Yaghootkar H, Cory G, Kos K, Frayling TM, Harries LW, et al (2016). Functional characterisation of ADIPOQ variants using individuals recruited by genotype.
Mol Cell Endocrinol,
428, 49-57.
Abstract:
Functional characterisation of ADIPOQ variants using individuals recruited by genotype.
Four non-coding GWAS variants in or near the ADIPOQ gene (rs17300539, rs17366653, rs3821799 and rs56354395) together explain 4% of the variation in circulating adiponectin. The functional basis for this is unknown. We tested the effect of these variants on ADIPOQ transcription, splicing and stability respectively in adipose tissue samples from participants recruited by rs17366653 genotype. Transcripts carrying rs17300539 demonstrated a 17% increase in expression (p = 0.001). Variant rs17366653 was associated with disruption of ADIPOQ splicing leading to a 7 fold increase in levels of a non-functional transcript (p = 0.002). Transcripts carrying rs56354395 demonstrated a 59% decrease in expression (p =
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Pulsford R, Blackwell J, Hillsdon M, Kos K (2016). Intermittent walking, but not standing, improves postprandial insulin and glucose relative to sustained sitting: a randomised cross-over study in middle-aged men. Journal of Science and Medicine in Sport, 20(3), 278-283.
Bowman K, Correa Delgado J, Henley W, Masoli J, Kos K, Brayne C, Thokala P, Lafortune L, Kuchel G, Ble A, et al (2016). Obesity in Older People with and Without Conditions Associated with Weight Loss: Follow-up of 955,000 Primary Care Patients. J Gerontol a Biol Sci Med Sci
Littlejohns TJ, Kos K, Henley WE, Kuźma E, Llewellyn DJ (2016). Vitamin D and Dementia.
J Prev Alzheimers Dis,
3(1), 43-52.
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Vitamin D and Dementia.
Emerging evidence suggests that low vitamin D concentrations are potentially involved in the pathogenesis of dementia. This is of particular interest when considering the high prevalence of vitamin D deficiency in elderly adults and the urgent need to identify modifiable risk factors for dementia. Studies have found that vitamin D is implicated in procognitive and neuroprotective functions, including the reduction of Alzheimer's disease hallmarks such as amyloid beta and phosphorylated tau. Cross-sectional studies have consistently found that vitamin D concentrations are significantly lower in individuals with Alzheimer's disease and cognitive impairment compared to healthy controls. Longitudinal studies support an association between low vitamin D concentrations and an increased risk of dementia and cognitive decline. Neuroimaging studies are beginning to uncover the potential neurodegenerative and cerebrovascular mechanisms that underlie these associations such as white matter hyperintensities and enlarged ventricular volume, although there is currently a lack of longitudinal studies. In contrast to observational studies, findings from interventional studies have produced mixed results on the benefits of vitamin D supplementation on dementia and cognitive outcomes. Interpretation of the findings from these studies is hampered by several major methodological limitations, such as small sample sizes, inadequate doses and inclusion of participants unlikely to benefit from vitamin D supplementation. There is a need for large double-blind randomised-control trials investigating whether vitamin D supplementation can halt or delay the risk of dementia-related outcomes in individuals with low vitamin D concentrations.
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Littlejohns TJ, Kos K, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PHM, Kestenbaum BR, Kuller LH, Langa KM, et al (2016). Vitamin D and Risk of Neuroimaging Abnormalities.
PLoS One,
11(5).
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Vitamin D and Risk of Neuroimaging Abnormalities.
Vitamin D deficiency has been linked with an increased risk of incident all-cause dementia and Alzheimer's disease. The aim of the current study was to explore the potential mechanisms underlying these associations by determining whether low vitamin D concentrations are associated with the development of incident cerebrovascular and neurodegenerative neuroimaging abnormalities. The population consisted of 1,658 participants aged ≥65 years from the US-based Cardiovascular Health Study who were free from prevalent cardiovascular disease, stroke and dementia at baseline in 1992-93. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected at baseline. The first MRI scan was conducted between 1991-1994 and the second MRI scan was conducted between 1997-1999. Change in white matter grade, ventricular grade and presence of infarcts between MRI scan one and two were used to define neuroimaging abnormalities. During a mean follow-up of 5.0 years, serum 25(OH)D status was not significantly associated with the development of any neuroimaging abnormalities. Using logistic regression models, the multivariate adjusted odds ratios (95% confidence interval) for worsening white matter grade in participants who were severely 25(OH)D deficient (
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Welters HJ, Bowen A, Whatmore J, Kos K, Richardson S (2016). Wnt4 antagonises Wnt3a mediated increases in growth and glucose stimulated insulin secretion in the pancreatic beta-cell line, INS-1. Biochemical and Biophysical Research Communications
McCulloch LJ, Rawling TJ, Sjöholm K, Franck N, Dankel SN, Price EJ, Knight B, Liversedge NH, Mellgren G, Nystrom F, et al (2015). COL6A3 is regulated by leptin in human adipose tissue and reduced in obesity.
Endocrinology,
156(1), 134-146.
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COL6A3 is regulated by leptin in human adipose tissue and reduced in obesity
Fibrosis of adipose tissue (AT) increases AT rigidity, reduces its expandability, and contributes to metabolic dysfunction. Collagen type VI, α3 (COL6A3) encodes 1 subunit of a fibrotic extracellular matrix protein highly expressed in rodent AT. Knockout of collagen VI in rodent AT led to a significant improvement in metabolic health in obese, diabetic ob/ob mice. However, it isunknown whether this collagen has the same metabolic significance in human AT. We therefore aimed to undertake a comprehensive assessment of COL6A3 in relation to human AT and obesity. Characterization of COL6A3 in human AT showed 5-fold higher expression in the stromalvascular fraction compared with adipocyte expression and significantly higher expression in subcutaneous AT (SCAT) than omental AT. In both depots, COL6A3 expression appeared to be lowered in obesity, whereas diet- and surgery-induced weight loss increased COL6A3 expression in SCAT. Leptin treatment caused a dose-dependent decrease in COL6A3 expression, although no effect was seen with insulin or glucose treatment and no difference observed in subjects with diabetes. In addition, we found that the collagen expression profile in humans differs significantly from rodents, because COL6A3 does not appear to be the predominant collagen in adipose, muscle, or liver. Our findings oppose those initially seen in rodent studies and, most importantly, demonstrate a direct regulation of COL6A3 by leptin. This highlights the importance of a paracrine leptin signaling pathway in human AT and suggests an additional mechanism by which leptin can regulate extracellular matrix composition and, with it, AT expandability.
