Cisterna magna cannulated repeated CSF sampling rat model--effects of a gamma-secretase inhibitor on Aβ levels.

Cerebrospinal fluid (CSF) provides a window into central nervous system (CNS) physiology and pathophysiology in human neurodegenerative conditions such as Alzheimer's disease. Changes in CSF bioanalytes also provide a direct readout of target engagement in the CNS following pharmacological interventions in clinical trials. Given the importance of tracking CNS bioanalytes in drug discovery, we have developed a novel cisterna magna cannulated rat model for repeated CSF sampling and used it to assess an amyloid beta (Aβ) lowering agent.

Nutritional supplementation with trans-10, cis-12-conjugated linoleic acid induces inflammation of white adipose tissue.

Conjugated linoleic acids (CLAs) are conjugated dienoic isomers of linoleic acid. Many people supplement their diets with CLAs to attempt weight loss, and the trans-10,cis-12 isomer (t10,c12-CLA) of CLA reduces adiposity in animal models and humans. However, CLA treatment in mice causes insulin resistance that has been attributed to the lipoatrophic state, which is associated with hyperinsulinemia and hepatic steatosis.

Abnormal glucose homeostasis due to chronic hyperresistinemia.

Resistin is an adipocyte-secreted protein that circulates at increased levels in obesity. Acute administration of resistin impairs glucose tolerance, but the effects of chronic hyperresistinemia have not been established. Here we describe the generation and characterization of transgenic mice that have high circulating levels of resistin in the setting of normal weight.

Regulation of fasted blood glucose by resistin.

The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver.

Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity.

Obesity-associated diabetes is epidemic in industrialized societies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and the presumed molecular target for antidiabetic thiazolidinedione drugs that reverse insulin resistance but also promote weight gain. Phosphorylation reduces the activity of PPARgamma in vitro, but physiological relevance has not been demonstrated.