Neutrophil regulation of brown adipose tissue homeostasis

Washington University, Saint Louis MO

Investigators

Abstract

PROJECT SUMMARY Brown adipose tissue (BAT) is a thermogenic fat pad that is essential for maintaining core body temperature and is associated with protection from numerous metabolic diseases. Adult patients with intact BAT activity are much less likely to have obesity, type 2 diabetes, or cardiovascular disease (CVD), and obese individuals exhibit impaired BAT activation after exposure to cold environmental temperatures. Consequently, there is significant interest in identifying novel pathways that regulate BAT function, with the goal of developing new therapeutic strategies to treat metabolic diseases such as obesity and type 2 diabetes. It is well established that sympathetic neurons are the dominant drivers of brown adipocyte activation by secreting the catecholamines epinephrine and norepinephrine (E/NE). Macrophages then degrade Epi/NE to form a negative feedback loop that is essential for maintaining BAT homeostasis. Recently, we characterized the immune cell landscape of BAT and surprisingly found that neutrophils are the most abundant immune cell type in this tissue, greatly outnumbering macrophages. However, the role of neutrophils in regulating BAT function is unknown. Neutrophils are best known for their role in phagocytosis of bacteria and foreign material and are highly glycolytic cells with few mitochondria. In new preliminary studies, we have found that neutrophils are recruited from the blood specifically into BAT following exposure to cold temperatures and undergo massive metabolic and transcriptional reprogramming to acquire a unique reliance on oxidative phosphorylation. Antibody-based depletion of neutrophils leads to decreased BAT mass, impaired adaptive thermogenesis, and hypothermia. Strikingly, mice that are born without any neutrophils die if subjected to cold stress but are rescued from this fate if they receive a single adoptive transfer of wildtype neutrophils into the BAT. In addition, we found that the recruitment of neutrophils into BAT is dependent on ATG14, and deletion of ATG14 in myeloid cells leads to decreased core body temperature, decreased BAT mass, loss of stored lipids in BAT, decreased expression of Uncoupling protein 1, and exacerbated HFD-indued obesity. Furthermore, neutrophils directly activate brown adipocyte metabolism. These findings lead to our central hypothesis that ATG14-dependent neutrophils are recruited into BAT and undergo local transcriptional and metabolic reprogramming to critically support BAT activation and adaptive thermogenesis. We will address this hypothesis in two aims. In Aim 1, we will identify the factors that drive neutrophil reprogramming upon entry into BAT and determine whether disruption of their metabolic reprograming impairs BAT thermogenesis. In Aim 2, we will determine the mechanisms by which ATG14-dependent neutrophils in BAT sustain adaptive thermogenesis to ameliorate metabolic disease pathogenesis. These studies will identify for the first time a role for neutrophils and ATG14 in regulating BAT function and adaptive thermogenesis, revealing a novel immunometabolic pathway that can be targeted to enhance BAT activity to treat multiple metabolic diseases, such as obesity, type 2 diabetes, and/or CVD.