ABSTRACT
Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.
Subject(s)
Adipose Tissue/metabolism , Antipsychotic Agents/adverse effects , Hypothalamus/metabolism , Insulin Resistance , Intramolecular Oxidoreductases/metabolism , Macrophage Migration-Inhibitory Factors/metabolism , Olanzapine/adverse effects , Adipose Tissue/pathology , Adolescent , Adult , Animals , Antipsychotic Agents/administration & dosage , Body Mass Index , Eating/drug effects , Female , HeLa Cells , Humans , Hypothalamus/pathology , Lipids/blood , Lipolysis/drug effects , Liver/metabolism , Liver/pathology , Male , Mice , Middle Aged , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Olanzapine/administration & dosageABSTRACT
Recently, studies reported that neonatal genistein treatment inhibited breakdown of oocyte nests and increased oocyte survival, resulting in multi-oocyte survival in adult mice. However, whether the inhibition effect in ovarian follicular development exists also in other stages during ovarian development (e.g. adult or climacteric) is unknown. So far, few studies have investigated the effect of genistein in adult or pre-menopausal ovarian follicular development and follicular reserves. We investigated ovarian follicular development in 4-month and 15-month-old rats after 4 weeks and 4 months treatment with genistein in a dose of 160 mg/kg d. Genistein-treated rats obtained a higher percentage of primordial follicles by 4 months of age and a greater number of surviving follicles at 15 months of age compared to a control group (P<0.05). In addition, vaginal cytology showed that age-dependent cessation of regular estrus was delayed for 2 months in the genistein-treated group than control group. These results suggest that genistein alters rat ovarian follicular development and increases the number of surviving follicles, which may prolong ovarian reproductive life.
Subject(s)
Genistein/pharmacology , Ovary/drug effects , Phytoestrogens/pharmacology , Animals , Estrous Cycle/drug effects , Female , Molecular Structure , Ovary/growth & development , Ovary/physiology , Random Allocation , Rats , Rats, Sprague-Dawley , Sexual Maturation/drug effectsABSTRACT
The pool of ovarian primordial follicles is established during embryonic development or at birth. During the development from primordial to primary, secondary, and antral follicles, only a small portion of follicles can mature and successfully ovulate; the others are destined to degenerate through apoptotic or atretic loss. As aging advances, females ultimately enter the cessation phase of the estrous cycle and are no longer capable of fertilization. The presumption is that if we can slow down the process of folliculogenesis or decrease follicle loss, females may have a larger ovarian follicular reserve and a longer reproductive lifespan. In our study, rats underwent intragastric administration with tea polyphenols, quercetin (meletin), genistein, or resveratrol, once a day for 4 months (from age 12 to 15 months), to test whether they have positive effects on follicular reserve or ovarian functions. The results showed that rats treated with tea polyphenols (27.8 +/- 3.2) and quercetin (36.5 +/- 4.1) had a comparable number of healthy follicles to those of controls (26.9 +/- 3.8), although significantly fewer atretic follicles were observed in the tea polyphenol group (43.4 +/- 5.9 vs 79.7 +/- 7.5; p < 0.001). Remarkably, both genistein- and resveratrol-treated rats had more healthy follicles (respectively, 42.8 +/- 3.9, p < 0.05; and 51.9 +/- 6.4, p < 0.001) and fewer atretic follicles (respectively, 58.4 +/- 8.0, p < 0.05; and 51.0 +/- 6.2, p < 0.01) than controls. These results indicate that genistein and resveratrol can increase the ovarian follicular reserve and prolong the ovarian lifespan in rats, and their positive effects may be not only due to their intervention in the transition from primordial to primary follicle, but also due to the inhibiting effect on follicular atresia.