Sympathetic Activity in Individuals With the Metabolic Syndrome: Benefits of Lifestyle Interventions

Background:

Autonomic dysfunction, namely increased sympathetic drive and reduced vagal tone, may participate in the pathogenesis and complications of the MetS. Weight loss and aerobic exercise are first-line therapeutic strategies that are known to be beneficial in lowering blood pressure, enhancing insulin action and preventing the development of type 2 diabetes. However, there is a paucity of data regarding their effects on sympathetic nervous system (SNS) activity. In a recently completed Pilot study in 22 MS subjects we demonstrated that moderate dietary weight loss (7% of initial body weight) is associated with marked reductions in whole-body norepinephrine spillover rate (by 43%, P= 0.005) and muscle sympathetic nervous activity (MSNA, by 15%, P=0.01). In the proposed project we wish to extend these observations by evaluating the clinical benefits of aerobic exercise and weight loss maintenance.

Aims:

1. To determine whether dietary weight loss in combination with aerobic exercise (WL + EX) is more beneficial than dietary weight loss alone (WL) in reducing SNS activity and improving cardiovascular and metabolic parameters in middle aged men and women with abdominal obesity and a diagnosis of the MetS.
2. To investigate the determinants of achieved weight loss, with a focus on the roles of SNS activity, b2-adrenoceptor polymorphisms, resting metabolic rate, plasma and interstitial adipocytokines.
3. To determine whether clinical benefits during active weight loss (negative energy balance) are sustained after a 4-month weight loss maintenance program and to investigate the determinants of successful weight loss maintenance (as above).
4. To examine the inter-relationships between SNS activity, insulin sensitivity, metabolic, anthropometric and haemodynamic parameters.

Subjects:

Sedentary men and women (n= 66) aged 45 to 65 years with a body mass index of 26 to 39 kg/m2, who fulfil Adult Treatment Panel III criteria for the MetS.

Study design:

Randomized, controlled, parallel design comparison of:

1. WL;
2. WL + EX; or
3. Control (no treatment).

Investigations will be performed at baseline, and at the end of 3-month lifestyle intervention, and a 4-month weight-maintenance program (WL and WL + EX groups).

Diets:

A modified version of the 'DASH' diet will be used at different caloric levels.

Exercise:

Bicycle riding, performed for 40 minutes on alternate days at a moderate intensity of 65% of maximum heart rate. Compliance will be assessed by VO2 max measurements.

Investigations:

SNS activity measurements (multiunit and single-unit microneurographic recordings of MSNA, whole-body norepinephrine spillover, and abdominal adipose tissue and skeletal muscle interstitial noradrenaline concentration determined by microdialysis) will be made before and during an oral glucose tolerance test, together with haemodynamic (calf blood flow measured by venous occlusion plethysmography) measurements. Changes in fat mass will be quantitated by DEXA scan. Metabolic measurements will include resting metabolic rate, insulin sensitivity, lipid profile, non-esterified fatty acids, plasma and interstitial adipokines/cytokines.

Clinical significance:

The proposed project will provide novel information about whole-body and regional sympathetic activity; the determinants of sympathetic activity and the relative clinical benefits of active weight loss, weight loss maintenance and aerobic exercise in middle-aged MetS subjects.