Hindsight: 2nd International Symposium on Obesity and Hypertension, Oct 28-30, 2001

Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany

Regular readers of these pages may recall a previous posting on the 1st International Symposium on Obesity and Hypertension (ISOH’99), where I brought together a panel of distinguished obesity and hypertension experts to discuss the latest research in these fields.

The 2nd Symposium in this series was held on October 28-30, 2001 at the Max Delbrück Center for Molecular Medicine in Berlin-Buch, Germany, to which I had moved from my old appointment at the Universitätsklinikum Benjamin Franklin of the Freie Universität Berlin a few months earlier.

The meeting, which again consisted of invited lectures, presented a state-of-the-art overview of the genetic and molecular mechanisms that link obesity and hypertension. This time around, the over 40 oral presentations were supplemented by 85 poster presentations from 27 countries.

Perhaps even more interestingly, this 2nd Symposium was attended by a rather impressive 250 participants from 48 countries including speakers and attendees from as far away as Australia and South Africa. While today, as similar meeting may draw well over twice that number, back in 2001, obesity had yet to make it to the forefront of people’s attention.

The following is a synopsis of the oral presentations, again reflecting the breath and depth of research in this area at the time. Researchers will once again recognise some of the top names in this community and appreciate the cutting-edge nature of the work presented at this symposium.

Obesity as a risk factor

Stephan Rössner (President, International Association for the Study of Obesity, Stockholm, Sweden) introduced the audience to the work and scope of IASO, stressing the importance of a global response to the worldwide obesity epidemic. He also stressed the alarming rate with which body weights are increasing among countries in transition, where the problems of obesity are becoming manifest even before the legacy of malnutrition is completely removed.

Jacob C Seidell (National Institute of Public Health and the Environment, Bilthoven, The Netherlands) pointed out that, in many Asian countries, the risk of type 2 diabetes and hypertension increases sharply at levels of body mass index (BMI) generally considered acceptable in European and North American white people. The suggested reclassification of obesity in Asians (ie 25 kg/m2) will greatly affect the prevalence of obesity estimates worldwide (currently at about 250 million).

Edward D Frohlich (Alton Ochsner Medical Foundation, New Orleans, USA) emphasized the multifactorial nature of obesity and hypertension and also described the profound hemodynamic changes observed in obese individuals. Despite its high prevalence, the understanding of the pathophysiology and management of obesity-related hypertension remains inadequate and clearly deserves more attention from the cardiovascular community.

The relationship between cardiac geometry and an increase in body mass was extensively described by Heribert Schunkert (University of Regensburg, Germany). He stressed that, while left ventricular hypertrophy (LVH) is common in obese individuals, this appears largely to reflect a physiological response to increased metabolic demand of fat-free mass. Thus, when indexed for fat-free mass, the risk for LVH is only 2.5-fold higher in obese individuals, a figure substantially lower than the 5.5-fold increase observed when indexed for height.

Paul E de Jong (Department of Nephrology, University Hospital Groningen, The Netherlands) drew attention to the relationship between obesity and renal dysfunction, a hitherto largely unrecognized consequence of obesity. Thus, in the recent PREVEND study, a population-based cross-sectional study in over 7000 individuals, obesity was independently associated with an increased risk for both hyperfiltration and impaired filtration. Furthermore, even in non-diabetics, increased waist circumference was associated with an increased prevalence of microalbuminuria, now recognized as an independent risk factor for overall cardiovascular morbidity and mortality.

Based on observations from the Prospective cardiovascular Münster (PROCAM) study in over 16 000 individuals, Gerd Assmann (Institute of Atherosclerosis Research, University of Münster, Germany) showed that high BMI was associated with increased mortality, largely attributable to coronary artery disease, both in smokers and non-smokers. Nevertheless, BMI failed to emerge as an independent risk factor, indicating that the effect of overweight on coronary artery disease is largely mediated via other risk factors.

