Modulation of Cell-Mediated Immunity to Suppress High Fat Diet-Induced Obesity and Insulin Resistance

Abstract

Purpose To assess the effect of immune modulators on high fat diet-induced obesity and insulin resistance. Methods C57BL/6 mice were fed a high fat diet and injected intraperitoneally with cyclosporine A, fingolimod, or vehicle twice weekly for 15 weeks. Body weight and food intake were manually measured every other day. Glucose tolerance test, insulin sensitivity, and body composition were examined and compared between the control and the immune modulator treated animals. Tissue samples were collected at the end of the experiment and examined for serum biochemistry, histology, and mRNA levels of marker genes for inflammation, and glucose and lipid metabolism in white and brown adipose tissues and in the liver. Results Cyclosporine A and fingolimod suppressed high fat diet-induced weight gain, reduced hepatic fat accumulation, and improved insulin sensitivity. The beneficial effects are associated with altered expression of F4/80, Cd68, Il-6, Tnf-α, and Mcp-1 genes, which are involved in macrophage-related chronic inflammation in adipose and hepatic tissues. Conclusion Immune modulation represents an important intervention for obesity and obesity-associated insulin resistance.

Targeting viperin improves diet-induced glucose intolerance but not adipose tissue inflammation

“…Instead, suppressing viperin expression improved glucose homeostasis in HFD-fed mice. This is in line with earlier findings showing that suppressing innate antiviral immunity using cyclosporine A protects against HFD-induced obesity and insulin resistance in mice [ 40 , 41 ]. Recent data revealed that insulin receptor tyrosine kinase substrate (IRTKS) mediates suppression of antiviral responses.…”

Decrease in αβ/γδ T‐cell ratio is accompanied by a reduction in high‐fat diet‐induced weight gain, insulin resistance, and inflammation

“…Data from several studies suggest that T-cell activation might be linked to weight gain. It was shown that treatment of mice on an obesogenic diet with anti-CD40L antibody (blocks costimulation needed for T-cell activation), cyclosporine A (interferes with activity and growth of T cells), or fingolimod (inhibits T-cell emigration from lymphoid organs) leads to decreased weight gain (14,15). This was accompanied by decreased liver weight/ steatosis, decreased (CD11c + ) macrophage infiltration of WAT, and improved insulin sensitivity, all phenotypes that we also observed in our Tg T-PPAR-b mice.…”

Low-Density Lipoprotein Receptor–Dependent and Low-Density Lipoprotein Receptor–Independent Mechanisms of Cyclosporin A–Induced Dyslipidemia

“…Improved insulin sensitivity in response to CsA has been reported recently in obese high-fat-fed C57Bl/6 mice. 26 However, caution must be exercised in applying these findings to clinical studies as immunosuppressive drugs such as CsA increase the risk of developing diabetes mellitus, most likely via effects on insulin secretion. 27 Analysis of individual lipid species in VLDL and IDL/ LDL fractions indicated that although absolute levels of lipid species in plasma were increased, lipid composition per particle (per phosphatidylcholine or apoB) did not change for the vast majority of lipid species.…”