engleski

NK cells promote obesity-induced insulin resistance by driving M1 macrophage differentiation

Obesity, and its main clinical complication diabetes mellitus type 2 (DM2), has a major impact on life expectancy and quality of life. DM2 is associated with chronic systemic inflammation, which is an important cause of its most life-threatening complications. Accumulation of fat in visceral adipose tissue (VAT) has long been recognized as an important contributor to the development of DM2. Recently it was shown that systemic inflammation in DM2 also originates from VAT: As body weight increases, pro-inflammatory cells accumulate in VAT in a Th1-like immune response. Moreover, these cells play a key role in the development of obesity-induced insulin resistance. However, much is still unclear about initial events that drive VAT-inflammation. NK cells play an important role in the initiation of Th1-type immune responses upon viral infection, but their role in obesity-driven VAT-inflammation is currently unknown. We therefore hypothesized that NK cells play an important role in the intial events that drive VAT inflammation during obesity. We oberved that NK cells are present in relatively high numbers in VAT, even of lean mice. Diet-induced obesity (DIO) resulted in a rapid increase of NK cells in this tissue, which reached a plateau after one month of feeding. Moreover, NK cells in VAT of mice fed with high-fat diet acquired an activated phenotype, which persisted over a long period of time. The increase of NK cells in fat of DIO animals preceded the influx of T cells by several months, but correlated closely with the conversion of macrophages to a pro-inflammatory M1 phenotype. Importantly, depletion of NK cells resulted in reduced insulin resistance, improved glucose tolerance and a reduction in plasma insulin levels of DIO mice. Similar observations were made after surgical removal of the abdominal fat pad, stressing the importance of VAT inflammation in the development of DM2. The effect of NK cells did not depend on the presence of the adaptive immune system, as depletion of NK cells in SCID mice resulted in a comparable reduction of insulin resistance. Rather, NK cells appeared to play an important role in the stimulation of macrophage polarization, since NK depletion resulted in a clear reduction of M1 pro-inflammatory macrophages. In summary, we show that NK cells play an important role in DM2 disease development druing diet-induced obesity and provide valuable new insights in the early events leading to the development of diabetes mellitus type 2.

NK cells; Visceral Adipose Tissue; M1 macrophages; Diabetes Mellitus type 2

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