fenretinide and Weight-Gain

Fenretinide (FEN), a ligand of retinol binding protein 4 (RBP4), has been suggested as a measure to reduce insulin resistance and its associated disorders such as obesity, and fatty liver by reducing serum RBP4. We investigated whether there is another possible mechanism by which fenretinide reduces insulin resistance and fatty liver in genetically obese (ob/ob) mice. Male obese mice fed a high-fat diet (45% of calories from fat) were divided into two groups (n=13 each). One (FEN) received fenretinide (20 mg/kg body weight, intraperitoneally) and the other (O) received vehicle three times weekly for 24 d. C57BL/6J mice fed a normal-fat diet (16% of calories from fat) were used as a control (C; n=13). No changes in fat weight and serum leptin level could be observed in FEN mice. Lower plasma RBP4 was observed in FEN mice compared with O mice. Fenretinide improved whole-body insulin sensitivity based on glucose and insulin tolerance tests and the homeostasis model assessment of insulin resistance. Fenretinide decreased the plasma lipid (triglyceride, cholesterol, and free-fatty acid) levels, hepatic TG level, and histological steatosis score. The mechanism by which fenretinide prevents fatty liver may be explained by an increased plasma adiponectin level, increased activation of hepatic AMP-activated protein kinase, and the expression of peroxisome proliferator-activated protein-α and peroxisomal acyl-CoA oxidase, which promote fat oxidation. FEN alleviated insulin resistance and fatty liver in obese mice and thus may act as an anti-lipidemic and anti-diabetic drug.

Topics: Adiponectin; Adipose Tissue, White; Alanine Transaminase; Animals; Aspartate Aminotransferases; Diet, High-Fat; Fatty Liver; Fenretinide; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Prealbumin; Retinol-Binding Proteins, Plasma; Weight Gain

These studies examined whether the small to moderate reductions in body weight gain (< or = 15%) affect mammary carcinogenesis. Beginning 1 week prior to methylnitrosourea (MNU) administration (experiment 1), rats received diets supplemented with 4-hydroxyphenylretinamide (4-HPR) (782 mg/kg of diet) and retinyl acetate (328 mg/kg of diet) or underwent food restrictions. Rats were administered an i.v. dose of MNU (50 mg/kg body wt) at 50 days of age. Although the final body weights were similarly depressed by 4-HPR (8%) and by retinyl acetate (11%) from rats fed ad libitum, the kinetics of inhibition were quite different. Whereas 4-HPR caused an acute decrease in body weight at the time it was administered, the effect of retinyl acetate was more chronic. At 110 days after the administration of MNU, the average number of mammary cancers per rat was 4.9 for rats fed ad libitum, 1.3 for rats fed 4-HPR, 3.1 when body weights were matched to 4-HPR-treated rats, 1.9 for retinyl acetate and 3.2 when body weights were matched to retinyl acetate. Experiment II was performed to determine the minimal degree of acute body weight gain reduction that would alter MNU-induced mammary carcinogenesis. Body weight gain depressions of 3, 6, 9, 12 and 15% were initiated at 43 days of age by dietary restrictions and MNU was administered at 50 days of age. At 120 days after MNU, the percentage decreases in mammary cancer multiplicity in the various groups were 14, 15, 41, 44 and 55%, respectively. These data demonstrate that moderate reductions (9-15%) in body weight gain, in particular when occurring during the initiation and early promotion stages can greatly affect cancer multiplicity.

Topics: Animals; Anticarcinogenic Agents; Diterpenes; Energy Intake; Female; Fenretinide; Food Deprivation; Mammary Neoplasms, Experimental; Methylnitrosourea; Rats; Rats, Sprague-Dawley; Retinyl Esters; Vitamin A; Weight Gain

Mammary tumors were induced in 48-52-day-old female Sprague-Dawley rats in metestrus or diestrus with a single jugular injection of MNU (50 mg/kg). Control rats received the saline vehicle (Group 4 n = 9). Rats were fed 4% Teklad diet containing either 0 (Group 3, n = 20) or 782 mg 4-HPR/kg diet. 4-HPR supplementation was initiated either 1 week prior to (Group 1, n = 14) or 4 weeks following MNU administration (Group 2, n = 19). Neither body weight nor food intake differed significantly between treatment groups. Feeding of 4-HPR 1 week prior to tumor induction reduced the number of tumors (0.8 +/- .2) when compared to MNU control rats (2.1 +/- .4). Immunohistochemical staining of mammary tumor sections for PCNA was quantitated by microdensitometry and expressed as an HSCORE. No differences in HSCORE were observed between tumor groups although the percentage of nuclear area occupied by intermediate and darkly stained nuclei was reduced in the late 4-HPR group. GC-->AT transitions in codon 12 of the H-ras gene were detected in 50% (12/24) of MNU control tumors, 60% (6/10) of early 4-HPR tumors, and 38% (6/16) of late 4-HPR tumors. Mutation rates did not differ significantly between groups. 4-HPR appears to be a more effective chemopreventive when fed during the initiation period.

Topics: Animals; Anticarcinogenic Agents; Base Sequence; Carcinogens; Codon; DNA Primers; Drug Administration Schedule; Feeding Behavior; Female; Fenretinide; Genes, ras; Immunohistochemistry; Mammary Neoplasms, Experimental; Methylnitrosourea; Mutation; Rats; Rats, Sprague-Dawley; S Phase; Weight Gain

The present study was designed to determine whether the chemopreventive effect of the synthetic retinoid N(4-hydroxyphenyl)retinamide (4-HPR) on mammary tumorigenesis was influenced by diet. Three diets were used: the closed-formula grain-based Wayne Lab Blox, the open-formula grain-based NIH-07, and the casein-based semipurified AIN-76A. Groups of 25 virgin female F-344 rats were fed the experimental diets beginning one week before a single injection of N-methyl-N-nitrosourea (NMU, 45 mg/kg body wt i.v.) at 50 days of age. The experimental design was as follows: Group 1, unsupplemented AIN-76A; Group 2, AIN-76A supplemented with 4-HPR starting seven days before NMU until termination (-7); Group 3, AIN-76A supplemented with 4-HPR seven days after NMU until termination (+7); Group 4, Wayne (no 4-HPR); Group 5, Wayne (4-HPR, -7); Group 6, Wayne (4-HPR, +7); Group 7, NIH-07; Group 8, NIH-07 (4-HPR, -7). 4-HPR [782 mg/kg diet (2 mM)] was given to all supplemented groups. Termination was 25 weeks post-NMU. Analysis of tumor incidence, multiplicity, and latency indicated that 1) control rats fed the AIN-76A diet exhibited significantly higher mammary tumor yields than rats fed unsupplemented natural-ingredient diets (Wayne and NIH-07) and 2) 4-HPR inhibited mammary tumor development in the two grain-based diets but enhanced tumor development in the AIN-76A diet. Animals fed the AIN-76A diet gained weight to a greater extent than those fed the Wayne or NIH-07 diets and exhibited lower levels of circulating 4-HPR.

Topics: Animals; Diet; Edible Grain; Female; Fenretinide; Liver; Mammary Neoplasms, Experimental; Methylnitrosourea; Rats; Rats, Inbred F344; Weight Gain