Single-Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

Abstract

SUMMARY Adipocytes deficient in fatty acid synthase (iAdFASNKO) emit signals that mimic cold exposure to enhance the appearance of thermogenic beige adipocytes in mouse inguinal white adipose tissues (iWATs). Both cold exposure and iAdFASNKO upregulate the sympathetic nerve fiber (SNF) modulator Neuregulin 4 (Nrg4), activate SNFs, and require adipocyte cyclic AMP/protein kinase A (cAMP/PKA) signaling for beige adipocyte appearance, as it is blocked by adipocyte Gsα deficiency. Surprisingly, however, in contrast to cold-exposed mice, neither iWAT denervation nor Nrg4 loss attenuated adipocyte browning in iAdFASNKO mice. Single-cell transcriptomic analysis of iWAT stromal cells revealed increased macrophages displaying gene expression signatures of the alternately activated type in iAdFASNKO mice, and their depletion abrogated iWAT beiging. Altogether, these findings reveal that divergent cellular pathways are sufficient to cause adipocyte browning. Importantly, adipocyte signaling to enhance alternatively activated macrophages in iAdFASNKO mice is associated with enhanced adipose thermogenesis independent of the sympathetic neuron involvement this process requires in the cold.

Macrophage beta2-adrenergic receptor is dispensable for the adipose tissue inflammation and function

“…Given the findings presented in this paper, we propose that the sympathetic nerve activity indirectly maintains ATMs in an anti-inflammatory state by modulating the phenotype of adipocytes. In accordance to our conclusion, numerous adipocyte-targeted genetic mouse models with altered adipocyte survival [ 48 ], lipogenesis [ 47 ], lipolysis [ 49 ], lipid storage [ 50 ], mitochondrial function [ 51 , 52 ] and thermogenesis [ [53] , [54] , [55] ] show changes in adipose tissue inflammation and ATM phenotypes.…”

“…Our findings somewhat contradict the current view, which outlines the presence of a bidirectional communication between the sympathetic nerves and macrophages within adipose tissues [ 2 , 15 ]. Abundant evidence indicates that ATMs can affect SNS outflow to adipose tissues by either locally modulating nerve development [ 10 , 12 ], degrading NE [ 9 , 11 ] or by producing some yet unidentified sympathomimetic signaling factors [ 47 ]. However, the view that the SNS can directly modulate ATM phenotype is based on either pharmacologically stimulating SNS outflow to WAT [ 14 ] or surgically denervating mouse fat pads and observing either decreased or increased ATM pro-inflammatory activation [ 13 ], respectively.…”

Blunting of insulin-stimulated glucose uptake in brown adipose tissue induces systemic metabolic dysregulation in female mice

“…An explanation for the differences in results is that disruption of the ChREBP pathway might impact the synthesis of specific lipids and or perturb the balance of lipid species in ways distinct from the loss of FASN. It has recently been shown that the effect of loss of adipocyte FASN is in part mediated through M2 macrophages and promotion of beiging of WAT (Henriques, 2020). In our brown adipocyte Rab10 knockout model we do not see an increase of beige adipocytes in WAT, supporting the hypothesis that disruption of ChREBP pathway is functionally distinct from the loss of FASN.…”

Chronic tissue inflammation and metabolic disease

“…The concept of macrophage-mediated catecholamine catabolism in adipose tissue was also reported by Dixit and his colleagues (Camell et al 2017), who showed that aging-induced catecholamine resistance is associated with increased ATM catecholamine catabolism. In support of the concept that ATMs regulate local catecholamine levels, systemic depletion of tissue macrophages using clodronate liposomes, but not sympathetic denervation, blocks inguinal WAT beiging in adipocyte Fasn KO mice (Henriques et al 2020).…”