Metabolic syndrome, new research underway
Obesity and associated co-morbidities, type 2 diabetes and cardiovascular disease (CVD) are increasing public health problems around the globe (Seidell 2000). One in five UK adults are obese, and if current trends persist, over half the adult population will be obese (BMI over 30 m/kg2) by the year 2030. In the UK, CVD accounted for over 240,000 deaths in 2001, with 40% of people dying from CVD (British Heart Foundation 2003). In the UK 1.3 million people have been diagnosed as having type 2 diabetes (Department of Health 2001a), although many cases currently go undiagnosed and the estimated prevalence is twice this (Amos et al. 1997). Furthermore, the disease is being seen for the first time in obese adolescents, following a trend first recognised in the US.
Obesity is a major public health problem throughout Europe, especially among women in Southern and Eastern European countries. Across Europe in general, 10-20% of men and 10-25% of women are obese and the prevalence is increasing (Goldberg 2003) but rates of obesity in the Baltic Republics are among the highest in the world (Pomerleau et al. 2000). In line with the higher rates of obesity found in Eastern European countries some of the highest rates for CVD (British Heart Foundation 2003) and type 2 diabetes (Goldberg 2003) also occur.
In the US, an indicator of European trends, more than 9.4% of the US health care budget is spent on the treatment of obesity and related diseases and it is recognised that this is likely to increase (Mokdad [Mokdad in list] et al. 2000). These estimates are influenced by the fact that people are living longer and, linked with this, the average age of the population is increasing. During the period 1995-2025, the number of people over the age of 80 years is expected to increase by 50% and the number over the age of 90 years will double (Department of Health 2001b). Currently, however, these extra years of life are largely associated with ill health. A key arm of public health policy is now directed at not just extending life but also ensuring that the increased years of life are spent free of chronic diseases.
Thus, in Europe, the treatment of obesity related diseases is now a major contributor to the cost of health care, accounting for 8% of all medical costs.
Abdominal fat stores are key in the development of type 2 diabetes and CVD, two of the major symptoms of the obesity-related condition known as the metabolic syndrome (Hansen 1999). In the US, the prevalence of metabolic syndrome is 6.7% for 20-30 year olds but rises to 43% between the ages of 60-70 years (Ford et al. 2002). However, because risk is influenced by ethnic background and BMI is not a precise indicator of percentage body fat or its localisation, many individuals at risk of obesity-related disease fail to be identified.
The ideal solution lies in prevention, as some stages of these diseases are likely to be irreversible. To facilitate this, it is necessary to have prognostic or diagnostic biomarkers of the development of such diseases. The development of such biomarkers is a primary objective of an EU-funded project on obesity and disease in ageing, known as OB-AGE (QLK6-2001-02288), which began in January 2003.
The project comprises 7 work packages, which are outlined below. Work package 7 is co-ordinated by the British Nutrition Foundation (BNF) and concerns dissemination of information about the project. This is the first of a series of articles written as part of the work package. Information will also be available in future via BNF?s website (www.nutrition.org.uk/ob-age.htm).
The rationale for the study is that in young, lean individuals, two hormones produced by white adipose tissue (fat), adiponectin and leptin, are pivotal in preventing the accumulation of fat outside the usual fat stores i.e. in places other than adipose tissue, known as ectopic lipid accumulation. In obesity, adiponectin levels fall and leptin levels rise, but leptin insensitivity develops. The drop in adiponectin coupled with the loss of response to leptin leads to ectopic lipid accumulation.
When this occurs in muscle, it leads to insulin insensitivity (a relative inability of insulin to facilitate the disposal of glucose in tissues). Insulin insensitivity is the first step towards the development of both type 2 diabetes and heart disease (Lovejoy 1999). Lipid accumulation in pancreatic b cells, the site of insulin production, contributes to the development of type 2 diabetes, and in cardiomyocytes contributes to cardiovascular disease. In addition, in obesity the release of growth hormone declines, exacerbating the decline normally seen with ageing, and perpetuating obesity through the loss of the hormone?s muscle building and fat burning effects.
One way that insensitivity to leptin may develop is via the desensitisation/ downregulation of the signalling form of the leptin receptor (Ob/ Rb) and the induction of a protein called SOCS3, which inhibits leptin signalling. Both Ob-Rb and SOCS3can be detected in blood monocytes and together with blood adiponectin concentrations, can potentially be used to predict the development of obesity-related diseases.
These measurements will be used to investigate the impact of the lipoytic fatty acids, conjugated linoleic acid (CLA) and n-3 polyunsaturated fatty acids on the development of CVD, type 2 diabetes and obesity. Given that the particularly harmful effects of obesity are associated with abdominal obesity, which increases disproportionately with age, comparisons will be made between this and other fat depots to investigate mechanisms underlying age-related obesity and disease.
Focus on n-3 fatty acids and CLA
A particular focus of the project is the study of naturally occurring fatty acids, in particular the n-3 (or omega-3) polyunsaturated fatty acids and the group of fatty acids known as the conjugated linolenic acids (CLA). CLA all have 18 carbon atoms and two double bonds, in various cis and trans configurations.
n-3 fatty acids
An overview of n-3 fatty acids and health is available in a BNF Briefing Paper, n-3 Fatty Acids and Health (British Nutrition Foundation 1999). There is currently considerable interest in the ability of n-3 fatty acids to influence cardiovascular health (Kris-Etherton et al. 2002, Thies et al. 2003). Randomised controlled trials have demonstrated that n-3 fatty acids, taken as oil-rich fish (Burr et al. 1989) or as supplements (GISSI-Prevenzione Investigators 1999) can reduce cardiac events (e.g. death, nonfatal MI and nonfatal stroke) and some prospective studies (e.g. the Nurses Health Study) have also shown an inverse association between fish consumption and n-3 fatty acids and CHD (coronary heart disease) deaths (Hu et al. 2002), supporting earlier data concerning fish intake (Stone 1997).