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McCulloch LJ, Rawling TJ, Sjöholm K, Franck N, Dankel SN, Price EJ, Knight B, Liversedge NH, Mellgren G, Nystrom F, et al (2015). COL6A3 is regulated by leptin in human adipose tissue and reduced in obesity.
Endocrinology,
156(1), 134-146.
Abstract:
COL6A3 is regulated by leptin in human adipose tissue and reduced in obesity.
Fibrosis of adipose tissue (AT) increases AT rigidity, reduces its expandability, and contributes to metabolic dysfunction. Collagen type VI, α3 (COL6A3) encodes 1 subunit of a fibrotic extracellular matrix protein highly expressed in rodent AT. Knockout of collagen VI in rodent AT led to a significant improvement in metabolic health in obese, diabetic ob/ob mice. However, it is unknown whether this collagen has the same metabolic significance in human AT. We therefore aimed to undertake a comprehensive assessment of COL6A3 in relation to human AT and obesity. Characterization of COL6A3 in human AT showed 5-fold higher expression in the stromalvascular fraction compared with adipocyte expression and significantly higher expression in subcutaneous AT (SCAT) than omental AT. In both depots, COL6A3 expression appeared to be lowered in obesity, whereas diet- and surgery-induced weight loss increased COL6A3 expression in SCAT. Leptin treatment caused a dose-dependent decrease in COL6A3 expression, although no effect was seen with insulin or glucose treatment and no difference observed in subjects with diabetes. In addition, we found that the collagen expression profile in humans differs significantly from rodents, because COL6A3 does not appear to be the predominant collagen in adipose, muscle, or liver. Our findings oppose those initially seen in rodent studies and, most importantly, demonstrate a direct regulation of COL6A3 by leptin. This highlights the importance of a paracrine leptin signaling pathway in human AT and suggests an additional mechanism by which leptin can regulate extracellular matrix composition and, with it, AT expandability.
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Lourida I, Thompson-Coon J, Dickens CM, Soni M, Kuźma E, Kos K, Llewellyn DJ (2015). Parathyroid hormone, cognitive function and dementia: a systematic review.
PLoS One,
10(5).
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Parathyroid hormone, cognitive function and dementia: a systematic review.
BACKGROUND: Metabolic factors are increasingly recognized to play an important role in the pathogenesis of Alzheimer's disease and dementia. Abnormal parathyroid hormone (PTH) levels play a role in neuronal calcium dysregulation, hypoperfusion and disrupted neuronal signaling. Some studies support a significant link between PTH levels and dementia whereas others do not. METHODS: We conducted a systematic review through January 2014 to evaluate the association between PTH and parathyroid conditions, cognitive function and dementia. Eleven electronic databases and citation indexes were searched including Medline, Embase and the Cochrane Library. Hand searches of selected journals, reference lists of primary studies and reviews were also conducted along with websites of key organizations. Two reviewers independently screened titles and abstracts of identified studies. Data extraction and study quality were performed by one and checked by a second reviewer using predefined criteria. A narrative synthesis was performed due to the heterogeneity of included studies. RESULTS: the twenty-seven studies identified were of low and moderate quality, and challenging to synthesize due to inadequate reporting. Findings from six observational studies were mixed but suggest a link between higher serum PTH levels and increased odds of poor cognition or dementia. Two case-control studies of hypoparathyroidism provide limited evidence for a link with poorer cognitive function. Thirteen pre-post surgery studies for primary hyperparathyroidism show mixed evidence for improvements in memory though limited agreement in other cognitive domains. There was some degree of cognitive impairment and improvement postoperatively in observational studies of secondary hyperparathyroidism but no evident pattern of associations with specific cognitive domains. CONCLUSIONS: Mixed evidence offers weak support for a link between PTH, cognition and dementia due to the paucity of high quality research in this area.
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Littlejohns TJ, Kos K, Henley WE, Cherubini A, Ferrucci L, Lang IA, Langa KM, Melzer D, Llewellyn DJ (2015). Serum leptin and risk of cognitive decline in elderly italians.
J Alzheimers Dis,
44(4), 1231-1239.
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Serum leptin and risk of cognitive decline in elderly italians.
BACKGROUND: US studies suggest that leptin, a fat-derived hormone, may be protective against the development of dementia. OBJECTIVE: to investigate the complex relationship between leptin levels and cognitive decline in elderly Italians. METHODS: We studied circulating fasting leptin levels in 809 elderly adults free from dementia who participated in the prospective Italian population-based InCHIANTI study between 1998 and 2009 (mean follow-up of 8.0 years). Global cognitive decline was defined as a reduction of ≥5 points on the Mini-Mental State Examination (MMSE). Trail-Making Tests a and B were also incorporated, with cognitive decline defined as discontinued testing or the worst 10% of change from baseline. We also investigated whether any association could be explained by midlife weight and whether cognitive decline was associated with changing leptin levels. RESULTS: the multivariate adjusted relative risk ([RR]; 95% confidence interval [CI]) of cognitive decline on the MMSE was 0.84 (95% CI 0.73-0.97) in relation to baseline sex-standardized log-leptin levels. High leptin levels showed a non-significant trend toward a reduced risk of decline on the Trail-Making Tests a (RR = 0.85, 95% CI 0.71-1.02) and B (RR = 0.90, 0.79-1.02). Adjusting for midlife weight or change in weight did not alter the pattern of results, and cognitive decline was not associated with changing leptin levels. CONCLUSIONS: High leptin levels were independently associated with a reduced risk of cognitive decline in elderly Italians.
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Lawrence NS, O'Sullivan J, Parslow D, Javaid M, Adams RC, Chambers CD, Kos K, Verbruggen F (2015). Training response inhibition to food is associated with weight loss and reduced energy intake.
Appetite,
95, 17-28.
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Training response inhibition to food is associated with weight loss and reduced energy intake
The majority of adults in the UK and US are overweight or obese due to multiple factors including excess energy intake. Training people to inhibit simple motor responses (key presses) to high-energy density food pictures reduces intake in laboratory studies. We examined whether online response inhibition training reduced real-world food consumption and weight in a community sample of adults who were predominantly overweight or obese (N = 83). Participants were allocated in a randomised, double-blind design to receive four 10-minute sessions of either active or control go/no-go training in which either high-energy density snack foods (active) or non-food stimuli (control) were associated with no-go signals. Participants’ weight, energy intake (calculated from 24-hour food diaries), daily snacking frequency and subjective food evaluations were measured for one week pre- and post-intervention. Participants also provided self-reported weight and monthly snacking frequency at pre-intervention screening, and one month and six months after completing the study. Participants in the active relative to control condition showed significant weight loss, reductions in daily energy intake and a reduction in rated liking of high-energy density (no-go) foods from the pre- to post-intervention week. There were no changes in self-reported daily snacking frequency. At longer-term follow-up, the active group showed significant reductions in self-reported weight at six months, whilst both groups reported significantly less snacking at one- and six-months. Excellent rates of adherence (97%) and positive feedback about the training suggest that this intervention is acceptable and has the potential to improve public health by reducing energy intake and overweight.
