Abstract
Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell–derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown. We show here that CD4+Foxp3+ regulatory T cells (Tregs) are a substantial source of IL-10 and that Treg-derived IL-10 can suppress adipocyte beiging. Unexpectedly, Treg-specific loss of IL-10 resulted in increased insulin sensitivity and reduced obesity in high-fat diet–fed male mice. Mechanistically, we determined that Treg-specific loss of the transcription factor Blimp-1, a driver of IL-10 expression by Tregs, phenocopied the Treg-specific IL-10–deficient mice. Loss of Blimp-1 expression in Tregs resulted in reduced ST2+KLRG1+, IL-10-secreting Tregs, particularly in the white adipose tissue. Blimp-1–deficient mice were protected from glucose intolerance, insulin resistance, and diet-induced obesity, through increased white adipose tissue browning. Taken together, our data show that Blimp-1–regulated IL-10 secretion by Tregs represses white adipose tissue beiging to maintain adipose tissue homeostasis.
Highlights
Obesity, an imbalance between energy intake and energy expenditure, is continuing to rise globally at an unchecked pace
It was recently reported that IL-10, secreted by immune cells, suppressed adipocyte thermogenesis by repressing expression of uncoupling protein 1 (UCP1) and other markers associated with adipocyte beiging [12, 13]
We first wanted to identify the principal source of IL-10 secreted by immune cells that acted to suppress adipocyte thermogenesis and beiging
Summary
An imbalance between energy intake and energy expenditure, is continuing to rise globally at an unchecked pace. Upregulation of uncoupling protein 1 (UCP1) in the mitochondria and subsequent uncoupling of the electron transport chain results in beige adipocytes that are adept at dissipating energy as heat [1,2,3]. This increase in energy expenditure by UCP1+ beige adipocytes can rebalance energy intake and expenditure, resulting in weight loss [1, 3]. Noninflammatory, alternatively activated macrophages have been reported by some groups to secrete norepinephrine to increase adipocyte beiging [6, 7], and ILC2s can produce methionine-enkephalins, opioid-like compounds, to induce beiging in a UCP1-dependent manner [8]
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