Psychiatric illness in the paediatric population is increasing and the weight effect of medications for these problems is often unclear. A comprehensive literature search was undertaken to identify studies reporting weight in relation to antipsychotic and antidepressant use in children and adolescents. From 636 articles, 42 were selected for review. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) do not cause weight gain and may lead to improvements in weight status over the short, but not, long term. Antipsychotics were generally associated with weight gain. In drug comparison studies, risperidone had a larger weight gain effect than lithium, divalproex sodium and pimozide. Studies assessing the weight-protective effects of augmentation therapy with metformin or topiramate show less weight gain with addition of these agents. In conclusion, prescribing of SSRIs and SNRIs may be associated with improvements in weight status in children and adolescents but trials assessing their use in obesity, outside of established psychiatric illness, are limited and still experimental. Youth prescribed antipsychotic medication should be monitored for exaggerated weight gain and in those where obesity is a pre-existing concern agents other than olanzapine, clozapine and risperidone may be advantageous.
Fibroblast growth factor 21 (FGF21) has emerged as an important beneficial regulator of glucose and lipid homeostasis but its levels are also abnormally increased in insulin-resistant states in rodents and humans. The synthetic retinoid Fenretinide inhibits obesity and improves glucose homeostasis in mice and has pleotropic effects on cellular pathways. To identify Fenretinide target genes, we performed unbiased RNA-seq analysis in liver from mice fed high-fat diet ± Fenretinide. Strikingly, Fgf21 was the most downregulated hepatic gene. Fenretinide normalised elevated levels of FGF21 in both high-fat diet-induced obese mice and in genetically obese-diabetic Leprdbmice. Moreover, Fenretinide-mediated suppression of FGF21 was independent of body weight loss or improved hepatic insulin sensitivity and importantly does not induce unhealthy metabolic complications. In mice which have substantially decreased endogenous retinoic acid biosynthesis, Fgf21 expression was increased, whereas acute pharmacological retinoid treatment decreased FGF21 levels. The repression of FGF21 levels by Fenretinide occurs by reduced binding of RARα and Pol-II at the Fgf21 promoter. We therefore establish Fgf21 as a novel gene target of Fenretinide signalling via a retinoid-dependent mechanism. These results may be of nutritional and therapeutic importance for the treatment of obesity and type-2 diabetes.
Objective: The synthetic retinoid fenretinide (FEN) inhibits adiposity in male mice fed a high-fat diet (HFD) in association with alterations in retinoic acid (RA) signaling. Young female mice are protected from obesity via estrogen signaling. We, therefore, investigated whether FEN also influences adiposity in aged female mice differing in parity and whether such effects are mediated by retinoid and estrogen signaling. Methods: Aged nulliparous and parous female mice were maintained on HFD 6 FEN, and adiposity was assessed. Quantitative polymerase chain reaction was performed on white adipose tissue (WAT), liver, and 3T3-L1 adipocytes treated with RA or FEN 6 estrogen. Results: Parous females were more obese than nulliparous mice independent of age. FEN-HFD prevented the HFD-induced increase in adiposity and leptin levels independently of parity. FEN-HFD induced retinoid-responsive genes in WAT and liver. Parous females had reduced expression of hepatic estrogenresponsive genes, but FEN-HFD up-regulated WAT Cyp19a1 and Esr2 in parous mice. Estrogen and RA acted synergistically to increase RA receptor-mediated gene expression in 3T3-L1 adipocytes. FEN increased Cyp19a1 and Esr2, similar to our findings in vivo. Conclusions: The prevention of adiposity by FEN in response to HFD in female mice seems to involve increased retinoid signaling in association with induction of local estrogen production and estrogen signaling in WAT.
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