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Lourida I, Soni M, Kuzma E, Thompson‐Coon J, Dickens C, Kos K, Llewellyn DJ (2014). P2‐309: DO PARATHYROID HORMONE LEVELS PLAY a ROLE IN DEMENTIA? a SYSTEMATIC REVIEW. Alzheimer's & Dementia, 10(4S_Part_15), p591-p592.
Littlejohns TJ, Kos K, Henley WE, Cherubini A, Ferrucci L, Lang IA, Langa KM, Melzer D, Llewellyn DJ (2014). SERUM LEPTIN AND RISK OF COGNITIVE DECLINE IN ELDERLY ITALIANS: a PROSPECTIVE COHORT STUDY.
JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH,
68, A4-A4.
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Littlejohns TJ, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PHM, Fried L, Kestenbaum BR, Kuller LH, Langa KM, et al (2014). Vitamin D and the risk of dementia and Alzheimer disease.
Neurology,
83(10), 920-928.
Abstract:
Vitamin D and the risk of dementia and Alzheimer disease.
OBJECTIVE: to determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease. METHODS: One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria. RESULTS: During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (
Abstract.
Author URL.
Harries LW, McCulloch LJ, Holley JE, Rawling TJ, Welters HJ, Kos K (2013). A role for SPARC in the moderation of human insulin secretion.
PLoS One,
8(6).
Abstract:
A role for SPARC in the moderation of human insulin secretion.
AIMS/HYPOTHESIS: We have previously shown the implication of the multifunctional protein SPARC (Secreted protein acidic and rich in cysteine)/osteonectin in insulin resistance but potential effects on beta-cell function have not been assessed. We therefore aimed to characterise the effect of SPARC on beta-cell function and features of diabetes. METHODS: We measured SPARC expression by qRT-PCR in human primary pancreatic islets, adipose tissue, liver and muscle. We then examined the relation of SPARC with glucose stimulated insulin secretion (GSIS) in primary human islets and the effect of SPARC overexpression on GSIS in beta cell lines. RESULTS: SPARC was expressed at measurable levels in human islets, adipose tissue, liver and skeletal muscle, and demonstrated reduced expression in primary islets from subjects with diabetes compared with controls (p< = 0.05). SPARC levels were positively correlated with GSIS in islets from control donors (p< = 0.01). Overexpression of SPARC in cultured beta-cells resulted in a 2.4-fold increase in insulin secretion in high glucose conditions (p< = 0.01). CONCLUSIONS: Our data suggest that levels of SPARC are reduced in islets from donors with diabetes and that it has a role in insulin secretion, an effect which appears independent of SPARC's modulation of obesity-induced insulin resistance in adipose tissue.
Abstract.
Author URL.
Weedon MN, Ellard S, Prindle MJ, Caswell R, Allen HL, Oram R, Godbole K, Yajnik CS, Sbraccia P, Novelli G, et al (2013). An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy.
Nature Genetics,
45(8), 947-950.
Abstract:
An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy
DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication. It carries out this synthesis with high fidelity owing to its intrinsic 3'- to 5'-exonuclease activity, which confers proofreading ability. Missense mutations affecting the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancers. Here we report a recurring heterozygous single-codon deletion in POLD1 affecting the polymerase active site that abolishes DNA polymerase activity but only mildly impairs 3'- to 5'-exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This discovery suggests that perturbing the function of the ubiquitously expressed POLD1 polymerase has unexpectedly tissue-specific effects in humans and argues for an important role for POLD1 function in adipose tissue homeostasis. © 2013 Nature America, Inc. All rights reserved.
Abstract.
Weedon MN, Ellard S, Prindle MJ, Caswell R, Lango Allen H, Oram R, Godbole K, Yajnik CS, Sbraccia P, Novelli G, et al (2013). An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy.
Nat Genet,
45(8), 947-950.
Abstract:
An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy.
DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication. It carries out this synthesis with high fidelity owing to its intrinsic 3'- to 5'-exonuclease activity, which confers proofreading ability. Missense mutations affecting the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancers. Here we report a recurring heterozygous single-codon deletion in POLD1 affecting the polymerase active site that abolishes DNA polymerase activity but only mildly impairs 3'- to 5'-exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This discovery suggests that perturbing the function of the ubiquitously expressed POLD1 polymerase has unexpectedly tissue-specific effects in humans and argues for an important role for POLD1 function in adipose tissue homeostasis.
Abstract.
Author URL.
Lourida I, Thompson‐Coon J, Dickens C, Soni M, Kos K, Llewellyn D (2013). P3–198: a systematic review of the relationship between parathyroid hormone levels and cognitive function and dementia. Alzheimer's & Dementia, 9(4S_Part_16), p627-p627.
Bowen AR, Whatmore J, Kos K, Welters HJ (2013). Role of non-canonical Wnt signalling in pancreatic beta cells.
DIABETIC MEDICINE,
30, 17-17.
Author URL.
Alkhouli N, Mansfield J, Green E, Bell J, Knight B, Liversedge N, Tham JC, Welbourn R, Shore AC, Kos K, et al (2013). The mechanical properties of human adipose tissues and their relationships to the structure and composition of the extracellular matrix.
Am J Physiol Endocrinol Metab,
305(12), E1427-E1435.
Abstract:
The mechanical properties of human adipose tissues and their relationships to the structure and composition of the extracellular matrix.
