Figure 1. Pathway for driving beige fat formation. Cold stimulus promotes beige fat formation and thermogenesis, but the pathways involved in such processes were unclear. The recently hypothesized immune system-mediated pathway for driving these processes could yield new ways to treat obesity, type 2 diabetes and related metabolic disorders.

Through this pathway, cold stimulus triggers recruitment of CC chemokine receptor 2 (CCR2; CD192)+ monocytes to white adipose tissues, where they differentiate into macrophages. Cold stimulus also induces eosinophils in those tissues to release type 2 cytokines, such as IL-4 (BSF1) and IL-13 (small yellow circles).

The cytokines induce alternative activation of macrophages. This process leads to increased expression of tyrosine hydroxylase in myeloid cell populations found in white adipose tissues, including the macrophages themselves.

The increased expression of tyrosine hydroxylase results in more secretion of catecholamines (small purple circles) from myeloid cells, which in turn drives the formation of beige adipocytes and increases their thermogenesis activity.

Whether these beige adipocytes are formed from white adipocytes or some precursor cell population in white adipose tissue has not been determined.

At least two points of intervention (red dashed arrows) have been identified. As reported in Rao et al., the hormone meteorin glial cell differentiation regulator-like (METRNL) (gray circles) can induce expression of IL-4 and IL-13 and promote beige fat formation and thermogenesis activity. Separately, Qiu et al. report that infusion of IL-4 itself has similar effects.