The Autonomic Nervous System and Obesity

In its simplest terms, obesity is the results of a positive balance between food intake and energy expenditure (EE). I.e., we take in more energy, in the form of food, than we expend, e.g., by exercise. In our sedentary society, resting EE accounts for most of total energy expenditure. The sympathetic nervous system (SNS, the one that produces adrenaline) is thought to contribute to resting EE. This conclusion is based on experiments where resting EE is decreased by beta-blockers, high blood pressure medicines that block only one aspect of the sympathetic nervous system. The investigators propose to use a different approach, by using a medication called trimethaphan that produces transient withdrawal of the autonomic nervous system. The investigators will then compare the measured resting EE before and after SNS withdraw and quantify the degree of contribution to the resting EE by the SNS and delineate differences between healthy normal, healthy obese, and patients with autonomic dysfunctions.

The rationale for this study is that even small alterations to energy metabolism can significantly change energy balance and body weight in the long term. We will test the hypothesis that the sympathetic nervous system (SNS) activity contributes to resting and thermogenic components of energy expenditure (EE). This study is divided in four different parts: (1), (2), (3), (4). Part (1): we will gauge the contribution of the sympathetic nervous system to resting energy expenditure, blood pressure, and determine differences between lean, obese, and patients with primary autonomic failure . Part (2): we will determine the degree of sympathetic blockade by a gradual infusion of the ganglionic blocker trimethaphan.[Part 2 has been closed] Part (3): we will determine the energy balance in patients with primary autonomic failure. Part (4): we will determine the contribution of the sympathetic nervous system to lipolysis.[Part 4 has been closed] Subjects selections*: For part (1) and (2) we will study six groups of subjects (n = 40 for each group): patients with pure autonomic failure, patients with multiple system atrophy, healthy normal controls (BMI <= 25), obese controls (BMI 30-40) and obese hypertensive (BMI 30-40) and lean hypertensive (BMI 20-28). A time interval of at least 1 week is required for those subjects who wish to participate in part (1) and part (2). For part (3) we will study two groups of subjects (n=12 for each group): patients with autonomic failure, and their age sex-matched sedentary, healthy controls. For part (4) we will study two groups of subjects (n=12 for each group): healthy normal controls (BMI 20-25), obese controls (BMI 30-40). *Part 2 and 4 have been closed.

Estimation of resting energy expenditure and effect of autonomic blockade with trimethaphan infusion.

Isoproterenol sensitivity in adipose and muscle tissue with and without systemic autonomic blockade with trimethaphan infusion.

Metabolic and hemodynamic response to submaximal exercise in adipose and muscle tissue with and without systemic autonomic blockade with trimethaphan infusion.

Start dose: 0.05 ml/min (0.5 mg/min), IV infusion. The dose will be increased every 2-4 minutes to 1, 2, 4, and 5 mg/min. Total duration: 1 hour

Start dose: 0.05 ml/min (0.5 mg/min), IV infusion. The dose will be increased every 30 minutes to 1, 2, 4, and 5 mg/min. Total duration: 1-2 hours

Inclusion Criteria: Healthy normal (BMI <= 25 Kg/m2), obese (BMI between 30 and 40)volunteers, lean hypertensive (BMI 20-28 Kg/m2), and obese hypertensive (BMI between 30 and 40) Ages 18-60 Patients with pure autonomic failure and multiple system atrophy ages 18-80, referred to our service for the diagnosis and treatment of their condition, and their age sex-matched sedentary, healthy controls ages 18-80 Exclusion criteria: All medical students Pregnant women Heart failure, symptomatic coronary artery disease, liver impairment, history of stroke or myocardial infarction, glaucoma History of serious allergies or asthma Subjects using beta-blockers

Shibao C, Gamboa A, Diedrich A, Ertl AC, Chen KY, Byrne DW, Farley G, Paranjape SY, Davis SN, Biaggioni I. Autonomic contribution to blood pressure and metabolism in obesity. Hypertension. 2007 Jan;49(1):27-33. doi: 10.1161/01.HYP.0000251679.87348.05. Epub 2006 Nov 20.

Shibao C, Buchowski MS, Chen KY, Yu C, Biaggioni I. Chronic sympathetic attenuation and energy metabolism in autonomic failure. Hypertension. 2012 May;59(5):985-90. doi: 10.1161/HYPERTENSIONAHA.111.190157. Epub 2012 Apr 2.