Adipose tissue (AT) expansion in obesity is characterized by cellular growth and continuous extracellular matrix (ECM) remodeling with increased fibrillar collagen deposition. It is hypothesized that the matrix can inhibit cellular expansion and lipid storage. Therefore, it is important to fully characterize the ECM's biomechanical properties and its interactions with cells. In this study, we characterize and compare the mechanical properties of human subcutaneous and omental tissues, which have different physiological functions. AT was obtained from 44 subjects undergoing surgery. Force/extension and stress/relaxation data were obtained. The effects of osmotic challenge were measured to investigate the cellular contribution to tissue mechanics. Tissue structure and its response to tensile strain were determined using nonlinear microscopy. AT showed nonlinear stress/strain characteristics of up to a 30% strain. Comparing paired subcutaneous and omental samples (n = 19), the moduli were lower in subcutaneous: initial 1.6 ± 0.8 (means ± SD) and 2.9 ± 1.5 kPa (P = 0.001), final 11.7 ± 6.4 and 32 ± 15.6 kPa (P < 0.001), respectively. The energy dissipation density was lower in subcutaneous AT (n = 13): 0.1 ± 0.1 and 0.3 ± 0.2 kPa, respectively (P = 0.006). Stress/relaxation followed a two-exponential time course. When the incubation medium was exchanged for deionized water in specimens held at 30% strain, force decreased by 31%, and the final modulus increased significantly. Nonlinear microscopy revealed collagen and elastin networks in close proximity to adipocytes and a larger-scale network of larger fiber bundles. There was considerable microscale heterogeneity in the response to strain in both cells and matrix fibers. These results suggest that subcutaneous AT has greater capacity for expansion and recovery from mechanical deformation than omental AT.
Abstract.
Author URL.
Soni M, Kos K, Lang IA, Jones K, Melzer D, Llewellyn DJ (2012). Vitamin D and cognitive function.
Scand J Clin Lab Invest Suppl,
243, 79-82.
Abstract:
Vitamin D and cognitive function.
The role of vitamin D in skeletal health is well established, but more recent findings have also linked vitamin D deficiency to a range of non-skeletal conditions such as cardiovascular disease, cancer, stroke and metabolic disorders including diabetes. Cognitive impairment and dementia must now be added this list. Vitamin D receptors are widespread in brain tissue, and vitamin D's biologically active form [1,25(OH)(2)D3] has shown neuroprotective effects including the clearance of amyloid plaques, a hallmark of Alzheimer's Disease. Associations have been noted between low 25-hydroxyvitamin D [25(OH)D] and Alzheimer's disease and dementia in both Europe and the US. Similarly, the risk of cognitive impairment was up to four times greater in the severely deficient elders (25(OH)D < 25 nmol/L) in comparison with individuals with adequate levels (≥ 75 nmol/L). Further studies have also shown associations between low 25(OH)D concentrations and cerebrovascular events such as large vessel infarcts, risk of cerebrovascular accident and fatal stroke. Cross-sectional studies cannot establish temporal relationships because cognitive decline and the onset of dementia itself may influence vitamin D concentrations through behavioural and dietary changes. However, two large prospective studies recently indicated that low vitamin D concentrations may increase the risk of cognitive decline. Large, well designed randomized controlled trials are now needed to determine whether vitamin D supplementation is effective at preventing or treating Alzheimer's disease and dementia.
Abstract.
Author URL.
Kos K, Wong S, Tan BK, Kerrigan D, Randeva HS, Pinkney JH, Wilding JPH (2011). Human RBP4 adipose tissue expression is gender specific and influenced by leptin.
Clin Endocrinol (Oxf),
74(2), 197-205.
Abstract:
Human RBP4 adipose tissue expression is gender specific and influenced by leptin.
OBJECTIVE: the role of retinol-binding protein-4 (RBP4) in human insulin resistance remains controversial, which may in part be explained by a gender-specific secretion of RBP4 in adipose tissue (AT). The aim of the study was to determine gender-specific depot expression of RBP4 and to identify metabolic parameters and cytokines/adipokines associated with RBP4. RESEARCH DESIGN AND METHODS: the study is an ex-vivo prospective analysis of paired AT-samples from 22 men and 26 women of similar age [men: 43·4 ± 13 (mean ± SD)years, women: 44·1 ± 12 years], BMI (men: 41·9 ± 18kg/m(2) , women: 38·4 ± 11kg/m(2) ) and homeostasis model assessment of insulin resistance taken during elective surgery and ex-vivo culture using visceral-AT (VAT)-explants (n = 10). Plasma RBP4 and cytokines were measured by ELISA and mRNA expression in AT by real-time PCR. VAT-explants were cultured with recombinant leptin and insulin and RBP4 determined by western blot analyses. RESULTS: Overall subcutaneous AT (SCAT)-RBP4 mRNA expression was higher than VAT-expression [3·1 ± 0·26 signal units (SU; mean ± SE) vs 1·79 ± 0·18SU, n = 48, P < 0·0001], but neither correlated with circulating RBP4. SCAT-RBP4 expression was higher in women and correlated with BMI (r =-0·5, P = 0·009) and fat mass (r= -0·5, P = 0·002). VAT-RBP4 correlated positively with GLUT-4 expression and adiponectin in men only (r= 0·54, P = 0·03 and r = 0·64, P < 0·002, respectively) when correcting for age and fat mass. Multiple regression determined leptin AT-expression as a positive predictor of AT-RBP4 in women (SCAT: β = 0·50, P = 0·002; VAT: β = 0·58, P = 0·003) and adiponectin for VAT-RBP4 in men (β = 0·69; P=0·001). AT-RBP4 mRNA expression showed no relation with insulin resistance. Leptin stimulated RBP-4 secretion ex-vivo, whilst insulin did not affect RBP4. CONCLUSION: AT-derived RBP4-mRNA expression is gender specific and regulated by leptin. Circulating RBP4 levels appear to be independent of AT-RBP4 secretion.
Abstract.
Author URL.
Dickens AP, Lang IA, Langa KM, Kos K, Llewellyn DJ (2011). Vitamin D, cognitive dysfunction and dementia in older adults.
CNS Drugs,
25(8), 629-639.
Abstract:
Vitamin D, cognitive dysfunction and dementia in older adults.
The physiologically active form of vitamin D, 1,25-dihydroxyvitamin D(3), is a fat-soluble steroid hormone with a well established role in skeletal health. A growing body of evidence suggests low vitamin D levels also play a role in the pathogenesis of a wide range of non-skeletal, age-associated diseases including cancer, heart disease, type 2 diabetes mellitus and stroke. Low levels of serum 25-hydroxyvitamin D [25(OH)D], a stable marker of vitamin D status, are also associated with increased odds of prevalent cognitive dysfunction, Alzheimer's disease and all-cause dementia in a number of studies, raising the possibility that vitamin D plays a role in the aetiology of cognitive dysfunction and dementia. To date, the majority of human studies reporting associations between vitamin D and cognition or dementia have been cross-sectional or case-control designs that do not permit us to exclude the possibility that such associations are a result of disease progression rather than being causal. Animal and in vitro experiments have identified a number of neuroprotective mechanisms that might link vitamin D status to cognitive dysfunction and dementia, including vasoprotection and amyloid phagocytosis and clearance, but the clinical relevance of these mechanisms in humans is not currently clear. Two recent, large, prospective studies go some way to establish the temporal relationship with cognitive decline. The relative risk of cognitive decline was 60% higher (relative risk = 1.6, 95% CI 1.2, 2.0) in elderly Italian adults with severely deficient 25(OH)D levels (
Abstract.
