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.

No 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.

Adipose-resident Tregs protect against systemic inflammation and metabolic disease by limiting expansion of pro-inflammatory cells, preserving insulin sensitivity and maintaining glucose tolerance. Although their basic markers and roles have been studied, less is known about the transcriptional machinery regulating their differentiation and function. B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional regulator known to be involved in development, polarization, and maintenance of various immune cells including CD4+ T cells. Using Blimp-1 reporter mice, we discovered that Blimp-1 is constitutively expressed in a subset of visceral adipose tissue (VAT) Tregs, and that Blimp-1+ VAT Tregs are phenotypically distinct from their Blimp-1-counterparts. We also found that Treg-specific Blimp-1 deletion led to altered differentiation and function of VAT and inguinal adipose tissue Tregs. Surprisingly, during diet-induced obesity, Blimp-1 Treg deficient mice gained less weight, had reduced body fat percentage, and exhibited improved insulin sensitivity compared to wild type mice. Furthermore, this was accompanied by upregulation of thermogenic genes such as Ucp1, Prdm16 and Dio2 in inguinal adipose tissue, and increased overall fatty acid oxidation. It has previously been shown that IL-10 can induce thermogenesis. Therefore, we repeated these experiments utilizing mice with Treg-specific deletion of IL-10 and found that they phenocopied the Blimp-1 Treg deficient mice. Based on these results, we hypothesize that cross-talk between Tregs and adipocytes via a Blimp-1-IL-10 axis suppresses thermogenesis, and that absence of Blimp-1+ Tregs is metabolically protective during diet-induced obesity.

Mirizzi syndrome (MS) is a rare complication of chronic cholelithiasis. The syndrome describes gallstone obstruction of Hartmann’s pouch or the cystic duct that extrinsically compresses the common hepatic duct, causing obstructive jaundice. In advanced cases, the gallstones may erode into the biliary tree creating a fistula, requiring prompt diagnosis and careful surgical management. We present a case of an 82-year-old female who presented with upper abdominal pain and jaundice, later diagnosed with suspected MS type I, and managed surgically. We aim to highlight MS type I because of the potential progression and damage to the bile duct, creating complications that may affect overall patient outcome.