T reg–specific insulin receptor deletion prevents diet-induced and age-associated metabolic syndrome

Wu, Dan; Wong, Ching; Han, Jonathan M.; Orban, Paul C.; Huang, Qing; Gillies, Jana; Mahdavi, Majid; Gibson, William T.; Levings, Megan K.

doi:10.1084/jem.20191542

Cited by 33 publications

(23 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, recent publications have revealed that the function of peripheral Tregs is more complex than initially reported and are tissue and context dependent. For example, adipose tissue resident Tregs (aTregs) have been shown to be pathogenic in age-associated obesity (34,35). In addition, wildtype female mice, which have reduced aTregs frequency and IL-10 secretion, are protected from glucose intolerance and fat gain, relative to age-matched male mice, although whether glucose tolerance and fat reduction in female mice is driven through an IL-10 deficient aTreg axis has not yet been established (15).…”

Section: Discussionmentioning

confidence: 99%

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

Beppu¹,

Mooli²,

Qu³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

Beppu¹,

Mooli²,

Qu³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

show abstract

“…Some Treg have developed specialized adaptations to their environment. As an example, VAT-Treg (visceral adipose tissue-Treg) express high levels of PPARγ in order to reduce insulin resistance associated with inflammation of fat tissue ( 36 ).…”

Section: Subsets Of Regulatory T Cellsmentioning

confidence: 99%

The Complex Role of Regulatory T Cells in Immunity and Aging

et al. 2021

View full text Add to dashboard Cite

The immune system is a tightly regulated network which allows the development of defense mechanisms against foreign antigens and tolerance toward self-antigens. Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses. Dysregulation of any of these processes can lead to serious consequences. Classically, Treg cell functions have been described in CD4+ T cells, but other immune cells also harbour the capacity to modulate immune responses. Regulatory functions have been described for different CD8+ T cell subsets, as well as other T cells such as γδT cells or NKT cells. In this review we describe the diverse populations of Treg cells and their role in different scenarios. Special attention is paid to the aging process, which is characterized by an altered composition of immune cells. Treg cells can contribute to the development of various age-related diseases but they are poorly characterized in aged individuals. The huge diversity of cells that display immune modulatory functions and the lack of universal markers to identify Treg make the expanding field of Treg research complex and challenging. There are still many open questions that need to be answered to solve the enigma of regulatory T cells.

show abstract

“…Additionally, VAT-T R may rely less on PI3K signals compared to T R found from other tissues, due to the presence of other supporting factors in the VAT of naïve mice, such as high levels of IL-33. Indeed, a recent study demonstrated that insulin receptor deletion in T R , which also results in reduced PI3K signaling, led to an increased suppressive phenotype in VAT-T R and enhanced insulin sensitivity (Wu et al, 2020). PI3K-mediated activation of mTORC1 also promotes glycolytic metabolism in T cells.…”

Section: Discussionmentioning

confidence: 99%

ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue

Mittelsteadt

Campbell

2020

Preprint

View full text Add to dashboard Cite

A unique population of Foxp3 + regulatory T cells (T R ) resides in visceral adipose tissue (VAT) that regulates adipose inflammation and helps preserve insulin sensitivity. The costimulatory molecule ICOS is highly expressed on effector (e)T R that migrate to nonlymphoid tissues, and contributes to their maintenance and function in models of autoimmunity. In this study, we report an unexpected cell-intrinsic role for ICOS expression and downstream PI3K signaling in limiting the abundance, VAT-associated phenotype, and function of T R specifically in VAT. Icos -/mice and mice expressing a knock-in form of ICOS that cannot activate PI3K had increased VAT-T R abundance and elevated expression of canonical VAT-T R markers. Loss of ICOS signaling facilitated enhanced accumulation of T R to VAT associated with elevated CCR3 expression, and resulted in reduced adipose inflammation and heightened insulin sensitivity in the context of high-fat diet. Thus, we have uncovered a new and surprising molecular pathway that regulates VAT-T R accumulation and function.

show abstract

T reg–specific insulin receptor deletion prevents diet-induced and age-associated metabolic syndrome

Cited by 33 publications

References 48 publications

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

The Complex Role of Regulatory T Cells in Immunity and Aging

ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue

Contact Info

Product

Resources

About