Joyce B. Harp

Genistein inhibits CCAAT/enhancer-binding protein β (C/EBPβ) activity and 3T3-L1 adipogenesis by increasing C/EBP homologous protein expression

The tyrosine kinase inhibitor genistein inhibits 3T3-L1 adipogenesis when present during the first 72 h of differentiation. In this report, we investigated the underlying mechanisms involved in the anti-adipogenic effects of genistein. We found that genistein blocked the DNA binding and transcriptional activity of CCAAT/enhancer-binding protein beta (C/EBPbeta) during differentiation by promoting the expression of C/EBP homologous protein, a dominant-negative member of the C/EBP family. Loss of C/EBPbeta activity was manifested as a loss of differentiation-induced C/EBPalpha and peroxisome-proliferator-activated receptor gamma protein expression and a dramatic reduction in lipid accumulation. Further, we documented for the first time that C/EBPbeta was tyrosine-phosphorylated in vivo during differentiation and in vitro by activated epidermal growth factor receptor. Genistein inhibited both of these events. Collectively, these results indicate that genistein blocks adipogenesis and C/EBPbeta activity by increasing the level of C/EBP homologous protein and possibly by inhibiting the tyrosine phosphorylation of C/EBPbeta.

EARLY TREATMENT-RELATED CHANGES IN DIABETES AND CARDIOVASCULAR DISEASE RISK MARKERS IN FIRST EPISODE PSYCHOSIS SUBJECTS

OBJECTIVE To examine prospective changes in cardiovascular disease (CVD) and type-2 diabetes risk factors in young adult first episode psychotic (FEP) patients treated with second generation antipsychotic medications. METHODS At baseline, fasting serum and anthropometric measures were obtained from 45 FEP patients and 41 healthy adults (controls) of similar age, ethnicity and sex; sixteen of the FEP patients remained on the same antipsychotic medication and were available for a second blood draw at 24 weeks of treatment. Serum was assayed for glucose, insulin, triglycerides, total cholesterol and high and low density lipoproteins (HDL, LDL), adiponectin, leptin, interleukin 6, E-selectin and VCAM-1. Wilcoxon nonparametric tests were used to compare risk markers between the FEP and control group at baseline and to evaluate pre-post treatment changes within the FEP group. RESULTS At baseline, the distributions of risk marker values were similar between the two groups and the percentages of FEP patients and healthy controls who were overweight/obese, dyslipidemic, hyperglycemic, and hyperinsulinemic did not differ. At 24 weeks, compared to baseline, FEP patients showed significant increases in BMI (p=0.0002), glucose (p=0.0449), insulin (p=0.0161), cholesterol (p=0.0129), leptin (p=0.0215), and E-selectin (p=0.0195), and a decrease in adiponectin (p=0.0371). CONCLUSIONS Among patients with first episode psychosis, 6-month treatment with second generation antipsychotics is associated with the exacerbation of pre-existing and emergence of new CVD and diabetes risk factors.

An assessment of the efficacy and safety of orlistat for the long-term management of obesity

Abstract Pancreatic and gastric lipases hydrolyze dietary triglycerides into 2-monoacylglycerols and free fatty acids prior to systemic absorption. Orlistat, a potent gastrointestinal lipase inhibitor, is undergoing review by the Food and Drug Administration as a new treatment for obesity. When given with a fat-containing meal, orlistat 120 mg three times a day reduces fat absorption by approximately 30%, which equates to a decrease in caloric absorption of approximately 200 kcal/d. A 2 year European study found that 75% of obese subjects on low-fat, energy-deficient diets plus orlistat lost and maintained a modest but medically significant amount of weight. The loss was twice as high as that of subjects taking placebo. Side effects in individuals taking the drug, which were related to orlistat’s mechanism of action, included oily spotting, flatulence, and frequent loose stools. Patients did not experience frank diarrhea or intestinal malabsorption. Vitamin D and β-carotene levels decreased but remained within the normal range. In summary, orlistat is the first example of a new class of antiobesity drugs that interferes with dietary fat absorption, enhances weight loss and weight maintenance, has tolerable gastrointestinal side effects, and has no major drug toxicity. Orlistat may prove to be useful in clinical practice as an adjunct to nonpharmacological weight management interventions, particularly low-fat energy-deficient diets.