Role of sympathetic innervation in obesity

Part of the results presented in this thesis were published in the following reference (DOI 10.1016/j.cell.2015.08.055): Wenwen Zeng*, Roksana M. Pirzgalska*, Mafalda M.A. Pereira, Nadiya Kubasova, Andreia Barateiro, Elsa Seixas, Yi-Hsueh Lu, Albina Kozlova, Henning Voss, Gabriel G. Martins, Jeffrey M. Friedman and Ana I. Domingos. Sympathetic Neuro-adipose Connections Mediate Leptin-Driven Lipolysis. Cell 163, 84-94 (2015). The work was also presented through poster presentations at iMED Conference 6.0 (Lisbon, 2014), Sociedade Portuguesa de Bioquímica Meeting (Coimbra, 2014) and Sociedade Portuguesa de Neurociências Meeting (Póvoa de Varzim, 2015).

Obesity is considered a world epidemic, but no efficient therapy is available so far. Besides, the anatomy of the adipose organ was not described in detail. Thus, different mechanisms were proposed to explain obesity condition. One of those is the MONA LISA hypothesis that states that Most Obesities kNown Are Low In Sympathetic Activity. However, this theory is based on measurements of norepinephrine decrease in the heart and there is no direct evidence of the role of sympathetic nervous system (SNS) in obesity. In this work, PEGyDT-mediated sympathectomy was developed to specifically ablate the SNS, without affecting the central nervous system. This was achieved by PEGylation of diphtheria toxin, a strategy that is approved by Food and Drug Administration and used to modulate pharmacokinetics of several biopharmaceuticals clinically approved. The results show that sympathectomy leads to irreversible obesity, without affecting food intake. SNS ablation also causes glucose tolerance and thermogenesis impairment. Moreover, it was discovered that the SNS is required for amphetamine effects and this is an additional mechanism of action for this anti-obesity drug, as it was thought that it had an exclusive effect in the brain to suppress appetite. Furthermore, the anatomy of adipose organ was revealed in detail using optical projection tomography coupled to tissue clearing. It was shown that not only the inguinal adipose organ contains nerve bundles and a network of vasculature, but also that in the proximity of these structures there is a lymph node. In the epididymal fat, granular substructures are present but not nerve bundles or lymph node. In conclusion, a strategy to study the role of the SNS in obesity was developed and causality of MONA LISA hypothesis was demonstrated. Moreover, an additional mechanism of action for amphetamine was shown and neuroanatomy of adipose organs was described for the first time.