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High-caloric diet has drastic effects on the immune system

A group of researchers at Ludwig Maximilian University of Munich, led by Dr Susanne Stutte and Professor Barbara Walzog, has shown that a high-caloric diet, even for a period of only three weeks, has drastic effects on the immune system. The results of this study, ‘High-Fat Diet Rapidly Modifies Trafficking, Phenotype, and Function of Plasmacytoid Dendritic Cells in Adipose Tissue, The Journal of Immunology’ and which was carried out in collaboration with Harvard Medical School in Boston, could now contribute to the development of new approaches toward a therapeutic intervention of the metabolic syndrome.

Diverse distribution of pDCs within the VAT. (A) VAT anatomy of the mouse and localization of fat-associated lymphoid clusters (FALCs). Male VAT was separated in the tip area (facing the liver), in the center part, and in the base part, which is attached to testis and epididymis. Confocal microscopy of FALC structures within VAT from chow-treated male mice. (B) VAT was stained for SiglecH (pDCs, green), CD31 (endothelia cells, white), and CD45 (hematopoietic cells, blue). Scale bar, 100 mm. (C) Representative images of VAT of 3-wk-old (left image) and 8-wk-old male mice (right image) stained for SiglecH (green), CD31 (white), and CD45 (blue). Scale bar, 50 mm. (D) Representative images of VAT of SFD or HDF mice, showing the adipocyte tissue in bright field (gray) and CD451 cells (red). Scale bars, 100 mm. (E) Number CD451 FALCs was quantified per volume of VAT from mice fed with a SFD (gray) and a HFD (red). Each dot represents total number of FALCs of one mouse. (F) The maximal MFI of CD45 was measured on the threedimensional projection images of FALCs, the mean intensity of SFD samples was set as 1, and the MFI of HFD FALCs was calculated accordingly. (G) Representative images of the VAT showing CD451 cells (red) at the tip of VAT, transferred SiglecH-GFP pDCs (green), and the adipose tissue labeled in blue by the second harmonic generation (SH). Images were acquired by multiphoton microscopy. Scale, 100 mm. (H) Left, After 3 wk of SFD and HFD, numbers of pDCs were quantified in relationship to the volume of VAT. (Middle) FALCs were visualized by three-dimensionalmaximum projection using Imaris (Bitplane) and numbers of pDCs were quantified per 1 mm2 . Right, Mean migratory speed of pDCs was measured by in vivo multiphoton microscopy after 3 wk of a HFD and compared with SFD. n 5 45 mice in each group. Statistical analyses were performed using a Student t test. Values represent mean ± SEM. **p < 0.05, ***p < 0.001, ****p < 0.0001. Credit: The Journal of Immunology (2022). DOI: 10.4049/jimmunol.2100022

"A particular kind of immune cells known as plasmacytoid dendritic cells (pDCs) begins to accumulate in the visceral adipose tissue," explained Stutte.

This adipose tissue is located inside the abdomen and surrounds internal organs. With high caloric diet, small clusters of immune cells form tertiary lymphoid structures inside this fat, resulting in fatal immune responses.

The researchers sought to decipher the molecular mechanisms of their recruitment to VAT and the functional relevance of this process. They observed increased pDC numbers in murine blood, liver, spleen, and VAT after feeding a high-fat diet (HFD) for three weeks compared with a standard diet. pDCs were enriched in fat-associated lymphoid clusters representing highly specific lymphoid regions within VAT. HFD led to an enlargement of fat-associated lymphoid clusters with an increased density and migratory speed of pDCs as shown by intravital multiphoton microscopy.

For their recruitment into VAT, pDCs employed P-selectin with E-selectin and L-selectin being only critical in response to HFD, indicating that the molecular cues underlying pDC trafficking were dependent on the nutritional state. Subsequent recruitment steps required α4β1 and α4β7 integrins and engagement of CCR7. Application of fingolimod (FTY720) abrogated egress of pDCs from VAT, indicating the involvement of sphingosine-1-phosphate in this process.

Furthermore, HFD altered pDC functions by promoting their activation and type 1 IFN expression. Blocking pDC infiltration into VAT prevented weight gain and improved glucose tolerance during HFD. In summary, a HFD fundamentally alters pDC biology by promoting their trafficking, retention, and activation in VAT, which in turn seems to regulate metabolism.

"Now, these pDCs in visceral fat are in a constant state of alarm and release type-I interferon," explains Walzog.

Further information

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