NLRP3 Inflammasome regulation of lipolysis in aged adipose tissue

Abstract

Visceral adiposity is increased in the elderly and this increase is associated with increased risk for metabolic diseases. During aging, there are also increases in inflammation, senescence and leukocyte alterations in white adipose tissue. Furthermore, catecholamine‐induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs), declines with age. 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. Here we show that unlike diet‐induced obesity, aging is associated with reduction in adipose tissue macrophages (ATMs). We found ATMs regulate age‐related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unbiased whole transcriptome analyses of ATMs revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome‐dependent manner. Deletion of NLRP3 inflammasome in aging restored catecholamine‐induced lipolysis through downregulation of monoamine oxidase‐a (MAOA) that is known to degrade NE. 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). Overall our findings suggest that NLRP3 inflammasome‐dependent immune‐metabolic interactions within AT contribute to age‐related inflammation and metabolic dysfunction. Our study also 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.Support or Funding InformationThis work was funded in part by a supplemental award from the National Institute of Aging (grant number: 3R01AG043608‐03S1 FAIN:R01AG043608), the Irene Diamond AFAR Postdoctoral Transition Award, and K99AG058800This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.