Abstract
The complex direct and indirect interplay between adipocytes and various adipose tissue (AT)-resident immune cells plays an important role in maintaining local and whole-body insulin sensitivity. Adipocytes can directly interact with and activate AT-resident invariant natural killer T (iNKT) cells through CD1d-dependent presentation of lipid antigens, which is associated with anti-inflammatory cytokine production in lean AT (IL-4, IL-10). Whether alterations in the microenvironment, i.e., increased free fatty acids concentrations or altered cytokine/adipokine profiles as observed in obesity, directly affect adipocyte-iNKT cell communication and subsequent cytokine output is currently unknown. Here we show that the cytokine output of adipocyte-iNKT cell interplay is skewed by a lipid-rich microenvironment. Incubation of mature 3T3-L1 adipocytes with a mixture of saturated and unsaturated fatty acids specifically reduced insulin sensitivity and increased lipolysis. Reduced activation of the CD1d-invariant T-Cell Receptor (TCR) signaling axis was observed in Jurkat reporter cells expressing the invariant NKT TCR, while co-culture assays with a iNKT hybridoma cell line (DN32.D3) skewed the cytokine output toward reduced IL-4 secretion and increased IFNγ secretion. Importantly, co-culture assays of mature 3T3-L1 adipocytes with primary iNKT cells isolated from visceral AT showed a similar shift in cytokine output. Collectively, these data indicate that iNKT cells display considerable plasticity with respect to their cytokine output, which can be skewed toward a more pro-inflammatory profile in vitro by microenvironmental factors like fatty acids.
Highlights
Insulin resistance is one of the hallmarks of type II diabetes mellitus (T2DM) pathogenesis, with both overlapping and unique molecular mechanisms affecting different metabolic organs, including muscle, liver and adipose tissue (AT) [1, 2]
The NK1.1− fraction from both epididymal white AT (eWAT) and spleen followed the same trend as their positive selection counterparts, but to a lower extent (Figures S3C,D). These data indicate that the eWAT invariant natural killer T (iNKT) cytokine secretion profile has a specific plasticity and is highly responsive to the adipose environment, with a key role for free fatty acids in this process. Aside from their CD1d restricted T-Cell Receptor (TCR), iNKT cells can have divergent functions, surface markers and cytokine secretion preferences, all of which seem to be determined by the nature of lipid antigens, the type of APC and the microenvironment of the tissue [21, 41, 42]
Using two iNKT model cell lines, DN32.D3, and JE6-1REP−iNKT−β2M_KO reporter cells, we show that cross-talk with the lipid enriched 3T3L1 adipocytes influences output following TCR stimulation (Figure 2)
Summary
Insulin resistance is one of the hallmarks of type II diabetes mellitus (T2DM) pathogenesis, with both overlapping and unique molecular mechanisms affecting different metabolic organs, including muscle, liver and adipose tissue (AT) [1, 2]. While the pathways leading from obesity to whole body insulin resistance and T2DM are complex and multifactorial [2], the increased uptake of nutrients leading to hyperplasia and hypertrophy of adipocytes is clearly an important early event, resulting in an altered adipokine secretion profile [5]. The resulting chronic low-grade inflammation causes dysregulation of lipolysis, where adipocytes secrete higher levels of FFA, and glycerol [8, 9], which together with adipokines and cytokines can be viewed as an additional AT output. Combined these factors can have local or systemic effects and contribute to the development of whole-body insulin resistance and T2DM
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