Gillian E. Walker

Acylated ghrelin decreases during acute exercise in the lean and obese state

Ghrelin, the GH-secretagogue receptor ligand, is chiefly acknowledged as a central modulator of energy homeostasis. 1 In addition to promoting the drive to eat and governing long-term energy accumulation, ghrelin has been shown to influence fuel oxidation, increase the respiratory exchange ratio (RER), decrease spontaneous physical activity and enhance cardiac function. 1 In the bloodstream, ghrelin circulates both as an acylated and desacylated peptide. Ghrelin concentrations are acutely suppressed after food ingestion or glucose infusion, while fat accumulation is a long-term negative regulator. 2,3 Recent studies in lean individuals prompted debated evidence that acute exercise decreases total and acylated ghrelin levels in relation to GH concentrations and perceived appetite ratings. 4–6

The pathophysiology of abdominal adipose tissue depots in health and disease.

Abstract Obesity is currently the most important contributor to ill health and expenditure worldwide. More alarming is the fact that the pediatric population parallels adults, with obesity closely associated to type 2 diabetes mellitus (T2D), cardiovascular disease, hypertension, non-alcoholic fatty liver disease, vitamin D deficiency (VDD) and certain types of cancer. The observation in the early 1950s that android or truncal adipose tissue (AT) distribution compared to gynoid had a greater association with metabolic dysfunction, in particular T2D and cardiovascular disease risk, led to the hypothesis that obesity-associated complications are not associated with fat mass per se, but the pattern of fat distribution. This concept was further supported by groups of individuals with metabolic dysfunction despite a lean phenotype, and healthy obese people protected from metabolic dysfunction. It is now well recognized that an increase in visceral AT is an independent risk factor for the development of obesity-associated comorbidities with AT depot distribution, their anatomic, cellular and molecular features defining their role. The differences and the plasticity of subcutaneous, visceral and ectopic ATs to store and release fatty acids and to synthesize and secrete adipokines, defines the metabolic outcomes. The present review will examine the phenotypic and pathophysiological differences between the different AT depots, with a particular focus on the abdominal depots and their link to metabolic complications.

Control of growth hormone and IGF1 in patients with acromegaly in the UK: responses to medical treatment with somatostatin analogues and dopamine agonists.

We investigated the control of GH and IGF1 in acromegaly in routine clinical practice in the UK on and off medical treatment.

High-end normal adrenocorticotropic hormone and cortisol levels are associated with specific cardiovascular risk factors in pediatric obesity: a cross-sectional study

BackgroundThe hypothalamic-pituitary-adrenal (HPA) axis, and in particular cortisol, has been reported to be involved in obesity-associated metabolic disturbances in adults and in selected populations of adolescents. The aim of this study was to investigate the association between morning adrenocorticotropic hormone (ACTH) and cortisol levels and cardiovascular risk factors in overweight or obese Caucasian children and adolescents.MethodsThis cross-sectional study of 450 obese children and adolescents (aged 4 to 18 years) was performed in a tertiary referral center. ACTH, cortisol, cardiovascular risk factors (fasting and post-challenge glucose, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, and hypertension) and insulin resistance were evaluated. All analyses were corrected for confounding factors (sex, age, puberty, body mass index), and odds ratios were determined.ResultsACTH and cortisol levels were positively associated with systolic and diastolic blood pressure, triglycerides, fasting glucose and insulin resistance. Cortisol, but not ACTH, was also positively associated with LDL-cholesterol. When adjusted for confounding factors, an association between ACTH and 2 h post-oral glucose tolerance test glucose was revealed. After stratification according to cardiovascular risk factors and adjustment for possible confounding factors, ACTH levels were significantly higher in subjects with triglycerides ≥90th percentile (P <0.02) and impaired fasting glucose or glucose tolerance (P <0.001). Higher cortisol levels were found in subjects with blood pressure ≥95th percentile and LDL-cholesterol ≥90th percentile. Overall, the highest tertiles of ACTH (>5.92 pmol/l) and cortisol (>383.5 nmol/l) although within the normal range were associated with increases in cardiovascular risk factors in this population.ConclusionsIn obese children and adolescents, high morning ACTH and cortisol levels are associated with cardiovascular risk factors. High ACTH levels are associated with high triglyceride levels and hyperglycemia, while high cortisol is associated with hypertension and high LDL-cholesterol. These specific relationships suggest complex mechanisms through which the HPA axis may contribute to metabolic impairments in obesity, and merit further investigations.

Pediatric obesity and vitamin D deficiency: a proteomic approach identifies multimeric adiponectin as a key link between these conditions.