Amanda Adler (Diabetes Tirals Unit, Radcliffe Infirmary, Oxford, UK) presented recent analyses from the United Kingdom Prospective Diabetes Study on the prevalence and role of obesity as a risk factor for diabetic complications.

Genetic factors

Stephen B Harrap (Department of Physiology, University of Melbourne, Australia) presented new results from the Victorian Family Heart Study (VFHS), where he found four quantitative trait loci (QTLs) for systolic blood pressure (SBP) on chromosomes 1, 4, 16 and X. After adjustment of systolic pressure for BMI there was little change in the additive genetic component of variation but a substantial reduction in the common environment component. This suggests that BMI represents an integrated signal of early life environment that contributes to variation in adult blood pressure.

Johannes Hebebrand (Department of Child and Adolescent Psychiatry, Philipps University Marburg, Germany) presented the results of his studies on the melanocortin-4 receptor gene (MC4R), which currently presents the most common genetic variants contributing to obesity in the population. Together with Friedrich C Luft (Franz Volhard Clinic-Charité and Max Delbrück Center for Molecular Medicine, Berlin, Germany), he also stressed the importance of family and twin studies for exploring the genetic components of complex disorders like obesity and hypertension. An example of the important findings that can be derived from twin studies was presented by Vojtech Hainer (Obesity Management Centre, Charles University Medical Faculty, Prague, Czech Republic), where in the recent Prague Twin Study the use of a very-low-calorie diet (VLCD) revealed large differences in weight loss in response to VLCD treatment between pairs of obese female monozygotic twins whereas a high within-pair resemblance was found for both weight loss and fat mass loss.

Claes Wahlestedt (Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden) identified nine common human sequence variations within the regulatory and coding sequence of NPY and investigated the association of these nine single nucleotide polymorphisms (SNPs) with body mass index (BMI) in Swedish populations. Analysis of 1246 individuals revealed 62 haplotypes at the NPY locus, with three major haplotypes having frequencies >0.1. Tests for recombination and linkage disequilibrium (LD) showed increased recombination and linkage disequilibrium (LD) at the NPY locus. One variant (T1128C) which causes an amino acid change from leucine (7) to proline (7) in the signal peptide of NPY was found to be significantly associated with BMI.

Peter Arner (Department of Medicine, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden) presented data on several polymorphisms in the exons of the beta3- and beta2-adrenergic receptor genes that have functional consequences for catecholamine-induced lipolysis. An intron polymorphism in hormone sensitive lipase (CA repeat), which associates with obesity, markedly impairs catecholamines-stimulated lipolysis at the lipase level in human fat cells. Finally, a G-beta3 variant significantly alters lipolytic sensitivity of alpha2A as well as of beta1- and beta2-adrenoceptors in fat cells.

Daniel Ricquier (CNRS-CEREMOD, Meudon, France) discussed the potential role of the recently identified uncoupling protein 1 (UCP1) homologs in mammals (UCP2 and UCP3), which represent candidate genes controlling energy partitioning, substrate utilization, metabolic efficiency and thermogenesis. Association or linkage studies in humans supporting a role for the UCPs in resting metabolic rate or fat gain remain inconclusive. However, the novel UCPs may be important to control oxidants and fluxes of substrates. UCP2 is also markedly expressed in pancreatic islets where it restricts insulin secretion during hyperinsulinemia. Recent studies also emphasize a role for UCP3 in thermogenesis regulated by thyroid hormones.

Jocelyne Magré (INSERM U.402, Faculty of Medicine Saint-Antoine, Paris, France) reported on the identification of a new locus for congenital generalized lipodystrophy or Berardinelli-Seip syndrome (BSCL), characterized by a near-absence of subcutaneous and visceral adipose tissues from birth or early infancy and severe insulin resistance. A first locus BSCL1 was found on chromosome 9q34. Using a positional cloning strategy in nine BSCL families originating from Lebanon and Norway, the new locus (BSCL2) was mapped to chromosome 11q13 and the disease gene was identified as a homolog of the murine guanine nucleotide-binding protein (G protein) 3-linked gene, Gng3lg, of unknown function. Further characterization of this gene should lead to new insights into the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Metabolism