Author URL.
Kos K, Wong SPY, Huda MSB, Cakir M, Jernas M, Carlsson L, Kerrigan D, Wilding JPH, Pinkney JH (2010). In humans the adiponectin receptor R2 is expressed predominantly in adipose tissue and linked to the adipose tissue expression of MMIF-1.
Diabetes Obes Metab,
12(4), 360-363.
Abstract:
In humans the adiponectin receptor R2 is expressed predominantly in adipose tissue and linked to the adipose tissue expression of MMIF-1.
In this study, the regional adipose tissue-adiponectin (AT-ADN) and adiponectin receptor (R1 and R2) expression and their relation with metabolic parameters, circulating and AT-derived cytokine expressions were compared. Paired subcutaneous adipose tissue (SCAT) and visceral adipose tissue (VAT) were taken from 18 lean and 39 obese humans, AT-mRNA expression of adipokines analysed by RT-PCR and corresponding serum levels by enzyme-linked immunosorbent assay (ELISA). R1 and R2 adipocyte expression was compared with 17 other human tissues. ADN-gene expression was lower in VAT than SCAT [mean (SD) 1.54 (1.1) vs. 2.84 (0.87); p < 0.001], and lower in obese subjects (VAT : p = 0.01;SCAT : p < 0.001). SCAT-ADN correlated positively with serum ADN (r = 0.33;p = 0.036) but not VAT-ADN. AT expressions of ADN and macrophage migration inhibiting factor (MMIF), IL18 and cluster of differentiation factor 14 (CD14) in both depots showed inverse correlations. R1 and R2 were expressed ubiquitously and R2 highest in SCAT, and this is much higher (x100) than R1 (x100). R expression was similar in lean and obese subjects and unrelated to the metabolic syndrome, however, receptors correlated with VAT-MMIF (R 1: r = 0.4;p = 0.008;R 2: r = 0.35,p = 0.02) and SCAT-MMIF expression (R 2: r = 0.43;p = 0.004). Unlike ADN, its receptors are expressed in many human tissues. Human R2 expression is not highest in the liver but in AT where it is associated with MMIF expression. The adiponectin-dependent insulin-sensitizing action of thiazolidinediones is thus probably to differ amongst species with weaker effects on the human liver.
Abstract.
Author URL.
Kos K, Wilding JPH (2010). SPARC: a key player in the pathologies associated with obesity and diabetes.
Nat Rev Endocrinol,
6(4), 225-235.
Abstract:
SPARC: a key player in the pathologies associated with obesity and diabetes.
SPARC (secreted protein acidic and rich in cysteine, also known as osteonectin or BM-40) is a widely expressed profibrotic protein with pleiotropic roles, which have been studied in a variety of conditions. Notably, SPARC is linked to human obesity; SPARC derived from adipose tissue is associated with insulin resistance and secretion of SPARC by adipose tissue is increased by insulin and the adipokine leptin. Furthermore, SPARC is associated with diabetes complications such as diabetic retinopathy and nephropathy, conditions that are ameliorated in the Sparc-knockout mouse model. As a regulator of the extracellular matrix, SPARC also contributes to adipose-tissue fibrosis. Evidence suggests that adipose tissue becomes increasingly fibrotic in obesity. Fibrosis of subcutaneous adipose tissue may restrict accumulation of triglycerides in this type of tissue. These triglycerides are, therefore, diverted and deposited as ectopic lipids in other tissues such as the liver or as intramyocellular lipids in skeletal muscle, which predisposes to insulin resistance. Hence, SPARC may represent a novel and important link between obesity and diabetes mellitus. This Review is focused on whether SPARC could be a key player in the pathology of obesity and its related metabolic complications.
Abstract.
Author URL.
Mracek T, Ding Q, Tzanavari T, Kos K, Pinkney J, Wilding J, Trayhurn P, Bing C (2010). The adipokine zinc-alpha2-glycoprotein (ZAG) is downregulated with fat mass expansion in obesity.
Clin Endocrinol (Oxf),
72(3), 334-341.
Abstract:
The adipokine zinc-alpha2-glycoprotein (ZAG) is downregulated with fat mass expansion in obesity.
INTRODUCTION: Zinc-alpha2-glycoprotein (ZAG) is a novel adipokine, which may act locally to influence adipocyte metabolism. This study assessed the effect of increased adiposity on ZAG expression in adipose tissue in human subjects. The study also examined the association between ZAG and adiponectin expression in human adipose tissue, and whether ZAG modulates adiponectin secretion by human adipocytes. METHODS: Adipose tissue (visceral and subcutaneous) was collected from human subjects with a wide range of BMIs. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were used for in vitro studies. ZAG mRNA levels were quantified by real-time PCR and protein by Western blotting. RESULTS: in human subjects, ZAG mRNA level was negatively correlated with BMI (r = -0.61, P < 0.001, n = 23, visceral; r = -0.6, P < 0.05, n = 14, subcutaneous) and fat mass (r = -0.62, P < 0.01, visceral; r = -0.6, P < 0.05, subcutaneous). Negative associations were also found between ZAG mRNA and insulin resistance parameters including plasma insulin (r = -0.65, P < 0.001, visceral; r = -0.55, P < 0.05, subcutaneous) and homeostasis model of insulin resistance (HOMA-IR) (r = -0.65, P < 0.001, visceral; r = -0.52, P = 0.055, subcutaneous), and C reactive protein (CRP) (r = -0.46, P < 0.05, visceral; r = -0.53, P < 0.05, subcutaneous). However, ZAG mRNA was positively correlated with adiponectin (r = 0.5, P < 0.05, visceral; r = 0.82, P < 0.001, subcutaneous) but negatively associated with leptin mRNA (r = -0.42, P < 0.05, visceral; r = -0.54, P < 0.05, subcutaneous). ZAG secretion by differentiated human adipocytes was abundant. Addition of recombinant ZAG stimulated adiponectin release from human adipocytes. CONCLUSION: ZAG gene expression in adipose tissue is downregulated with increased adiposity and circulating insulin. ZAG mRNA is positively correlated with adiponectin mRNA, and ZAG enhances adiponectin production by human adipocytes. We suggest that ZAG is linked to obesity and obesity-related insulin resistance.