Key circulating molecules that link vitamin D (VD) to pediatric obesity and its co-morbidities remain unclear. Using a proteomic approach, our objective was to identify key molecules in obese children dichotomized according to 25OH-vitamin D (25OHD) levels. A total of 42 obese children (M/Fu200a=u200a18/24) were divided according to their 25OHD3 levels into 25OHD3 deficient (VDD; nu200a=u200a18; 25OHD<15 ng/ml) or normal subjects (NVD; nu200a=u200a24; >30 ng/ml). Plasma proteomic analyses by two dimensional (2D)-electrophoresis were performed at baseline in all subjects. VDD subjects underwent a 12mo treatment with 3000 IU vitamin D3 once a week to confirm the proteomic analyses. The proteomic analyses identified 53 “spots” that differed between VDD and NVD (p<0.05), amongst which adiponectin was identified. Adiponectin was selected for confirmational studies due to its tight association with obesity and diabetes mellitus. Western Immunoblot (WIB) analyses of 2D-gels demonstrated a downregulation of adiponectin in VDD subjects, which was confirmed in the plasma from VDD with respect to NVD subjects (p<0.035) and increased following 12mo vitamin D3 supplementation in VDD subjects (p<0.02). High molecular weight (HMW) adiponectin, a surrogate indicator of insulin sensitivity, was significantly lower in VDD subjects (p<0.02) and improved with vitamin D3 supplementation (p<0.042). A direct effect in vitro of 1α,25-(OH)2D3 on adipocyte adiponectin synthesis was demonstrated, with adiponectin and its multimeric forms upregulated, even at low pharmacological doses (10−9 M) of 1α,25-(OH)2D3. This upregulation was paralleled by the adiponectin interactive protein, DsbA-L, suggesting that the VD regulation of adiponectin involves post-transciptional events. Using a proteomic approach, multimeric adiponectin has been identified as a key plasma protein that links VDD to pediatric obesity.

Influence of Ultraviolet Radiation on the Association between 25-Hydroxy Vitamin D Levels and Cardiovascular Risk Factors in Obesity

OBJECTIVEnTo establish if the correction with estimates of ultraviolet (UV) exposure influences the association between 25-OH-vitamin D (25OHD) levels and metabolic variables.nnnSTUDY DESIGNnA cross-sectional study was performed in 575 obese children and adolescents (>6 years of age) in a tertiary referral center. Cardiovascular risk factors were measured. The estimate of UV exposure was evaluated by 3 methods: (1) season; (2) mean of UV radiation (UVR); and (3) mean of UV index (UVI). UVR and UVI were considered at 1 (UVR 1 month prior to testing [UVR1], UVI 1 month prior to testing [UVI1]) or 3 (UVR 3 months prior to testing [UVR3], UVI 3 months prior to testing [UVI3]) months prior to testing. All analyses were corrected for confounders (sex, age, puberty, body mass index, waist circumference, the inclusion and exclusion of estimates of UV exposure).nnnRESULTSnThe 25OHD levels were associated with seasons, UVR1, UVR3, UVI1, and UVI3, and best associations with UVR3 and UVI3. In all models, total cholesterol, low-density lipoprotein cholesterol and triglycerides were negatively associated with 25OHD levels. The strength of the association increased with no correction, correction for seasons, UVR, and UVI. UVR3 and UVI3 performed better than UVR1 and UVI3.nnnCONCLUSIONSnHigher lipid concentrations were associated with low 25OHD levels in obese children and adolescents with the power of the association dependent on the estimates of UVR. As the mean values 3 months prior to testing for both UVR and UVI determined the best associations, the interval of the steady state time of 25OHD levels could be preferentially used in the metabolic studies. Controlling for an estimate of UVR is important to decrease the heterogeneity of studies.

Lymphocytes and immunoglobulin patterns across the threshold of severe obesity

The proinflammatory state of metabolic disorders encompasses the alterations in leukocyte counts and acute-phase reactants, and thus, predisposes to acute and chronic cardiovascular events linked to fat accumulation. Leptin is a marker of adiposity and also yields regulatory effects on innate and adaptive immunity; however, its role on the immune function of obese subjects remains to be elucidated. The aim of this study is to determine the influence of obesity and the role of leptin concentrations on lymphocyte counts and immunoglobulin levels as broad markers of immune function. Cross-sectional analysis in 147 obese (64 M, BMI 43xa0±xa08.1xa0kg/m2) and 111 age- and sex-matched controls (36 M, BMI 22.5xa0±xa02.6xa0kg/m2) by assessment of peripheral leukocyte counts, immunoglobulin (Ig) A, G, M levels, leptin, glucose and lipid homeostasis, and acute-phase reactants. Compared to controls, all the leukocyte components were significantly increased in obesity (pxa0<xa00.0001 for all) except for basophils and eosinophils. While IgA and IgG levels were similar between groups, IgM levels were lower (pxa0<xa00.001) in obese individuals. A significant relationship was evident between leptin and leukocyte counts (pxa0<xa00.001), with this latter being correlated to insulin resistance, adiposity, and lipid profile. At the stepwise multiple regression analysis, leukocytes were best predicted by leptin (βxa0=xa00.43, pxa0<xa00.0001) and male gender (βxa0=xa00.15, pxa0<xa00.05), yet when obesity entered the equation, it acted as an independent predictor of leukocytes (βxa0=xa00.51, pxa0<xa00.0001). Leptin also acted as a predictor of IgA levels (βxa0=xa00.20, pxa0<xa00.01). Current results show that IgM levels are significantly decreased in patients with obesity in association to significant increments in leukocyte counts. These latter are markedly correlated to leptin levels, insulin resistance, lipid profile, and adiposity. This circumstance, and the significant correlation seen between leptin and IgA levels, may suggest an indirect intervention of leptin in the immunologic alterations consequent to obesity and related to its cardiovascular risk.

