Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Abstract

Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3

“…Relatively little is known of mammalian Gdf3 function on glucose homeostasis in vivo. Gdf3 is highly expressed in white adipose tissue with levels increasing with age and obesity [25,36,46]. Our data support a model in which Gdf3 blocks beneficial BMP receptor signaling, decreasing phosphorylation of SMAD 1/5/9, and inhibiting Id2, a SMAD target gene ( Fig.…”

“…An emerging literature is developing on the contribution of macrophages to catecholamine production and degradation. Macrophages expressing Gdf3 have been implicated in controlling catecholamine degradation and rates of lipolysis [46]. Mice with global deletion of Gdf3 from birth maintain lean body masses when challenged with HFD [34,53].…”

Contributions of innate type 2 inflammation to adipose function

“…These findings were disputed in a multilaboratory paper providing strong evidence that WAT macrophages cannot express TH and therefore can't produce catecholamines to beige WAT [97], which called into question the upstream role of eosinophils in beiging as well. Additional studies have provided further insight by revealing the presence of nerve-associated macrophages (NAMs/SAMs) that line TH-producing sympathetic nerves within WAT [98,99]. It was found that the NAMs/SAMs could collect and catabolize catecholamines secreted by nerves, and in this way modulate the available pool of catecholamines that could otherwise act on proximal adipocytes (Figure 1).…”

Single Cell Analysis Reveals Immune Cell-Adipocyte Crosstalk Regulating the Transcription of Thermogenic Adipocytes

“…Clearance of catecholamine is critical in terminating b-adrenergic signals, and local catabolism of catecholamine is an established mechanism for negative regulation of adrenergic signaling in adipose tissue (Camell et al, 2017;Pirzgalska et al, 2017;Song et al, 2019).…”