Serum concentrations of resistin-like molecules β and γ are elevated in high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bone marrow

Aims/hypothesis: Resistin and the resistin-like molecules (RELMs) comprise a novel class of cysteine-rich proteins. Among the RELMs, RELMβ and RELMγ are produced in non-adipocyte tissues, but the regulation of their expression and their physiological roles are largely unknown. We investigated in mice the tissue distribution and dimer formation of RELMβ and RELMγ and then examined whether their serum concentrations and tissue expression levels are related to insulin resistance. Methods: Specific antibodies against RELMβ and RELMγ were generated. Dimer formation was examined using COS cells and the colon. RELMβ and RELMγ tissue localisation and expression levels were analysed by an RNase protection assay, immunoblotting and immunohistochemical study. Serum concentrations in high-fat-fed and db/db mice were also measured using the specific antibodies. Results: The intestinal tract produces RELMβ and RELMγ, and colonic epithelial cells in particular express both RELMβ and RELMγ. In addition, RELMβ and RELMγ were shown to form a homodimer and a heterodimer with each other, in an overexpression system using cultured cells, and in mouse colon and serum. Serum RELMβ and RELMγ levels in high-fat-fed mice were markedly higher than those in mice fed normal chow. Serum RELMβ and RELMγ concentrations were also clearly higher in db/db mice than in lean littermates. Tissue expression levels revealed that elevated serum concentrations of RELMβ and RELMγ are attributable to increased production in the colon and bone marrow. Conclusions/interpretation: RELMβ and RELMγ form homo/heterodimers, which are secreted into the circulation. Serum concentrations of RELMβ and RELMγ may be a novel intestinal-tract-mediating regulator of insulin sensitivity, possibly involved in insulin resistance induced by obesity and a high-fat diet.