A Novel Effect of Growth Hormone on Macrophage Modulates Macrophage-Dependent Adipocyte Differentiation

The GH receptor (GHR) is expressed on macrophages. However, the precise role of GH in regulation of macrophage function is unclear. We hypothesized that soluble factors including cytokines produced by macrophages in a GH-dependent manner regulate adipogenesis. We confirmed expression and functional integrity of the GHR in the J774A.1 macrophage cells. Conditioned medium (CM) from macrophages inhibited adipogenesis in a 3T3-L1 adipogenesis assay. CM from GH-treated macrophages decreased the inhibitory effect of CM from macrophages on adipogenesis. This effect on preadipocyte differentiation was active only during the first (early) phase of adipocyte differentiation. CM from stromal vascular compartment macrophages of mice with macrophage-specific deletion of the GHR exhibited more inhibitory effect on 3T3-L1 preadipocyte differentiation compared with CM from stromal vascular compartment macrophages of control mice, indicating that intact GH action in primary macrophages also increases preadipocyte differentiation. GH did not increase IGF-1 expression in macrophages. PCR array analysis identified IL-1 beta as a candidate cytokine whose expression was altered by GH in macrophages. Levels of IL-1 beta mRNA and protein were significantly decreased in GH-treated J774A.1 macrophages. Nuclear factor-kappa B stimulates IL-1 beta gene expression, and GH induced a significant decrease in the levels of phosphorylated nuclear factor-kappa B in macrophages. IL-1 beta is a known inhibitor of adipogenesis, and these results support GH-dependent down-regulation of macrophage IL-1 beta expression as one mechanism for the observed increase in adipogenesis with CM from GH-treated macrophages. We conclude that GH decreases secretion of IL-1 beta by the macrophage and thus in a paracrine manner increases adipocyte differentiation. These results provide a novel mechanism for GH's actions in the control of adipogenesis. (Endocrinology 151: 2189-2199, 2010)