Abstract
Fibroblast growth factor 21 (FGF21) has evolved as a major metabolic regulator, the pharmacological administration of which causes weight loss, insulin sensitivity and glucose control in rodents and humans. To understand the molecular mechanisms by which FGF21 exerts its metabolic effects, we developed a human in vitro model of adipocytes to examine crosstalk between FGF21 and insulin signaling. Human adipose stem cell-derived (hASC) adipocytes were acutely treated with FGF21 alone, insulin alone, or in combination. Insulin signaling under these conditions was assessed by measuring tyrosine phosphorylation of insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), and serine 473 phosphorylation of Akt, followed by a functional assay using 14C-2-deoxyglucose [14C]-2DG to measure glucose uptake in these cells. FGF21 alone caused a modest increase of glucose uptake, but treatment with FGF21 in combination with insulin had a synergistic effect on glucose uptake in these cells. The presence of FGF21 also effectively lowered the insulin concentration required to achieve the same level of glucose uptake compared to the absence of FGF21 by 10-fold. This acute effect of FGF21 on insulin signaling was not due to IR, IGF-1R, or IRS-1 activation. Moreover, we observed a substantial increase in basal S473-Akt phosphorylation by FGF21 alone, in contrast to the minimal shift in basal glucose uptake. Taken together, our data demonstrate that acute co-treatment of hASC-adipocytes with FGF21 and insulin can result in a synergistic improvement in glucose uptake. These effects were shown to occur at or downstream of Akt, or separate from the canonical insulin signaling pathway.
Highlights
Fibroblast growth factor 21 (FGF21) is an atypical member belonging to the fibroblast growth factor family, and serves as an endocrine hormone, which was originally identified to increase glucose uptake in fat cells [1]
We assessed the expression of FGR1c and KLB in Human adipose stem cell-derived (hASC) differentiated into adipocytes. hASC-adipocytes express both FGFR1 and KLB (Fig. 1a)
The expression ratio of KLB and FGFR1 is similar in hASC-adipocytes and human adipose tissue suggesting that these cells could serve as a useful model to dissect FGF21 signaling
Summary
Fibroblast growth factor 21 (FGF21) is an atypical member belonging to the fibroblast growth factor family, and serves as an endocrine hormone, which was originally identified to increase glucose uptake in fat cells [1]. Adipocyte-specific deletion of FGFR1 or KLB ameliorates the metabolic effects of pharmacological FGF21 administration [3,9] Given that both FGFR1 and KLB are required for FGF21 action [9], and since there is negligible expression of FGFR1c in mouse liver [2], one can hypothesize that FGF21 does not have a direct effect on the liver [11]. Studies have shown that adiponectin is required for glycemic control and insulin sensitizing effects of pharmacological FGF21 administration in obese mice [12,13]. Both FGFR1c and KLB are required for FGF21 action since the loss of either of these proteins abolishes the metabolic effects of FGF21 [8,9]
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