Several speakers addressed the issue of insulin resistance as an important determinant of obesity-related cardiovascular dysfunction. Stephan Jacob (Albert Schweitzer Clinic Königsfeld, University of Tübingen, Germany) stressed the role of intramyocellular lipid deposition as a key factor in the development of insulin resistance. Hannele Yki-Jarvinen (Department of Medicine, University of Helsinki, Finland) suggested that defects in insulin-mediated stimulation of nitric oxide synthesis in endothelial cells may contribute to endothelial dysfunction. Brent M Egan (Medical University of South Carolina, Charleston, USA) described the importance of non-esterified fatty acids (NEFAs), in the metabolic syndrome. Thus, while an increase in plasma NEFAs is predictive of the development of hypertension, acute elevations of fatty acids increase oxidative stress, impair baroreflex sensitivity, enhance vascular 1-adrenoceptor-mediated reactivity, reduce endothelium-dependent vasodilatation, and decrease arterial dispensability. NEFAs also induce growth, proliferation and migration of vascular smooth muscle cells, thus possibly contributing to the structural vascular changes that accompany the metabolic syndrome.

Max Lafontan (Unité INSERM 317, Institut Louis Bugnard, Université Paul Sabatier, Toulouse, France) discussed the importance of the functional heterogeneity of human adipose tissues. Thus, the efficiency of lipolytic and antilipolytic pathways markedly differ according to the adipose tissue location, whereby maximal lipolytic capacity is higher in subcutaneous (SC) than in omental (OM) adipocytes. Also, the effects of insulin on antilipolysis and NEFA re-esterification are greatly reduced in OM fat cells, while the hypertrophic SC fat cells are known to be less responsive to the lipolytic actions of catecholamines. Tessa van der Merwe (Department of Endocrinology, Johannesburg General Hospital, Johannesburg, South Africa) presented new results from studies utilizing the in situ microdialysis technique, indicating that lipolytic rate is increased in SC femoral adipose tissue, possibly reflecting insulin resistance in obese and diabetic women compared with non-obese controls.

Achim Leutz (Max Delbrück Center for Molecular Medicine, Berlin, Germany) presented new evidence that c-Myb plays a pivotal role in the oxLDL-induced conversion of vascular smooth muscle cells to typical foam cells. Identification of SWI/SNF recruiting chromatin remodeling domains in distinct CCAAT/enhancer binding protein (C/EBP) isoforms accounts for the activation of differentiation genes in precursors of myeloid and adipogenic cells, suggesting a link between c-Myb, C/EBP and signaling-dependent recruitment of chromatin remodeling complexes in the generation of atherogenic lesions.

Several speakers addressed the role of ‘cardiovascular’ genes in adipose tissue. Stefan Engeli (Franz Volhard Clinic-Charité and Max Delbrück Center for Molecular Medicine, Berlin, Germany) described the expression of renin-angiotensin system genes in human adipocytes and discussed the potential role of angiotensin in adipocyte growth and differentiation. He also speculated that inhibition of adipogenic differentiation by Ang II may promote the development of insulin resistance by promoting the extra-adipocytic deposition of lipids. Gerard Ailhaud (Centre de Biochimie, CNRS, University of Nice, Faculty of Sciences, Nice, France) presented the results of comparative studies in angiotensinogen-deficient (agt -/-) mice and control wild-type (WT) mice, showing that agt -/- mice gain less weight than WT mice, despite similar levels of food intake. Furthermore, agt -/- mice presented with hypotrophy of adipocytes whereas targeted expression of AGT in adipose tissue increased fat mass. Mice, where AGT expression is restricted to adipose tissue, have AGT circulating in the blood stream, are normotensive, and exhibit restored renal function as compared with AGT-deficient mice, supporting a role of adipose AGT in adipose tissue development and blood pressure regulation. Hans Hauner (Diabetes Research Institute, Heinrich Heine University Düsseldorf, Germany) presented data indicating that adipose tissue is a major source of Plasminogen activator inhibitor type 1 (PAI-1), whereby visceral adipocytes release significantly more PAI-1 than subcutaneous fat cells. While insulin and glucocorticoids moderately up-regulate PAI-1 production, catecholamines have a potent inhibitory action. In vitro studies demonstrated that TGF-1, TNF- and interleukin-1 are also potent promoters of PAI-1 production. These findings may at least partly explain the increased risk of thrombembolic complications in obese subjects.

