The ␣-isoform of the peroxisome proliferator-activated receptor (PPAR␣) is a nuclear transcription factor activated by structurally diverse chemicals referred to as peroxisome proliferators. Activators can be endogenous molecules (fatty acids/steroids) or xenobiotics (fibrate lipid-lowering drugs). Upon pharmacological activation, PPAR␣ modulates target genes encoding lipid metabolism enzymes, lipid transporters, or apolipoproteins, suggesting a role in lipid homeostasis. Transgenic mice deficient in PPAR␣ were shown to lack hepatic peroxisomal proliferation and have an impaired expression and induction of several hepatic target genes. Young adult males show hypercholesterolemia but normal triglycerides. Using a long term experimental set up, we identified these mice as a model of monogenic, spontaneous, late onset obesity with stable caloric intake and a marked sexual dimorphism. Serum triglycerides, elevated in aged animals, are higher in females that develop a more pronounced obesity than males. The latter show a marked and original centrilobular-restricted steatosis and a delayed occurrence of obesity. Fat cells from their liver express substantial levels of PPAR␥2 transcripts when compared with lean cells. These studies demonstrate, in rodents, the involvement of PPAR␣ nuclear receptor in lipid homeostasis, with a sexually dimorphic control of circulating lipids, fat storage, and obesity. Characterization of this pathological link may help to delineate new molecular targets for therapeutic intervention and could lead to new insights into the etiology and heritability of mammalian obesity.Obesity, an increasing health problem in wealthy societies, has been causatively linked to hyperlipidemia, diabetes, hypertension, and atherosclerosis. Adipose cell hypertrophy and hyperplasia occur as the ultimate consequence of a disequilibrium in energy balance and exert adverse effects on longevity (1, 2). Several causal genetic determinants responsible for spontaneous monogenic obesity in mice (ob, db, tub, A r , and fat genes) have been identified (reviewed in Ref. 3). In humans, a limited number of obese syndromes have been related to single gene disorders (e.g. Ahlstrom, Bardet Biedl, Cohen, Prader Willi). Recently, two mutations, affecting the leptin signal transduction pathway and leading to human early onset morbid obesity, have been characterized. They affect the ob gene (4), encoding leptin, and the leptin receptor gene (5), respectively. A mutation in the human prohormone convertase 1 gene, leading to childhood obesity, has been documented (6), and tissue-specific attenuation of the prohormone convertase 2 gene has been reported in two patients with Prader-Willi syndrome (7). Proconvertases act, proximally to carboxypeptidase E, in the pathway of post-translational processing of prohormones and neuropeptides, therefore associating this syndrome with the fat/fat murine phenotype. Prevalence of these mutations in the human obese population was reported as being rather limited (4, 5), and human counterparts ...
Because exacerbation of colitis seems to be associated with stress, we proposed evaluating the influence of stress and the involvement of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) on experimental colitis in rats. Partial restraint stress was applied during 4 consecutive days, before or after intracolonic 2,4,6-trinitrobenzenesulfonic acid (TNB) instillation (15 mg) in rats. Finally, two groups of rats were centrally injected with alpha-helical CRF-(9-41) (5 micrograms) or AVP antagonist (5 micrograms) before each session of stress. Stress was applied before or right after TNB enhanced colitis, with an increase in macroscopic and histological scores and myeloperoxidase activity, alpha-Helical CRF-(9-41) or AVP antagonist had no effect on TNB-induced colitis but enhanced the effects of stress on colitis. These results show that stress may exacerbate experimental colitis in rats and that CRF and AVP are not responsible for this effect.
The natural vitamin E family is composed of 8 members equally divided into 2 classes: tocopherols (TCP) and tocotrienols (TE). A growing body of evidence suggests TE possess potent biological activity not shared by TCP. The primary objective of this work was to determine the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg α-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Eighty participants were studied. Skin and blood vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. Vital organ vitamin E levels were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1-96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. α-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. In prospective liver transplantation patients, oral TE lowered the model for end-stage liver disease (MELD) score in 50% of patients supplemented, whereas only 20% of TCP-supplemented patients demonstrated a reduction in MELD score. This work provides, to our knowledge, the first evidence demonstrating that orally supplemented TE are transported to vital organs of adult humans. The findings of this study, in the context of the current literature, lay the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans.
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