Obesity modifies expression profiles of metabolic markers in superficial and deep subcutaneous abdominal adipose tissue depots

Abstract While visceral adipose tissue (VAT) associates to obesity, there is debate for subcutaneous adipose tissue (SAT). One explanation may be SAT subcompartments, superficial-SAT (sSAT) and deep-SAT (dSAT), recently recognized as independent depots. Our aim was to establish roles for sSAT/dSAT with obesity by examining the expression of proteins key to adipocyte metabolism. Paired biopsies from sSAT and dSAT of 10 normal-weight (BMI 21.8xa0±xa00.8xa0kg/m2) and 11 obese subjects (BMI 44xa0±xa02.1xa0kg/m2) were analyzed for differences in insulin sensitivity using adiponectin, GLUT4 and resistin, glucocorticoid metabolism by 11βHSD1 and alterations of the adipokines leptin and TNFα. Between lean and obese subjects, sSAT and dSAT changes for GLUT4, resistin and TNFα were equivalent. Resistin and TNFα increased in both obese SAT sub-compartments; 33-fold (sSAT; Pxa0<xa00.006) and 18.5-fold (dSAT; Pxa0<xa00.003) higher resistin, with undetectable in leans to significant TNFα levels in obese. In contrast, GLUT4 showed 5.5-fold (sSAT; Pxa0<xa00.03) and 7-fold (dSAT; Pxa0<xa00.03) lower levels in obese, correlating to BMI (rxa0=xa0−0.6423, Pxa0=xa00.007) and HOMA-IR (rxa0=xa0−0.5882, Pxa0=xa00.017). Exclusive sSAT-specific differences were observed for adiponectin, leptin, and 11βHSD1. Both sSAT 11βHSD1 and leptin increased in obese, with 11βHSD1 2.5-fold (Pxa0=xa00.052) and leptin 3.3-fold (Pxa0<xa00.008) higher, with 11βHSD1 correlating to HOMA-IR (rxa0=xa00.5203, Pxa0=xa00.0323) and leptin to BMI (rxa0=xa00.5810, Pxa0=xa00.01). In contrast, obese had 7-fold (Pxa0<xa00.02) lower sSAT adiponectin, correlating to BMI (rxa0=xa0−0.5178, Pxa0=xa00.027) and HOMA-IR (rxa0=xa0−0.4570, Pxa0=xa00.049). Overall, sSAT and dSAT are distinct abdominal adipose tissue depots with independent metabolic functions. Between the two, sSAT shows clear independent effects that associate to obesity and its metabolic complications.

Dynamics of GH secretion during incremental exercise in obesity, before and after a short period of training at different work‐loads

Backgroundu2002 Growth hormone (GH) secretion is normally sensitive to physical exercise. Intensity and duration of exercise, fitness and age can all influence the GH response to exercise. In obesity, GH secretion is decreased both in basal conditions and in response to exercise.

Effect of monomeric adiponectin on cardiac function and perfusion in anesthetized pig

Adiponectin, the most abundant adipokine released by adipose tissue, appears to play an important role in the regulation of vascular endothelial and cardiac function. To date, however, the physiological effects of human monomeric adiponectin on the coronary vasculature and myocardial systo-diastolic function, as well as on parasympathetic/sympathetic involvement and nitric oxide (NO) release, have not yet been investigated. Thus, we planned to determine the primary in vivo effects of human monomeric adiponectin on coronary blood flow and cardiac contractility/relaxation and the related role of autonomic nervous system, adiponectin receptors, and NO. In 30 anesthetized pigs, human monomeric adiponectin was infused into the left anterior descending coronary artery at constant heart rate and arterial blood pressure, and the effects on coronary blood flow, left ventricular systo-diastolic function, myocardial oxygen metabolism, and NO release were examined. The mechanisms of the observed hemodynamic responses were also analyzed by repeating the highest dose of human monomeric adiponectin infusion after autonomic nervous system and NO blockade, and after specific adiponectin 1 receptor antagonist administration. Intracoronary human monomeric adiponectin caused dose-related increases of coronary blood flow and cardiac function. Those effects were accompanied by increased coronary NO release and coronary adiponectin levels. Moreover, the vascular effects of the peptide were prevented by blockade of β2-adrenoceptors and NO synthase, whereas all effects of human monomeric adiponectin were prevented by adiponectin 1 receptor inhibitor. In conclusion, human monomeric adiponectin primarily increased coronary blood flow and cardiac systo-diastolic function through the involvement of specific receptors, β2-adrenoceptors, and NO release.