Sympathetic and immune mechanisms underlying obesity

The era of molecular genetics has enabled the mechanistic dissection of brain circuits as well as the immune system in spectacular ways. However, the molecular and cellular organization of the sympathetic nervous system (SNS), which innervates all known organs, is essentially unexplored – this issue is addressed in this project. In an attempt to push this frontier, we have recently uncovered a direct physical functional connection between the SNS and the adipose tissue. Further, we found this neuro-adipose junction to drive lipolysis and fat mass reduction (1). In this proposal we aim to define the molecular mechanisms that link SNS neurons and the immune system. A major entry point is our recent discovery of a novel population of Sympathetic Associated Macrophages (SAMs) that suppress the output of SNS. We propose to unravel their contribution to obesity in rodents (Aim 1) and in humans (Aim 2). Another major objective of this proposal is to establish a functional and molecular neuronanatomical map of the SNS, which defines subpopulations of neurons that specifically innervate fat (Aim 3). To achieve this, we will build molecular genetics tools for rapid non-invasive optocoustic visualization and functional probing of SNS circuits. A molecular and realistic atlas of the SNS will allow us to systematically access the functional anatomy of one of the most elusive tissues of the mammalian body and will form a blueprint upon which our neuroimmune mechanistic studies can be build. Our overall objectives point towards the identification of the fundamental biological mechanisms that govern the neuro-adipose junction will set the stage for a new anti-obesity therapy that would circumvent the challenge of drug delivery to the brain, i.e. by targeting an excitatory drug directly to SAMs or sympathetic inputs in adipose tissue. This is important for society as it paves the way to the identification of novel therapeutic approaches addressing obesity, which is a major public health concern

During the first year of this ERC-funded project, my lab relocated countries and we spent most of the year setting up to recreate the adequate conditions for carrying forward this project. This entailed exporting the mouse colony from the previous institute it in Portugal and expanding, a process that is still ongoing. Aim 1.1 and 1.2 were successfully attained and published in Nature Medicine. Aim 2 relies on a collaboration with the Organ Transplantation Unit at the Curry Cabral Hospital in Lisbon, and we have taken the necessary steps towards having the required ethical approvals for human SNS tissue harvesting and dissections from organ donors. These approvals were to be delivered in the first year and have been uploaded on the ERC portal. Aim 3 relies on mouse line Line EF1-LSL-GFPL10, which is homozygous lethal, and particularly difficult to rederive and expand.

Attaining Aim 1 of this project represented progress beyond the state of the art, which we published in Pirsgalska et al, Nature Medicine. Our findings were further disseminated in the following feature articles:
-- Stefan Jung: Year in Review — Macrophages and monocytes in 2017: Macrophages and monocytes: of tortoises and hares. Nature Reviews Immunology 2017 (link).
-- Conor A. Bradley (2017). Specialized macrophages contribute to obesity. Nature Reviews Endocrinology. (link)
-- Making Fat Mice Lean: Novel Immune Cells Control Neurons Responsible For Fat Breakdown. ScienMag. (link)
-- Wei Wong (14 Nov 2017). Fat expansion through norepinephrine catabolism. Editor's Choice, Science Signalling. (link)
-- Seth Thomas Scanlon (17 Nov 2017), Unusual macrophages contribute to obesity. Editor's Choice, Science (link)
-- Guttenplan, Kevin A. et al. (2018) Play It Again, SAM: Macrophages Control Peripheral Fat Metabolism, Trends in Immunology (link)
-- Michael P Czech (7 Nov 2017), Macrophages dispose of catecholamines in adipose tissue. Nature Medicine (link)

Until the end of the project we expect to molecularly identify subpopulations of SNS neurons and have them functionally probed.

Periodic Reporting for period 3 - SympatimmunObesity (Sympathetic and immune mechanisms underlying obesity)

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