Gema Frühbeck (Department of Endocrinology, Clínica Universitaria de Navarra, Pamplona, Spain) discussed the potential role of adipocytes as a source of NO and the physiological role of NO on white adipose tissue which may include modulation of glucose transport, lipoprotein hydrolysis and lipolysis. Furthermore, in brown adipose tissue, NO is possibly involved in the regulation of blood flow, thermogenesis, calcium-activated non-selective cation channel activity, as well as proliferation and differentiation. Maik Gollasch (Franz Volhard Klinik-Charité and Max Delbrück Center for Molecular Medicine, Berlin, Germany) presented novel data suggesting that perivascular adipose tissue releases a vascular relaxing factor that antagonizes the vasoconstrictive action of angiotensin II, serotonin and phenylephrine. He showed that this effect was independent of NO and suggested that perturbations in the release of this factor could contribute to the development of hypertension.

Emma Espinosa (Clinica di Medicina Interna, University of Ancona, Ancona, Italy) explained how down-regulation of the natriuretic peptide type C receptor (NPr-C), or clearance receptor, may contribute to diuresis and natriuresis induced by very-low-calorie diet or fasting. Thus, the NPr-A:NPr-C mRNA ratio in adipose tissue was significantly lower in obese hypertensive patients as compared with non-obese hypertensives, indicating that increased clearance of natriuretic peptides by adipose tissue may contribute to sodium and volume retention and thus obesity-related hypertension.

Central and renal mechanisms

Per Björntorp (Department Heart and Lung Diseases, Sahlgren’s Hospital, University of Göteborg, Göteborg, Sweden) reviewed the evidence suggesting that neuroendocrine mechanisms are involved in the generation of abdominal obesity, whereby the activation of a sensitive hypothalamic-pituitary-adrenal (HPA) axis with elevated cortisol secretion appears to play a central role. As a consequence the gonadal and growth hormone axes become inhibited and the resulting peripheral endocrine abnormalities induce the other hallmarks of the metabolic syndrome. Parallel activation of both stress axes, ie the HPA axis and the sympathetic nervous system appear to account for the association of the metabolic syndrome with hypertension.

Indeed, several speakers dealt with the importance of the sympathetic activity in the development of obesity-related hypertension. According to Murray Esler (Baker Medical Research Institute, Melbourne, Australia), activation of the sympathetic nervous outflow to the kidneys is crucial in raising blood pressure. A confusing aspect, however, is that the regional pattern of sympathetic stimulation in obese people is similar whether or not hypertension is present. What tips the balance towards the development of hypertension is not clear. The regional pattern of sympathetic activation in obesity differs from that of lean hypertensive patients primarily in not involving the sympathetic nerves of the heart. The cause of sympathetic nervous activation in obesity is unclear, but may involve the stimulatory action of leptin. In this regard extra-adipocytic origins of leptin may be important. Thus, leptin is expressed in multiple regions of the human brain, and is released from the brain into the internal jugular vein in humans at a rate influenced by both gender and obesity. The importance of leptin as a mediator of increased sympathetic activity was also discussed by Allyn L Mark (Hypertension Genetics SCOR, The University of Iowa College of Medicine, Iowa City, Indiana, USA). He reviewed evidence from his laboratory supporting a new concept of selective leptin resistance that may have important implications for arterial pressure regulation in obesity. Thus, while leptin restores arterial pressure in ob/ob mice, hyperleptinemic agouti yellow obese mice have elevated arterial pressure secondary to blockade of hypothalamic MC4-R by agouti peptide. This suggests the presence of selective leptin resistance with preservation of the sympathoexcitatory actions of leptin despite resistance to the metabolic actions of leptin. Based on the observation that catecholamines are powerful inhibits of ob gene transcription, Paul Trayhurn (Department of Medicine, University of Liverpool, University Clinical Departments, Liverpool, UK) presented the view that the sympathetic nervous system is a key regulator of leptin production and provides a negative feedback loop to adipose tissue. Indeed, the sympathetic system may play a pivotal role in the secretory function of white adipose tissue. Thus, contrary to earlier views, it is now recognized that white fat has an extensive sympathetic innervation (albeit less than brown fat) and sympathetic activation is central to the stimulation of lipolysis in the adipose tissues.

