Neuro-mesenchymal units control ILC2 and obesity via a brain–adipose circuit

Filipa Cardoso, Roel G. J. Klein Wolterink, Cristina Godinho-Silva, Rita G. Domingues, Hélder Ribeiro, Joaquim Alves da Silva, Inês Mahú, Ana I. Domingos and Henrique Veiga-Fernandes ()
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Filipa Cardoso: Champalimaud Centre for the Unknown
Roel G. J. Klein Wolterink: Champalimaud Centre for the Unknown
Cristina Godinho-Silva: Champalimaud Centre for the Unknown
Rita G. Domingues: Champalimaud Centre for the Unknown
Hélder Ribeiro: Champalimaud Centre for the Unknown
Joaquim Alves da Silva: Champalimaud Centre for the Unknown
Inês Mahú: Max Planck Institute for Metabolism Research
Ana I. Domingos: Oxford University
Henrique Veiga-Fernandes: Champalimaud Centre for the Unknown

Nature, 2021, vol. 597, issue 7876, 410-414

Abstract: Abstract Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as important regulators of host defence and inflammation1–4. Nevertheless, it is unclear whether neuronal and immune cells co-operate in brain–body axes to orchestrate metabolism and obesity. Here we describe a neuro-mesenchymal unit that controls group 2 innate lymphoid cells (ILC2s), adipose tissue physiology, metabolism and obesity via a brain–adipose circuit. We found that sympathetic nerve terminals act on neighbouring adipose mesenchymal cells via the β2-adrenergic receptor to control the expression of glial-derived neurotrophic factor (GDNF) and the activity of ILC2s in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to alterations in ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing and chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates ILC2s in gonadal fat and connects to higher-order brain areas, including the paraventricular nucleus of the hypothalamus. Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity.

Date: 2021
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DOI: 10.1038/s41586-021-03830-7

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