Lack of Overt FGF21 Resistance in Two Mouse Models of Obesity and Insulin Resistance

Abstract

Circulating levels of fibroblast growth factor 21 (FGF21), a metabolic regulator of glucose, lipid, and energy homeostasis, are elevated in obese diabetic subjects, raising questions about potential FGF21 resistance. Here we report tissue expression changes in FGF21 and its receptor components, and we describe the target-organ and whole-body responses to FGF21 in ob/ob and diet-induced obese (DIO) mice. Plasma FGF21 concentrations were elevated 8- and 16-fold in DIO and ob/ob mice, respectively, paralleling a dramatic increase in hepatic FGF21 mRNA expression. Concurrently, expression levels of βKlotho, FGF receptor (FGFR)-1c, and FGFR2c were markedly down-regulated in the white adipose tissues (WAT) of ob/ob and DIO mice. However, dose-response curves of recombinant human FGF21 (rhFGF21) stimulation of ERK phosphorylation in the liver and WAT were not right shifted in disease models, although the magnitude of induction in ERK phosphorylation was partially attenuated in DIO mice. Whole-body metabolic responses were preserved in ob/ob and DIO mice, with disease models being more sensitive and responsive than lean mice to the glucose-lowering and weight-loss effects of rhFGF21. Endogenous FGF21 levels, although elevated in diseased mice, were below the half-maximal effective concentrations of rhFGF21, suggesting a state of relative deficiency. Hepatic and WAT FGF21 mRNA expression levels declined after rhFGF21 treatment in the absence of the increased expression levels of βKlotho and FGFR. We conclude that overt FGF21 resistance was not evident in the disease models, and increased hepatic FGF21 expression as a result of local metabolic changes is likely a major cause of elevated circulating FGF21 levels.

Basal and postprandial change in serum fibroblast growth factor-21 concentration in type 1 diabetic mellitus and in healthy controls

“…Contrary to expectations, higher FGF-21 concentrations were found in patients with type 2 diabetes mellitus (T2DM), obesity and metabolic syndrome [2][3][4][5][6][7]. The results were explained by potential FGF-21 resistance [8,9] or compensatory protective elevation of FGF-21 [10,11]. FGF-21 is considered a metabolic protector, but its true physiological effects in humans remain unclear.…”

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

“…Indeed, FGF21 has several beneficial effects on insulin sensitivity and glucose and lipid metabolism (33)(34)(35)(36)(37). Subsequent studies reported that serum FGF21 levels are elevated in obese rodents and humans (43)(44)(45). Additionally, the expression levels of FGF21 receptors were downregulated in the liver and WAT of obese mice, leading to metabolic defects of FGF21, suggesting an obesity-associated FGF21 resistance (43,44).…”

“…Subsequent studies reported that serum FGF21 levels are elevated in obese rodents and humans (43)(44)(45). Additionally, the expression levels of FGF21 receptors were downregulated in the liver and WAT of obese mice, leading to metabolic defects of FGF21, suggesting an obesity-associated FGF21 resistance (43,44). However, the mechanisms whereby obesity induces FGF21 resistance remained unknown.…”

“…FGF21 also acts directly in the hypothalamus to modulate energy balance and insulin sensitivity (41,42). Recent studies have reported that serum FGF21 levels are elevated in obese rodents and humans (43)(44)(45). In obese mice, the expression levels of FGFRs were also markedly downregulated.…”

“…In obese mice, the expression levels of FGFRs were also markedly downregulated. This blunts the metabolic effects of FGF21, promoting an obesity-associated FGF21 resistance state (43,44).…”