Various mechanisms have been considered, including blood lipid lowering, decreased inflammation, a fall in growth factor production, antithrombotic effects, antiarrhythmic actions, or a combination of these (Thies et al. 2003). A recent randomised controlled study, in patients awaiting surgery to remove atherosclerotic plaques in the carotid artery, has shown that an anti-inflammatory response might be involved, by demonstrating an association between the intake of long chain n-3 polyunsaturated fatty acids as a supplement (1.4 g/day, an amount that could be achieved by diet) and the stability of atherosclerotic plaques (Thies et al. 2003). This improved stability was achieved by incorporation of the long chain n-3 fatty acids into the plaque.
In addition, interest has rapidly developed in the potential of n-3 fatty acids to influence type 2 diabetes and associated risks (Lovejoy 1999) because of reported effects on insulin sensitivity (Roche 1999). Storlein and colleagues (1991) have systematically studied the effects of dietary fat on insulin action in animal models and have shown that long chain n-3 fatty acids improves insulin sensitivity in the liver and skeletal muscle relative to n-6 polyunsaturated intake. Initial concern that moderate intakes of n-3 fatty acids can have adverse effects on glucose or insulin levels in patients with diabetes appear to be unfounded (Lovejoy 1999). In fact, there is published evidence that such intakes have a favourable effect on plasma triglyceride levels (Sirtori et al. 1997). Furthermore, Fasching et al. (1991) have shown that in obese patients with impaired glucose tolerance, supplementation with fish oil for 2 weeks significantly improves insulin sensitivity.
A number of roles for CLA have been proposed (British Nutrition Foundation 2003). A potential role in cancer protection has been reported based on studies with rodent models of mammary and colon cancer, and also various in vitro models of cancer (Sebedio et al. 1999). More recently, the ability of CLA to influence the lean: fat tissue ratio, in favour of lean tissue, has been shown in animal models and humans (Roche et al. 2001).
Interest has also focused on cardiovascular risk factors and inflammatory markers. Much of this work has been conducted in animal models and encouraging findings have prompted a series of studies in humans (Calder 2002). A consistent result emerging from the various studies in humans is the ability of CLA to reduce body fatness, regardless of whether the subjects are lean or overweight. There have also been some inconsistent findings with regard to blood lipids which might be attributed to the variability of the dose level and/ or the mix of CLA isomers used, particularly as results from animal studies show that specific isomers of CLA may be responsible for specific biological effects (De Deckere et al. 1999, Park et al. 1999).
The main dietary sources of CLA in the human diet are meat from ruminant animals and dairy products, particularly cheese. The amount present varies with the breed and the animals? diet, being high in grass-fed animals (Lawson et al. 2001). As CLA is present in milk fat, the amount present is also directly affected by processing. More than 90% of the CLA present in cow?s milk is in the cis-9, trans-11 form and the majority is produced within the mammary gland itself from the rumen-derived substrate vaccenic acid, although small amounts derive directly from biohydrogenation of linoleic acid in the rumen.
The hypothesis to be tested is whether serum adiponectin levels and the desensitisation / downregulation of Ob/Rb can be used as prognostic/ diagnostic biomarkers for the development of obesity-related type 2 diabetes and CVD. The effectiveness of CLA plus n-3 PUFA (polyunsaturated fatty acids) as therapeutic agents in ameliorating these conditions will also be tested, including the impact on biomarkers. This will be conducted by investigating the effects of CLA plus n-3 PUFA on cardiac function, glucose metabolism and pancreatic islet function in humans. The subjects for these studies will be lean (BMI 20-25) and obese (BMI 30-32) young males (aged 20-25 years), and lean and obese older males (50-55 years). The aim is to recruit 15 subjects within each group at each of 2 sites (Aberdeen in the UK and Lund in Sweden). A cross-over experimental design will be employed: initially half the subjects will receive a placebo for 12 weeks and the other half CLA (3 g/day) plus n-3 PUFA (3 g/day). Following a 12-week wash out period, the treatments will be crossed over, so that each subject acts as his own control.
The objective of this part of the project is to examine the functional importance of Ob-Rb desensitisation/ down-regulation, adiponectin levels and lipid accumulation in pancreatic b -cells, and to assess how CLA plus n-3 PUFA enhance b -cell function in obesity. This work will be conducted using normal obese mice (with and without CLA/n-3 PUFA supplementation) and spontaneously low body fat rats. The obese mice exhibit insulin resistance, impaired insulin secretion and leptin ?resistance?, and will serve as a model of type 2 diabetes. The effects of adiposity will be related to leptin sensitivity and ectopic lipid accumulation and the extent to which this influences insulin sensitivity and secretion will be assessed.
This workpackage will examine the functional importance of Ob-Rb desensitisation/ down-regulation and lipid accumulation in cardiomyocytes, and will investigate how CLA plus n-3 PUFA supplementation enhance cardiomyocyte function in obesity. It is hypothesised that obesity contributes to the development of CVD, in part, via the loss of leptin regulation of ectopic lipid accumulation in cardiomyocytes. Also plasma leptin levels are associated with myocardial hypertrophy, independently of blood pressure.
The effects of varying levels of adiposity on lipid accumulation and leptin-induced potassium and calcium channel function will be measured in cardiomyocytes from normal, obese (with and without CLA plus n-3 PUFA supplementation) and spontaneously low body fat rodents. Related Ob-Rb and SOCS3 gene expression will also be studied. Continues??.British Nutrition Foundation
Metabolic syndrome, new research underway
Metabolic syndrome, new research underway