Abstract.
Author URL.
Kos K, Wilding JPH (2009). Adipokines: emerging therapeutic targets.
Curr Opin Investig Drugs,
10(10), 1061-1068.
Abstract:
Adipokines: emerging therapeutic targets.
Adipose tissue can affect human physiology through its secreted products, collectively termed adipokines, which mediate complex crosstalk between organs. Adipokines have been linked to a wide range of pathologies in many tissues; however, the pathophysiological significance of these cytokines remains poorly understood, and more research is needed in this area. Adipokines may have both beneficial and potentially harmful effects; for example, leptin reduces body weight, but also impairs immune responses. A cautious approach is therefore warranted when considering the pharmacological manipulation of adipokines to treat diseases, and novel approaches may be required to target specific organs or actions to reduce the potential for adverse effects.
Abstract.
Author URL.
Kos K, Baker AR, Jernas M, Harte AL, Clapham JC, O'Hare JP, Carlsson L, Kumar S, McTernan PG (2009). DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue.
Diabetes Obes Metab,
11(4), 285-292.
Abstract:
DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue.
CONTEXT: Dipeptidyl peptidase IV (DPP-IV) inactivates the incretin hormone glucagon-like peptide. It can also affect the orexigenic hormone neuropeptide Y (NPY(1-36)) which is truncated by DPP-IV to NPY(3-36), as a consequence NPY's affinity changes from receptor Y1, which mediates the antilipolytic function of NPY, to other NPY receptors. Little is known whether DPP-IV inhibitors for the treatment of type 2 diabetic (T2DM) patients could influence these pathways. AIMS: to investigate the in vitro effects of NPY with DPP-IV inhibition in isolated abdominal subcutaneous (AbdSc) adipocytes on fat metabolism, and assessment of NPY receptor and DPP-IV expression in adipose tissue (AT). METHODS: Ex vivo human AT was taken from women undergoing elective surgery (body mass index: 27.5 (mean +/- s.d.) +/- 5 kg/m2, age: 43.7 +/- 10 years, n = 36). Isolated AbdSc adipocytes were treated with human recombinant (rh)NPY (1-100 nM) with and without DPP-IV inhibitor (1 M); glycerol release and tissue distribution of DPP-IV, Y1 and Y5 messenger RNA (mRNA) were measured and compared between lean and obese subjects. RESULTS AND CONCLUSION: rhNPY reduced glycerol release, an effect that was further enhanced by co-incubation with a DPP-IV inhibitor [control: 224 (mean +/- s.e.) +/- 37 micromol/l; NPY, 100 nM: 161 +/- 27 micromol/l. ; NPY 100 nM/DPP-IV inhibitor, 1 M: 127 +/- 14 micromol/l. ;. p < 0.01, n = 14]. DPP-IV was expressed in AbdSc AT and omental AT with relative DPP-IV mRNA expression lower in AbdSc AT taken from obese [77 +/- 6 signal units (SU)] vs. lean subjects (186 +/- 29 SU*, n = 10). Y1 was predominantly expressed in fat and present in all fat depots but higher in obese subjects, particularly the AbdSc AT-depot (obese: 1944 +/- 111 SU vs. lean: 711 +/- 112 SU. n = 10). NPY appears to be regulated by AT-derived DPP-IV. DPP-IV inhibitors augment the antilipolytic effect of NPY in AT. Further studies are required to show whether this explains the lack of weight loss in T2DM patients treated with DPP-IV inhibitors.
Abstract.
Author URL.
Kos K, Harte AL, O'Hare PJ, Kumar S, McTernan PG (2009). Ghrelin and the differential regulation of des-acyl (DSG) and oct-anoyl ghrelin (OTG) in human adipose tissue (AT).
Clin Endocrinol (Oxf),
70(3), 383-389.
Abstract:
Ghrelin and the differential regulation of des-acyl (DSG) and oct-anoyl ghrelin (OTG) in human adipose tissue (AT).
OBJECTIVES: Ghrelin, an important central acting orexigenic hormone, is predominantly secreted in the gastrointestinal tract. However little is known about the action of ghrelin in human adipose tissue (AT). AIM: to study the expression of ghrelin in AT, the effects of octanoyl-(OTG) and des-acyl (DSG) ghrelin on lipolysis and lipogenesis, leptin release and potential peripheral signalling through the Y1 receptor. METHODS: Ex vivo human AT was obtained from women undergoing elective surgery (46 (mean +/- SD) 6.8 years, body mass index (BMI): 25.6 +/- 5.0 kg/m(2), n = 20). Abdominal-subcutaneous (AbdSc) adipocytes were isolated and treated with recombinant human (rh) OTG and DSG to assess lipid metabolism leptin release and the influence of Y1-receptor blocker. RESULTS: Ghrelin was expressed in AbdScAT and negatively correlated with BMI (lean: 3.6 +/- 0.74 optical-density-units (OD), obese: 1.64 +/- 0.45 OD. P < 0.05). Only DSG significantly suppressed glycerol release (Control (C): 286 +/- 58 microl/l; DSG 1 nm: 224 +/- 38 microl/l downward arrow*; DSG 100 nm: 172 +/- 13 microl/l downward arrow*. downward arrow P < 0.05, n = 7) and reduced hormone sensitive lipase expression (C: 1.0 +/- 0.3 OD; DSG 1 nm: 0.8 +/- 0.3 OD downward arrow*; DSG 100 nm: 0.6 +/- 0.1 OD downward arrow*, n = 4). However, both isoforms increased lipoprotein lipase expression (C: 1.0 +/- 0.3OD; DSG 100 nm: 0.2 +/- 0.4 OD upward arrow*; OTG 100 nm: 2.5 +/- 0.3 OD upward arrow*, n = 4), whilst blockade of Y1 eliminated this effect in both. Leptin was down-regulated by DSG only (DSG 1 nm: 5.3 +/- 0.7 ng/ml; DSG 100 nm: 4.1 +/- 0.7 ng/ml*) and was significant after BMI adjustment (P = 0.029). CONCLUSION: Ghrelin was expressed in human AbdSc AT. In vitro, both OGT and DSG appear to mediate fat deposition with the lipogenic effects in part mediated by the Y1 receptor, whilst the influence of DSG affected lipolysis, lipogenesis and leptin secretion. Taken together, these studies support a local action for ghrelin isoforms on lipid and adipokine metabolism that further supports a cross talk between organs.
