Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis

Abstract

The synthetic retinoid Fenretinide (FEN) increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis (46). We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wild-type mice were fed a high-fat diet (HFD) with or without FEN from 4-5 wk to 36-37 wk of age (preventive study) or following 22 wk of HF diet-induced obesity (12 wk intervention study). Retinol-binding protein-4 (RBP4) knockout mice were also fed the HFD with or without FEN in a preventive study. FEN had minimal effects on HFD-induced body weight gain but markedly reduced HFD-induced adiposity and hyperleptinemia in both studies. FEN-HFD mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HFD mice without FEN. FEN did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HFD mice compared with controls and was improved 3.6-fold in FEN-HFD compared with HFD mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production, and suppression of serum FFA levels in HFD mice. Remarkably, FEN also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced the HFD-induced increase in adiposity and hyperleptinemia. In conclusion, long-term therapy with FEN partially prevents or reverses obesity, insulin resistance, and hepatic steatosis in mice on HFD. The anti-adiposity effects are independent of the RBP4 lowering effect.

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

“…However, brain RBP4 protein levels tended to be higher in APP/PSEN1 mice on chow diet and significantly higher in PSEN1 and APP/PSEN1 mice on HFD, suggesting that increased RBP4 levels may be another mechanism by which Alzheimer's disease genotype predisposes to diet-induced glucose intolerance. RBP4 is an adipokine that was recently found to be elevated in insulin-resistant states as well as in obesity in mice [23,39,40] and humans [41][42][43][44], although not all studies have reported this [24,45]. These data suggest that there are early markers of insulin resistance already present with the APP genotype, making these mice more susceptible to the effects of HFD feeding and associated insulin resistance.…”

“…These data suggest that there are early markers of insulin resistance already present with the APP genotype, making these mice more susceptible to the effects of HFD feeding and associated insulin resistance. They also raise an interesting therapeutic possibility that reduction PTP1B and/or RBP4 levels by pharmacological means [39] may in turn protect against body weight gain and the associated glucose intolerance in Alzheimer's disease mouse models. This could be an interesting avenue for further studies.…”

Ceramides as modulators of cellular and whole-body metabolism

“…For example, myriocin-treated mice experienced an increase in oxygen consumption rates, fatty acid oxidation, and heat production when compared with vehicle-treated controls. Interestingly, fenretinide, an inhibitor of dihydroceramide desaturase (18), has also been shown to prevent and reverse diet-induced obesity (19). In particular, in exploring the insulin-sensitizing nature of fenretinide treatment, Preitner et al (19) found that regardless of when fenretinide supplementation was introduced in the life of DIO mice (i.e., at the onset or after 22 weeks of high-fat feeding), it reduced adiposity, particularly in subcutaneous and visceral fat depots.…”

Palmitate Contributes to Insulin Resistance through Downregulation of the Src-Mediated Phosphorylation of Akt in C2C12 Myotubes

“…Increasing evidence 3,4) indicates that chronic elevation of plasma free fatty acids (FFAs) often coexists with type 2 diabetes and obesity, and is responsible for a great deal of impaired insulin-induced glucose uptake and disposal. Experimental plasma FFA elevation impairs glucose oxidation/glycogen synthesis and decreases glucose transport, which leads to organ-specific insulin resistance in adipocytes, skeletal muscle cells, and hepatocytes, 5,6) whereas lowering FFA levels in vivo and vitro significantly improves insulin sensitivity. 7,8) Prolonged exposure to elevated FFA results in the production of inflammatory factors by stimulating the nuclear factor-B (NF-B) pathway, [9][10][11] and induces activation of Jun N-terminal kinase-3 (JNK3), which accelerates -oxidation of FFA, brings about excessive electron flux in the mitochondrial respiratory chain, and subsequently causes increased reactive oxidant species (ROS) generation.…”