Adipose lymph node as a crosstalk mediator of neuroimmune signaling during cold-induced adaptive thermogenesis

Abstract

Many researchers have provided unequivocal evidence of functional brown or beige adipocytes in human adults, which converts chemical energy into heat upon activation. Cold-induced browning of white adipose tissue (WAT) has been strongly correlated with energy expenditure and glucose metabolism in both human and mouse models. Although the formation of brown/beige adipocytes has been proposed as a potential therapeutic strategy to combat obesity, different magnitudes of browning have limited its therapeutic value. It is widely accepted that subcutaneous, but not visceral fat, can undergo extensive browning in response to cold exposure. However, the reason for this adipose depot-specificity remains poorly understood. Lymph node (LN) is one of the essential components in the lymphatic system. It is a highly organized hub for the interaction of immune cells and foreign antigens to mediate host defense. In both human and mouse models, LNs always occur embedded in WAT for fuel supply to support the function of immune cells in LNs. Interestingly, the anatomical location of LNs overlaps largely with the regions of adipose depots which are susceptible to browning / beiging. However, its role in adipose tissue browning has never been explored. Therefore, the objectives of this study are to investigate the role of inguinal lymph node (iLN) and its mechanism underlying the regulation of browning of inguinal WAT (iWAT). Our results demonstrated that mice with surgical removal of iLN embedded in iWAT displayed impaired browning of iWAT in response to chronic cold exposure, as evidenced by reduced multilocular lipid droplets, lower expression of uncoupled protein 1 (UCP1) and other thermogenic genes as compared to sham controls. Likewise, LN-depleted progeny mice, generated by maternal transfer of lymphotoxin-beta receptor immunoglobulin (LTβR-IgG2α) fusion protein to suppress the development of iLNs in embryos, also exhibited defective cold-induced browning of iWAT. Chronic cold exposure led to a significantly increased activity of sympathetic nerve and downregulated protein expression of interleukin-33 (IL-33) in iLN. Local sympathetic denervation of iLN using 6-hydroxydopamine (6-OHDA) abrogated cold-induced browning in iWAT whereas these impairments were restored by replenishment with recombinant mouse (rmIL-33) protein. Mechanistically, sympathetic nervous input into iLN promotes the release of IL-33 from LN fibroblastic reticular cells (FRCs) into the surrounding iWAT via stimulation of beta adrenergic receptors (βARs), which drives activation of group 2 innate lymphoid cells (ILC2s), followed by the recruitment of eosinophils and its downstream effectors, including alternatively-activated (M2) macrophages and beige progenitor cells, eventually leading to beige cell biogenesis in iWAT. Collectively, the increasing sympathetic innervation in iLN triggers the activation of type 2 immune responses in iWAT through the production of IL-33. Thus, iLN plays an obligatory role in mediating cold-induced adipose tissue browning by facilitating the neurological and immunological crosstalk.