Immune Protection from Metabolic Syndrome?

Science Signaling  04 Jan 2011:
Vol. 4, Issue 154, pp. ec8
DOI: 10.1126/scisignal.4154ec8

Noting that immune cells reside in peripheral tissues involved in controlling organismal metabolism, such as the liver and fat, Ricardo-Gonzalez et al. explored how the immune response to allergic inflammation or helminth infection, immune responses dominated by anti-inflammatory T helper 2 (TH2) signaling through cytokines such as interleukin-4 (IL-4), affected hepatic metabolism, the response to a high-fat diet, and adipose inflammation. IL-4 signals through the transcriptional regulator STAT6, which was present in the liver and adipose tissue. Both liver and isolated mouse hepatocytes exhibited increased tyrosine phosphorylation of STAT6 in response to IL-4, and this was associated with increased glucose oxidation and decreased β-oxidation of fatty acids. STAT6-null hepatocytes had increased abundance of peroxisome proliferator–activated receptor α (PPARα), which induces genes associated with fatty acid metabolism, and exhibited a metabolic shift opposite to that of wild-type hepatocytes exposed to IL-4, which showed increased use of fatty acids rather than glucose. STAT6 inhibited PPARα reporter gene expression in an IL-4–dependent manner; moreover, recruitment of PPARα to target gene promoters was inhibited by IL-4 treatment of hepatocytes, and PPARα target gene expression was inhibited by IL-4 in mouse liver. STAT6 and PPARα coimmunoprecipitated from IL-4–treated mouse livers. STAT6-null mice were resistant to obesity induced by the high-fat diet and exhibited increased oxygen consumption and a catabolic metabolic profile with increased utilization of fatty acids in both adipose tissue and liver. However, STAT6-null mice on a high-fat diet exhibited glucose intolerance, high circulating insulin concentrations, and hepatic steatosis and decreased hepatic phosphorylation of Akt, which are hallmarks of hepatic insulin resistance. In wild-type mice, administration of IL-4 with the high-fat diet reduced weight and adiposity and increased locomotor activity, which increased energy expenditure. The IL-4–treated animals also exhibited improved glucose tolerance and robust hepatic activation of Akt in response to insulin. IL-4 reduced the transcriptional induction of genes associated with inflammation in the adipose tissue of animals fed the high-fat diet. These metabolic effects of IL-4 were dependent on STAT6 and PPARα, which implicated antagonism of the catabolic effects of PPARα. Mice fed a high-fat diet and treated to cause allergic inflammation, which creates an immune response biased toward TH2, showed improved glucose tolerance and insulin sensitivity compared with control mice fed the high-fat diet. These results reveal a complex role for the immune system in hepatic metabolism and adipose inflammation, which contribute to organismal glucose handling and insulin sensitivity.

R. R. Ricardo-Gonzalez, A. Red Eagle, J. I. Odegaard, H. Jouihan, C. R. Morel, J. E. Heredia, L. Mukundan. D. Wui, R. M. Locksley, A. Chawla, IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc. Natl. Acad. Sci. U.S.A. 107, 22617–22622 (2010). [Abstract] [Full Text]