The fact that abnormal kidney function is an important cause as well as a consequence of obesity was stressed by John E Hall (University of Mississippi Medical Centre, Jackson, MS, USA). Thus, excess renal sodium reabsorption and a hypertensive shift of pressure natriuresis play a major role in raising blood pressure during weight gain. These changes are initiated by activation of the renin-angiotensin and sympathetic nervous systems, and physical compression of the kidneys due to accumulation of intra- and extrarenal fat and extracellular matrix in the kidneys. Chronic hyperleptinemia raises arterial pressure and heart rate via adrenergic activation and transgenic mice overexpressing leptin develop hypertension. Obesity alters expression of many genes in the renal medulla and cortex, especially those closely associated with sympathetic activation, extracellular matrix formation and inflammatory responses. These changes, as well as increased lipids and glucose intolerance, may eventually cause glomerulosclerosis, loss of nephron function and a slowly developing cycle that requires additional increases in arterial pressure to maintain sodium balance, resulting in further renal injury.

The relationship between obesity, obstructive sleep apnea (OSA) and hypertension was discussed by Virend K Somers (Mayo Clinic and Mayo Foundation, Rochester, NY, USA). While there is a high prevalence of undiagnosed OSA in obese subjects, patients with OSA appear to have a propensity to weight gain in the year prior to the diagnosis of OSA, as compared with similarly obese subjects without OSA. In male subjects with OSA, leptin levels are substantially higher than would be expected based on the level of obesity alone, suggesting the possibility of leptin resistance in OSA patients. Prior studies examining the pathophysiology of obesity in humans have not generally corrected for the presence of OSA in obese subjects. Thus, occult OSA may contribute in part to the association between obesity and increased cardiovascular risk.

The complexity of central regulation of blood pressure and energy balance was also illustrated by Jens Jordan (Franz Volhard Clinic-Charité and Max Delbrück Center for Molecular Medicine, Berlin, Germany), who presented intriguing data on increased sympathetic activity and energy expenditure induced by water drinking in man.

Management

As outlined by Krzysztof Narkiewicz (Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland), the complex causes and consequences of obesity require multidisciplinary approach to reduce obesity-related risk. Only a continuous-care model of lifestyle and medical interventions that views obesity as a chronic disease can be expected to provide long-term benefits. Available data clearly support a preventive approach to obesity beginning in early childhood. The population-based efforts should focus on such areas as the media, community, and schools. Importantly, as pointed out by Luc F Van Gaal (Department of Endocrinology and Metabolism, Faculty of Medicine, University of Antwerp, Belgium) moderate weight loss, expressed as 5-10% weight loss, already has beneficial effects on these cardiovascular risk factors. Such modest weight loss, combined with exercise, significantly decreases triglyceride levels, while significantly increasing levels of high density lipoprotein (HDL)-cholesterol. In addition, limited weight loss (<7 kg) decreases levels of factor VII and PAI, while increasing the tissue plasminogen activator levels. The importance of physical activity in the prevention and treatment of hypertension in the obese was emphasized by Robert H Fagard (Hypertension and Cardiovascular Rehabilitation Unit, University of Leuven, Leuven, Belgium), who presented a meta-analyses of randomized controlled intervention trials showing that the weighted net reduction of blood pressure in response to dynamic physical training averages 3.4/2.4 mmHg. While the blood pressure reduction was more pronounced in hypertensive than in normotensive subjects, the response appeared unrelated to the initial body mass index (BMI) or to training-induced changes of BMI. Data on the truly obese (BMI 30 kg/m2) is, however, lacking.

