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

Abstract

Signals from sympathetic neurons and immune cells regulate adipocytes contributing to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as major regulators of host defence and inflammation 1-4 . Nevertheless, whether neuronal and immune cells cooperate in brain-body axes to orchestrate metabolism and obesity remains elusive. Here we report a novel neuro-mesenchyme unit that controls group 2 innate lymphoid cells (ILC2), 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 beta-2 adrenergic receptor to control the expression of the glial-derived neurotrophic factor (GDNF) and the activity of ILC2 in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to altered ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing, chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates gonadal fat ILC2 and connects to high-order brain areas, including the paraventricular nucleus of the hypothalamus (PVH). Our work decodes a neuro-mesenchymal unit that translates long-range neuronal circuitry cues into adipose-resident ILC2 function, shaping the host metabolism and obesity.Obesity results from an excessive accumulation of lipid depots, while these fat reservoirs can be used as high-energy sources during periods of dietary deprivation. Sympathetic neuronal activity drives lipolysis 5-7 , while group 2 innate lymphoid cells (ILC2) contribute to visceral adipose tissue metabolism via type 2 innate cytokines and Met-Enkephalin (Met-Enk) [8][9][10][11][12][13] . This raises the hypothesis that the nervous system and ILC2 cooperate to drive adipose physiology via higher-order brain-body interfaces. Development Fund). pAAV-Ef1a-mCherry-IRES-Cre was a gift from Karl Deisseroth.PRV-614 (PRV-Bartha) was a kind gift of Prof. Lynn Enquist and Dr. Esteban Engel.

Nuclear Retention of Leptin/Upd2 Regulates Organismal Resilience to Nutrient Extremes

“…Hence, we postulate that increased AMP expression in Upd2-AIM-may impinge on systemic processes, perhaps by altering brain function, and this might underlie their increased hunger feeding motivation (Figure 5D). Furthermore, the increased lipolysis we observe with Upd2-AIM over-expression flies (Figure 5C) aligns with the emerging role in mammalian studies for AMPs in TAG mobilization [86, 87]. In sum, our current working hypothesis is that the secreted immune peptide signature downstream of Upd2 nuclear retention enables the organism to adapt to starvation and promotes hunger-driven feeding.…”

Heterogeneity of type 2 innate lymphoid cells

“…In turn, these cells produce glial-derived neurotropic factor, the receptor for which, RET, is particularly highly expressed on visceral adipose tissue ILC2s. This interaction leads to the production of type 2 cytokines and enkephalins by ILC2s, which promotes beiging of WAT and counteracts the development of obesity following a high-fat diet 78 . In addition, it was recently shown that ILC2s regulate the downstream effects of obesity, namely metabolic syndrome , limiting both the onset of insulin resistance and established insulin resistance in a mouse model of obesity 79 .…”

Eosinophils regulate intra-adipose axonal plasticity

“…The immune cells highly express β2 adrenergic receptor ( Adrβ2 ), which confers their responsiveness to NE. However, no significant effect on adipose metabolism was observed upon deletion of Adrβ2 in macrophage or ILC2s ( 64 , 65 ). It is yet to be known how adrenergic signaling may affect the cellular pathways in the adipose immune cells and thereby influence energy homeostasis.…”