Chronic low-grade inflammation links obesity to metabolic syndrome – a cluster of disorders including insulin resistance, glucose intolerance, and type 2 diabetes. Suppressing adipose tissue inflammation in mice and humans improves metabolism and reduces the risk of cardiovascular disease, neuropathy, and cancer.
Foxp3+CD4+ regulatory T cells (Treg) are central to immune regulation. In VAT, a specialized subset of Treg differs from those in lymphoid organs in gene expression patterns, growth factor dependence, and their ability to influence inflammation both locally and systemically.
In mice, Treg residing in epididymal VAT (eVAT) reduce inflammation in this tissue and throughout the body. Through interactions with neighboring immune cells, mature adipocytes, and their precursors, Treg help maintain metabolic balance.
Another way to reduce adipose tissue inflammation is to increase energy expenditure and improve glucose utilization. SAT – and especially BAT – is capable of thermogenesis. At the same time, newborns have abundant BAT; its amount and activity decline with age.
Inflammation Suppresses Thermogenesis
Signaling molecules secreted by brown adipocytes (BA) can directly stimulate sympathetic innervation of neurons. Inflammation – particularly macrophage activity – can interfere with this process. Macrophages may capture and degrade norepinephrine, the neurotransmitter that activates thermogenesis through the nervous system. By contrast, γδ T cells stimulate sympathetic innervation via IL-17F, which binds to receptor C on adipocytes and induces transforming growth factor-β1 (TGF-β1) production.
In young mice, BAT contains Treg cells. Their depletion reduces BAT thermogenesis – weakening activation of thermogenic genes and oxygen consumption in response to cold exposure. However, the properties of BAT Treg and the mechanisms linking them to thermogenesis have remained poorly understood.
How BAT Treg Influence Thermogenesis
The Harvard/Dana-Farber team analyzed BAT Treg composition and function at rest and during cold exposure, comparing them with SAT and eVAT Treg. They found that BAT Treg are a heterogeneous population that supports thermogenesis by protecting BAT mitochondria from IFN-γ–induced damage.
BAT Treg resemble SAT Treg but differ substantially from VAT Treg in location and subtype composition.
Selective depletion of Treg in BAT – but not in SAT – increased local T and NK cell activity, boosting IFN-γ production, which in turn damaged mitochondria and disrupted metabolism, impairing non-shivering thermogenesis. A Tbet+ BAT Treg subset suppressed the IFN-γ response and likely contributed to maintaining thermogenesis.
Another key subtype was Il18r1hi Treg, whose numbers rose during cold exposure alongside a sharp increase in IL-18 levels in BAT. Loss of IL-18R1 in Treg led to excessive IFN-γ production and impaired thermogenesis, similar to the effects of total Treg depletion.
IL-18R1 on Treg limits IL-18 activity, thereby reducing IFN-γ production – analogous to how CD25 on Treg binds IL-2 and prevents effector cell proliferation and activation.
Il18r1hi Treg may support thermogenesis through additional mechanisms: they express more CD73, an enzyme linked to heat generation, and less IL-10, which suppresses thermogenesis.
Conclusion
BAT Treg help maintain the tissue’s thermogenic capacity by reducing local IFN-γ production, which otherwise damages mitochondria, disrupts metabolism, and suppresses thermogenic gene activity. IFN-γ also inhibits the differentiation of brown adipocyte precursors into mature cells.
While this study did not examine SAT browning, the authors note similarities to previous research in skeletal muscle, where Treg preserved mitochondrial integrity and enhanced exercise effects.
This parallel suggests that one of the core functions of Treg in metabolically active tissues is to shield neighboring cell mitochondria from damage under various stress conditions. Such protection may be a crucial link between immune and metabolic systems, explaining why modulating Treg with immunotherapies could benefit patients with metabolic disorders.
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