Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-␤ (A␤), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor ␥ (PPAR␥) agonists suppress inflammatory gene expression, we tested whether activation of PPAR␥ would also result in improved microglial A␤ phagocytosis. The PPAR␥ agonist pioglitazone and a novel selective PPAR␣/␥ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of A␤ in a PPAR␥-dependent manner. This PPAR␥-stimulated increase of A␤ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPAR␥, the retinoid X receptors (RXRs), showed additive enhancement of the A␤ uptake that was mediated by RXR␣ activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial A␤ phagocytosis in vivo, which subsequently resulted in a reduction of cortical and hippocampal A␤ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPAR␥/RXR␣ heterodimer may prove beneficial in prevention of AD.

Neurotrophins are important regulators in the embryogenesis, development and functioning of nervous systems. In addition to the efficacy of brain-derived neurotrophic factor (BDNF) in neurological disorders, we have found that BDNF demonstrates endocrinological functions and reduces food intake and blood glucose concentration in rodent obese diabetic models, such as C57BL/KsJ-db/db mice. The hypoglycemic effect of BDNF was found to be stronger in younger db/db mice with hyperinsulinemia than in older mice. While BDNF itself did not alter blood glucose in normal mice and streptozotocin (STZ)-treated mice, BDNF enhanced the hypoglycemic effect of insulin in STZ-treated mice. These data indicate that BDNF needs endogenous or exogenous insulin to show hypoglycemic action. In addition, BDNF treatment enhanced energy expenditure in db/db mice. The efficacy of BDNF in regulating glucose and energy metabolism was reproduced through intracerebroventricular administration, suggesting that BDNF acted directly on the hypothalamus, the autonomic center of the brain.

Taken together with the accelerating effect of BDNF on energy metabolism, these findings indicate that BDNF improves glucose and lipid metabolism in obese diabetic animals without enlarging liver or adipose tissues.

OBJECTIVE: Obesity in rodents and humans is mostly associated with elevated plasma leptin concentrations, suggesting a new pathological concept of 'leptin resistance'. We have demonstrated that brain-derived neurotrophic factor (BDNF) can improve obesity and diabetes of C57BL/KsJ db/db (db/db) mice. In this study, we investigated whether or not BDNF is effective in two different models of leptin resistance, an acquired model and a genetic model. DESIGN: C57BL/6J mice rendered obese by consumption of a high-fat diet (diet-induced obesity (DIO) mice) were used as an acquired model and lethal yellow agouti mice (KKA y mice) as a genetic model of leptin resistance. Food intake and glucose metabolism were studied after acute or repetitive administration of BDNF. RESULTS: Intraperitoneal administration of BDNF (10 mg/kg, twice/day) significantly reduced cumulative food intake of DIO and KKA y mice, whereas they were unresponsive to leptin administration. Repetitive subcutaneous administration of BDNF (10 mg/kg daily for 6 days) reduced food intake and improved impaired glucose tolerance in DIO mice. Pair feeding of vehicletreated DIO mice with the same amount of chow consumed by the BDNF-treated group did not improve the impaired glucose homeostasis, indicating that the antidiabetic effect is not due to decreased food intake. We also observed that BDNF is effective in improving obesity and diabetes of KKA y mice. CONCLUSION: This study demonstrated antiobesity and antidiabetic effects of BDNF in two different models of leptin resistance, thereby suggesting the therapeutic potential of BDNF in the treatment of leptin-resistant obesity and diabetes.

These data indicate that BDNF ameliorates glucose metabolism by enhancement of glucose utilization in muscle and BAT, with this effect caused by modulation of the central and peripheral nervous systems.