Abstract.
Author URL.
Ding Q, Mracek T, Gonzalez-Muniesa P, Kos K, Wilding J, Trayhurn P, Bing C (2009). Identification of macrophage inhibitory cytokine-1 (MIC-1) in adipose tissue and its secretion as an adipokine by human adipocytes. Proceedings of the Nutrition Society, 68(OCE2).
Ding Q, Mracek T, Gonzalez-Muniesa P, Kos K, Wilding J, Trayhurn P, Bing C (2009). Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes.
Endocrinology,
150(4), 1688-1696.
Abstract:
Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes.
Macrophage inhibitory cytokine-1 (MIC-1), a divergent member of the TGF-beta superfamily, is involved in the control of multiple cellular processes and mediates cachexia through the inhibition of appetite. Adipose tissue as an endocrine organ secretes proteins (adipokines) that regulate energy homeostasis and other cellular functions. This study investigated whether MIC-1 is expressed in adipose tissue and whether MIC-1 is a secretory product of adipocytes. Mouse and human adipose tissues were collected from different depots. 3T3-L1 preadipocytes and human preadipocytes were induced to differentiate into adipocytes in cell culture. MIC-1 mRNA was detected in the major mouse adipose depots (epididymal, perirenal, sc). In these depots, MIC-1 gene expression was evident in both isolated mature adipocytes and stromal-vascular cells. In 3T3-L1 adipocytes, MIC-1 mRNA was detected before and after differentiation. MIC-1 mRNA and protein secretion were evident in human preadipocytes as well as differentiated adipocytes. MIC-1 production by human adipocytes was stimulated by H(2)O(2) and 15d-prostaglandin J(2). In addition, recombinant MIC-1 increased adiponectin secretion by differentiated human adipocytes. MIC-1 mRNA and protein were also observed in human sc and visceral fat. MIC-1 mRNA levels were positively correlated with adiponectin mRNA. Moreover, MIC-1 mRNA was negatively associated with body mass index and body fat mass in human subjects. We conclude that MIC-1 is expressed in adipose tissue and secreted from adipocytes and is therefore a new adipokine. MIC-1 may have a paracrine role in the modulation of adipose tissue function and body fat mass.
Abstract.
Author URL.
Kos K, Wong S, Tan B, Gummesson A, Jernas M, Franck N, Kerrigan D, Nystrom FH, Carlosson LM, Randeva HS, et al (2009). Regulation of the fibrosis and angiogenesis promoter SPARC/osteonectin in human adipose tissue by weight change, leptin, insulin and glucose. Diabetes, 8(58), 1780-1788.
Mracek T, Ding Q, Tzanavari T, Kos K, Pinkney J, Wilding J, Trayhurn P, Bing C (2009). The aipokine zinc-α2-glycoprotein is down regulated with fat mass expansion in obesity. Proceedings of the Nutrition Society, 68(OCE2).
Kos K, Wong S, Kerrigan D, Wilding JPH, Pinkney JH (2008). Adipose tissue derived SPARC and obesity related inflammation in healthy.
DIABETOLOGIA,
51, S330-S331.
Author URL.
Parving H-H, Persson F, Lewis JB, Lewis EJ, Hollenberg NK (2008). Aliskiren combined with losartan in type 2 diabetes and nephropathy.
NEW ENGLAND JOURNAL OF MEDICINE,
358(23), 2433-2446.
Author URL.
Kos K, Syn W-K, Lewandowski KC, Bennett J, Nwokolo CU, O'Hare JP, Randeva H (2008). Comparison of maternal ghrelin and leptin in healthy mothers and mothers with Type 1 diabetes.
Diabet Med,
25(12), 1400-1405.
Abstract:
Comparison of maternal ghrelin and leptin in healthy mothers and mothers with Type 1 diabetes.
AIMS: Maternal leptin affects placental growth hormone (GH), whereas ghrelin, a natural ligand of the growth-hormone-secretagogue receptor, modulates GH action. Both hormones may affect fetal growth, and dysregulation in diabetes may lead to fetal growth disturbances. The aim was to investigate changes in maternal ghrelin during pregnancy with diabetes and to establish reference leptin levels. METHODS: Twelve healthy non-diabetic (ND) and 12 pregnant women with Type 1 diabetes (T1DM) were recruited. Age and body mass index (BMI) [ND: age 29.9 +/- 4.7 years (mean +/- sd), BMI 25.2 +/- 3.7 kg/m2; T1DM: age 31 +/- 5.5 years, BMI 27 +/- 3.1 kg/m2] were similar in the groups. HbA1c in T1DM was 6.2 +/- 1.1% at 20 weeks, 6.3 +/- 1.1% at 30 weeks' gestation and 7.8 +/- 2.1% postpartum. Fasting plasma ghrelin, total leptin, free leptin (FL) and soluble leptin receptor (sOB-R) levels were measured at 20 and 30 weeks' gestation and postpartum and determined by radioimmunoassay. RESULTS: all pregnancies resulted in full-term singleton births with no differences in birth weight between groups [T1DM: 3.4 +/- 0.56 kg (mean +/- SE); ND: 3.6 +/- 0.3 kg, P = NS]. Ghrelin levels were lower in T1DM when corrected for age and mothers' weight (T1DM: 458 +/- 36 pg/ml and 432.9 +/- 26.6 pg/ml; ND: 562 +/- 52 pg/ml and 515.8 +/- 63 pg/ml at 20 and 30 weeks, respectively, P < 0.05). T1DM mothers had higher levels of sOB-R and FL levels declined at 30 weeks' gestation in T1DM (P = 0.04) but not in ND. CONCLUSION: in a population of pregnant women with expected changes in leptin levels as previously reported, ghrelin levels were lower in T1DM pregnancies at 20 and 30 weeks. This may have implications for fetal development and requires further study in diabetes, particularly in pregnancies that result in macrosomia.
Abstract.
Author URL.
Pinkney JH, Wong SPY, Kerrigan D, Kos K, Wilding JPH (2008). Distribution and characteristics of adiponectin R1 and R2 receptor in RNA gene expression in human visceral and subcutaneous adipose tissue.
DIABETOLOGIA,
51, S90-S90.
Author URL.
Kos K, Harte AL, da Silva NF, Tonchev A, Chaldakov G, James S, Snead DR, Hoggart B, O'Hare JP, McTernan PG, et al (2007). Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus.