Given the rather limited long-term success of non-pharmacological management strategies, John Wilding (Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK) looked at the role of the serotonin and noradrenaline reuptake inhibitor sibutramine in the pharmacological management of obesity. Weight loss, ranging from 5 to 15%, in several large randomized clinical trials in uncomplicated obesity, and in obese patients with type 2 diabetes with sibutramine resulted in significant in improvements in insulin resistance, and in lipid profile. Although these data have been tempered by concerns that sibutramine results in small increases in pulse rate (mean increase 3-7 beats per minute) and blood pressure (mean increase 2-3 mmHg), because weight loss generally causes a fall in blood pressure, smaller increases or even falls may be seen in those patients who lose weight with treatment. Stephan Rössner (Obesity Unit, Huddinge University Hospital, Huddinge, Sweden) presented data on orlistat, a non-systemically acting anti-obesity agent that inhibits gastrointestinal lipase activity, thereby reducing the absorption of dietary fat. In several large-scale, randomized, double-blind, placebo-controlled trials of up to 2 y duration, orlistat combined with a mildly hypoenergetic diet promoted significantly greater mean weight loss than diet alone in obese non-diabetic and diabetic patients. Furthermore, Orlistat treatment was also associated with significant improvements in several cardiovascular risk factors, including systolic and diastolic blood pressure, serum lipid profile and glycemic control.

Arya M Sharma (Medical Faculty of the Charité, Humboldt University of Berlin, Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, Berlin, Germany), speaking on the pharmacological management of the obese hypertensive, drew attention to the almost complete lack of data from controlled trials in obese hypertensive patients. Furthermore, current guidelines (eg JNC VI, ISH/WHO) ignore obese hypertensives as a ‘special population’ and provide no recommendations that go beyond the general advice to lose weight. Thus, there is clearly an urgent need for studies that specifically address the efficacy and outcome of obese patients on different antihypertensive agents.

To round up the symposium, Peter Kopelman (Queen Mary and Westfield College, St Bartholomew’s and the Royal School of Medicine and Dentistry, University of London, London, UK) outlined how recent breakthroughs in the understanding of the molecular mechanisms regulating body fat in animal models will allow the development of new drugs for the management of overweight and obesity in humans. Such drugs must, however, ultimately affect both energy intake and energy expenditure in order to have a significant and long-lasting impact on body weight drugs that act purely on one side of the energy balance are unlikely to achieve long-term efficacy because of compensatory adjustments ensuring the maintenance of body fat homeostasis. Drugs for the treatment of obesity should be regarded as ‘palliative’: when an effective drug is discontinued weight regain is probable. Furthermore, given that fat storage is critical to survival in times of food scarcity, he also cautioned that the potential adverse effects of modulating body weight regulation must be considered. Clearly, the substantial cost of pharmacological treatments underlines the importance of establishing effective preventive strategies for the immediate future.

Awards for the best clinical and basic science poster presentations were awarded to Sandra Schiffelers et al (Maastricht, The Netherlands) and Florence Massiera et al (Nice, France), respectively, for their work on the relationship between -adrenoceptor-mediated blood pressure response and polymorphisms of the 2-adrenoceptor gene in obesity and the demonstration that adipose angiotensinogen contributes to adipose tissue growth and blood pressure regulation.

Since these exciting days in Berlin, many of these researchers remain close personal friends and colleagues – many continue to shape my own ideas and views on obesity and its management.

The proceedings of this meeting were published in the International Journal of Obesity.

Berlin, Germany