Reduced adiposity attenuates FGF21 mediated metabolic improvements in the Siberian hamster

Abstract

FGF21 exerts profound metabolic effects in Siberian hamsters exposed to long day (LD) photoperiods that increase appetite and adiposity, however these effects are attenuated in short day (SD) animals that display hypophagia and reduced adiposity. The aim of this study was to investigate whether the beneficial effects of a novel mimetic of FGF21 in the LD state are a consequence of increased adiposity or of the central photoperiodic state. This was achieved by investigating effects of FGF21 in aged hamsters, which is associated with reduced adiposity. In LD hamsters with increased adiposity, FGF21 lowered body weight as a result of both reduced daily food intake and increased caloric expenditure, driven by an increase in whole-body fat oxidation. However, in LD animals with reduced adiposity, the effect of FGF21 on body weight, caloric intake and fat oxidation were significantly attenuated or absent when compared to those with increased adiposity. These attenuated/absent effects were underpinned by the inability of FGF21 to increase the expression of key thermogenic genes in interscapular and visceral WAT. Our study demonstrates the efficacy of a novel FGF21 mimetic in hamsters, but reveals attenuated effects in the animal model where adiposity is reduced naturally independent of photoperiod.

Figure 1

Reduced adiposity attenuates the effects of the FGF21 in the Siberian hamster. Percentage body weight loss (A), average daily food intake (B), meal duration (C and D) and meal frequency (E and F) of young and aged Siberian hamsters treated with vehicle (saline) or FGF21. Values are group mean ± SEM, n = 5–6 per treatment: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Figure 2

CT assessment demonstrates FGF21 reduces total adiposity in young and aged Siberian hamsters. Percentage change in total adiposity (A). Values are group mean ± SEM, n = 5–6 per treatment: *p < 0.05, **p < 0.01, ****p < 0.0001. Representative images of young (B and C) and aged (D and E) Siberian hamsters treated with vehicle (saline) or FGF21 respectively.

Figure 3

Treatment with FGF21 increases energy expenditure but fails to reduce RER in the aged cohort of Siberian hamsters. Energy expenditure (A and B), ambulatory activity (C and D) and RER (E and F) of young and aged Siberian hamsters treated with vehicle (saline) or FGF21. Values are group mean ± SEM, n = 5–6 per treatment: *p < 0.05.

Figure 4

Treatment with FGF21 reduces blood glucose, and plasma leptin and insulin in the young Siberian hamster. Blood glucose (A), leptin (B) and insulin (C) of young and aged Siberian hamsters treated with vehicle (saline) or FGF21. Values are group mean ± SEM, n = 5–6 per treatment: *p < 0.05.

Figure 5

Treatment with FGF21 increases thermogenic genes in the hypothalamus and iBAT in young and aged Siberian hamsters, whilst the effects of treatment are lost in iWAT and prWAT in the aged Siberian hamster. Hypothalamus (A and B), iBAT (C and D), iWAT (E and F) and prWAT (G and H) gene expression profiles in young and aged Siberian hamsters treated with FGF21. Values are group mean ± SEM, n = 5–6 per treatment: *p < 0.05, **p < 0.01.

Figure 6

Treatment with FGF21 reduces prWAT TAG content and increases key phosphorylation events and AGTL in young Siberian hamsters. prWAT TAG content (A and B) of young and aged Siberian hamsters treated with FGF21. pERK1/2 and total ERK (C and D), ATGL (E and F) and HSL (G and H) content of prWAT. Values are group mean ± SEM, n = 5–6 per treatment: *p < 0.05 **p < 0.01.