Sympathetic activation in obesity

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Project Summary Obesity is associated with an increased risk of diabetes and cardiovascular disease. Sympathetic nervous system (SNS) dysfunction has been described in individuals with obesity and may be implicated in the pathogenesis of obesity-related comorbidities. SNS regulates energy homeostasis by promoting a coordinated multi-organ response. Regionalized SNS hyperactivation of certain organs (fat, skeletal muscle and kidneys) but not others (adrenal glands, heart) has been observed in individuals with obesity. Dysfunctional coordination of SNS activation to target organs may explain the increased risk of cardiometabolic disorders in obesity. SNS activates target-organs by releasing norepinephrine (NE) which is then recycled back by pre-synaptic norepinephrine transporters (NET). Whole-body positron emission tomography (PET) with the radiotracer for norepinephrine transporters ((S,S)-11C-O- methylreboxetine ([11C]MRB) has been used to quantify NET availability in vivo in humans and rodents in: a) peripheral tissues (brown and white adipose tissues and skeletal muscle); and b) in the central nervous system. Studies using [11C]MRB PET imaging showed that NET-availability in brown adipose tissue (BAT) was reduced in women with obesity. In addition, [11C]MRB binding in skeletal muscle (deltoid) inversely correlated with body mass index (BMI) in healthy women. Therefore, to determine whether regionalized SNS activation of target organs is altered by obesity, healthy men and women with normal body mass index (BMI) and with obesity will undergo whole body [11C]MRB PET imaging and microneurography (gold standard test for assessment of muscle SNS activity). To further investigate the impact of obesity in coordinating SNS multi-organ activation, SNS activity will be also measured in response to a food challenge. Parallel animal studies will be performed to clarify the relationship between peripheral and central NET dynamics and the time course of which each of these NET sources change as obesity develops. Whole body [11C]MRB PET imaging allows simultaneous multi-organ measurements and this project will help further understand the impact of obesity in SNS activity. Dysregulated coordination of SNS activity may play a role in the pathophysiology of obesity-related cardiometabolic disorders.