Pleiotropic adipose Treg subsets, defined by Atf3 expression, modulate adipocyte energy expenditure and weight loss

Abstract

Chronic obesity occurs when there is imbalance between caloric intake and energy expenditure. It is now clear that immune cells, through their communication with adipocytes, can drive or suppress adipocyte energy expenditure, thus regulating weight gain and obesity. Adipose tissue resident regulatory T cells (aTregs) are a dominant, unique CD4+ T cell population in the adipose tissue depots of mice and humans. Here we show that the transcription factor Activating Transcription Factor 3 (Atf3), defines a population of aTregs that secrete opioid-like peptides called Methionine-Enkephalins (Met-Enk). We show that aTreg-derived Met-Enk increases adipocyte function and energy expenditure by upregulating Uncoupling Protein 1 (Ucp-1) and other genes associated with adipocyte thermogenesis. Loss of Atf3 expression in aTregs, resulted in loss of Met-Enk expressing aTregs and conversely, resulted in increased Interelukin-10 (IL-10)-secreting aTregs. Physiologically, Atf3+ aTregs are required to maintain metabolic homeostasis and loss of Atf3+ aTregs increased insulin resistance in mice. Taken together, our data reveal that distinct aTreg populations with unique gene expression and cytokine secretion profiles, work together to modulate adipocyte function and energy expenditure.