J Clin Endocrinol Metab,
92(3), 1129-1136.
Abstract:
Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus.
CONTEXT: the adipokine leptin has critical importance in central appetite regulation. In contrast to some suggestion of adiponectin influencing energy homeostasis in rodents, there is no evidence for adiponectin or resistin entering the human blood-brain barrier. OBJECTIVE: the objective was to establish the presence of adiponectin or resistin in human cerebrospinal fluid (CSF) and to compare their distribution with leptin. Furthermore, we wished to examine the expression of the adiponectin receptors 1 and 2 (AdipR1, AdipR2) in the human hypothalamus. METHODS: for this purpose, serum and CSF samples were collected from 20 men and 19 women matched for age [men, 69.8 +/- 8.6 yr (mean +/- SD); women, 69.4 +/- 4.3 yr] and BMI (men, 29.4 +/- 3.4 kg/m(2); women, 27.3 +/- 4.8 kg/m(2)) undergoing elective surgery under spinal anesthesia. RESULTS: Adiponectin was identified in CSF with levels 1000-fold less than serum, whereas resistin and leptin levels were 100-fold less. Unlike their serum levels, adiponectin CSF levels showed no gender difference or correlation with insulin resistance, which is similar to resistin CSF levels. The adiponectin and leptin CSF/serum ratios in our study exhibit the same pattern of gender-specific BMI association with inverse correlation in women (r = -0.61; P = 0.02) and no correlation in men (r = 0.026; P = not significant). Furthermore, immunostaining established AdipR1 and -2 in the hypothalamus and increased AdipR2 expression in the paraventricular nucleus, which is involved in energy regulation. CONCLUSION: in summary, our findings show both the presence of adiponectin and resistin in human CSF, with no effect of insulin resistance on CSF levels. The CSF entry of adiponectin and leptin in women appears to be impaired in obesity.
Abstract.
Author URL.
Kusminski CM, McTernan PG, Schraw T, Kos K, O'Hare JP, Ahima R, Kumar S, Scherer PE (2007). Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum.
Diabetologia,
50(3), 634-642.
Abstract:
Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum.
AIMS/HYPOTHESIS: Adiponectin is an adipocyte-derived secretory factor that is specifically produced in adipocytes. It exerts effects on energy homeostasis via peripheral and central mechanisms. However, it is not clear whether adiponectin crosses the blood-brain barrier in humans. In serum, adiponectin circulates in several different complexes, each of which has distinct functions. Here, we wanted to test whether adiponectin can be found in human cerebrospinal fluid (CSF) and whether specific adiponectin complexes are enriched in CSF compared with peripheral serum samples. We also wanted to establish whether there is a sex-related difference with regard to the distribution of adiponectin oligomers in CSF. MATERIALS AND METHODS: We studied 22 subjects (11 men, 11 women) in this study. Their average BMI was 28.0+/-4.7 kg/m2; average age was 70+/-7 years. RESULTS: Analysis of total adiponectin revealed that adiponectin protein is present in human CSF at approximately 0.1% of serum concentration. The distribution of adiponectin oligomers differs considerably in CSF from that of serum within matched samples from the same patients. Only the adiponectin trimeric and low-molecular-mass hexameric complexes are found in CSF, with a bias towards the trimeric form in most patients. Male subjects have a higher CSF:serum ratio of total adiponectin (p
Abstract.
Author URL.
Kos K, Baker A, Harte A, O'Hare JP, McTernan P, Kumar S (2007). DPP IV in human adipose tissue may regulate adipose tissue mass through modulation of NPY.
DIABETIC MEDICINE,
24, 35-35.
Author URL.
Kos K, Harte AL, James S, Snead DR, O'Hare JP, McTernan PG, Kumar S (2007). Secretion of neuropeptide Y in human adipose tissue and its role in maintenance of adipose tissue mass.
Am J Physiol Endocrinol Metab,
293(5), E1335-E1340.
Abstract:
Secretion of neuropeptide Y in human adipose tissue and its role in maintenance of adipose tissue mass.
NPY is an important central orexigenic hormone, but little is known about its peripheral actions in human adipose tissue (AT) or its potential paracrine effects. Our objective was to examine NPY's role in AT, specifically addressing NPY protein expression, the effect of NPY on adipokine secretion, and the influence of insulin and rosiglitazone (RSG) on adipocyte-derived NPY in vitro. Ex vivo human AT was obtained from women undergoing elective surgery [age: 42.7 +/- 1.5 yr (mean +/- SE), BMI: 26.2 +/- 0.7 kg/m(2); n = 38]. Western blot analysis was used to determine NPY protein expression in AT depots. Abdominal subcutaneous (AbSc) adipocytes were isolated and treated with recombinant (rh) NPY, insulin, and RSG. NPY and adipokine levels were measured by ELISA. Our results were that NPY was localized in human AT and adipocytes and confirmed by immunohistochemistry. Depot-specific NPY expression was noted as highest in AbSc AT (1.87 +/- 0.23 ODU) compared with omental (Om; 1.03 +/- 0.15 ODU, P = 0.029) or thigh AT (Th; 1.0 +/- 0.29 ODU, P = 0.035). Insulin increased NPY secretion (control: 0.22 +/- 0.024 ng/ml; 1 nM insulin: 0.26 +/- 0.05 ng/ml; 100 nM insulin: 0.29 +/- 0.04 ng/ml; 1,000 nM insulin: 0.3 +/- 0.04 ng/ml; P < 0.05, n = 13), but cotreatment of RSG (10 nM) with insulin (100 nM) had no effect on NPY secretion. Furthermore, adipocyte treatment with rh-NPY downregulated leptin secretion (control: 6.99 +/- 0.89 ng/ml; 1 nmol/l rh-NPY: 4.4 +/- 0.64 ng/ml; 10 nmol/l rh-NPY: 4.3 +/- 0.61 ng/ml, 100 nmol/l rh-NPY: 4.2 +/- 0.67 ng/ml; P < 0.05, n = 10) but had no effect on adiponectin or TNF-alpha secretion. We conclude that NPY is expressed and secreted by human adipocytes. NPY secretion is stimulated by insulin, but this increment was limited by cotreatment with RSG. NPY's antilipolytic action may promote an increase in adipocyte size in hyperinsulinemic conditions. Adipose-derived NPY mediates reduction of leptin secretion and may have implications for central feedback of adiposity signals.
Abstract.
Author URL.
Kos K, Baker C, Kumar S (2005). Current treatment strategies for obesity. Journal of clinical practice, 2(6), 955-967.
