Two recent studies in Cell have provided mechanistic insight into the interactions of adipose tissue and the immune system in the regulation of energy expenditure and glucose tolerance (Cell 157, 1279–1291, 2014, and Cell 157, 1292–1308, 2014).

In previous studies, Bruce Spiegelman and his colleagues showed that Pgc-1α4 is a unique isoform form of Pgc-1α that is expressed in mouse muscle during exercise and that exercise in mice induces 'beiging' of the white fat. In their new study, they link these previous findings by identifying meteorin-like (Metrnl) as a protein induced by Pgc-1α4 in skeletal muscle in mice and humans and one that promotes beiging and improved glucose tolerance—its expression is also induced by cold exposure in mouse adipose. Mechanistically, Metrnl expression is associated with recruitment to adipose tissue of eosinophils. This resulted in the Metrnl-dependent expression of the cytokines interleukin-4 (IL-4) and IL-13 in the adipose and promotion of the alternate activation of macrophages, thus possibly further explaining the increased insulin sensitivity upon Metrnl expression.

In a separate study, Ajay Chawla and his colleagues found that cold exposure of mice results in alternative activation of macrophages in white adipose tissue in response to eosinophil recruitment and their IL-4 secretion. They further found that these alternatively activated macrophages are a key source of catecholamines that result in beiging of the local white adipose tissue. At thermoneutrality, they could replicate the effects of cold exposure, including the increase in beige fat mass and the reversal of established diet-induced obesity and insulin resistance, by treating mice with IL-4.