Since reconstitution of WT adipose tissue restored efficacy of rmuFGF21 (Figure 4H–J) we hypothesized that not only was the absolute amount of adipose tissue relevant but possibly a factor from adipose alone such as leptin could elicit some of the effects observed since Tg mice are severely hypoleptinemic and the Tx animals received WT adipose tissue (with intact leptin). We treated 4 groups of Tg mice with either rmuFGF21, recombinant murine leptin, both, or vehicle for 15 days. Recombinant muFGF21 was ineffective in reducing body weight, blood glucose or insulin levels, or in improving glucose tolerance (Figures 6A–D). Leptin significantly reduced body weight, and insulin levels, with a modest reduction in blood glucose and glucose tolerance. Impressively, rmuFGF21 and leptin co-administration resulted in significant reductions in body weight, blood glucose and insulin levels, and improved glucose tolerance. Furthermore, FGF21 and leptin in combination exhibited greater efficacy than leptin alone, and in the case of glucose tolerance it reached statistical significance (Figure 6D).
