Introduction: Adipokines, such as resistin and fasting-induced adipose factor (FIAF), are implicated in the regulation of insulin sensitivity and regulated by nuclear receptors like peroxisome proliferator activated receptor gamma (PPARγ), and retinoic acid receptor alpha (RARα). Primarily expressed in murine fat, we also showed that these adipokines are expressed in the mouse hypothalamus, as well as in N-1 hypothalamic neurons. We hypothesized that rosiglitazone (ROSI) and all-trans retinoic acid (ATRA), ligands for these receptors, would modulate the expression of brain-derived adipokines.
Methods: (1) Differentiated 3T3-L1 adipocytes and N-1 neurons were treated with either ROSI or ATRA (1μM), and controls were treated with vehicle, 24 h prior to total RNA isolation. (2) Adult male CD-1 mice were injected with either ROSI or ATRA (100 mg/Kg), whereas controls received vehicle alone, and tissues (hypothalamus-HYP, and visceral adipose tissue-FAT) were collected 24 h later and snap frozen until total RNA isolation. Rstn and fiaf gene expression were quantified using realtime RT-PCR.
Results: ATRA significantly inhibited the expression of rstn in both N-1 and 3T3-L1 cells (-35% and -50% respectively), whereas fiaf mRNA was increased only in N-1 neurons (35%). In contrast ROSI had no effect on rstn, but significantly induced fiaf in N-1 cells (80%) and 3T3-L1 adipocytes (150%) as expected. ATRA treatment in vivo also significantly inhibited rstn in HYP and FAT (25% and 21% respectively), whereas fiaf mRNA was reduced in HYP (- 25%), but increased in FAT (+75%). In contrast ROSI significantly increased rstn mRNA in HYP by 35%, but had no effect in FAT, and induced fiaf expression in both HYP and FAT (50% and 65% respectively).
Conclusions: These data reveal an inhibitory effect of ATRA on rstn gene expression, whereas ROSI increased fiaf mRNA, both in vitro and in vivo, strengthening the value of the N-1 neuronal model as we further unravel the molecular mechanisms responsible for the regulation of brain-derived adipokines. However, since ATRA had a differential effect on gene expression in HYP and FAT, this further supports tissue-specific roles. Supported by IWK, UIMRF/Capital Health.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.