In addition to neurological deficits, Huntington's disease (HD) patients and transgenic mice expressing mutant human huntingtin exhibit reduced levels of brain-derived neurotrophic factor, hyperglycemia, and tissue wasting. We show that the progression of neuropathological (formation of huntingtin inclusions and apoptotic protease activation), behavioral (motor dysfunction), and metabolic (glucose intolerance and tissue wasting) abnormalities in huntingtin mutant mice, an animal model of HD, are retarded when the mice are maintained on a dietary restriction (DR) feeding regimen resulting in an extension of their life span. DR increases levels of brain-derived neurotrophic factor and the protein chaperone heat-shock protein-70 in the striatum and cortex, which are depleted in HD mice fed a normal diet. The suppression of the pathogenic processes by DR in HD mice suggests that mutant huntingtin promotes neuronal degeneration by impairing cellular stress resistance, and that the body wasting in HD is driven by the neurodegenerative process. Our findings suggest a dietary intervention that may suppress the disease process and increase the life span of humans that carry the mutant huntingtin gene.is an inherited neurodegenerative disorder characterized by degeneration of neurons in the striatum and cerebral cortex resulting in abnormal involuntary movements (chorea), and psychiatric and cognitive abnormalities (1). The genetic defect involves expansion of CAG trinucleotide repeats in exon 1 of the HD gene resulting in polyglutamine expansions in the huntingtin protein (2-4). Neither the normal function of huntingtin nor the mechanism whereby polyglutamine expansions result in selective loss of striatal neurons is known, although impaired energy metabolism (5, 6), excitotoxicity (7), and oxidative stress (8) are implicated. It has been proposed that the mutant huntingtin causes neuronal dysfunction and death by altering the transcription of certain genes, including those encoding neurotransmitters and neurotrophic factors (9). Transgenic mice expressing polyglutamine expanded full-length or N-terminal fragments of huntingtin exhibit neurodegenerative changes in the striatum, progressive motor dysfunction, and premature death (10, 11). Oxidative stress and apoptosis are suggested in the pathogenic process because antioxidants (12) and caspase inhibitors (13) can slow disease progression in huntingtin mutant mice.Deficits in striatal and cortical glucose metabolism precede the appearance of symptoms in HD patients (14-16). Many HD patients and huntingtin mutant mice also exhibit hyperglycemia, apparently as the result of decreased insulin production and͞or sensitivity (17,18). A deficit in cellular energy metabolism may contribute to disease onset and progression because administration of creatine, an agent that reduces ATP depletion, delays the onset of symptoms and increases the survival times of huntingtin mutant mice (19). Another alteration in HD is decreased production of brain-derived neurotrophic factor (BDNF) (...

Leptin plays a pivotal role in the regulation of energy homeostasis and metabolism, primarily by acting on neurons in the hypothalamus that control food intake. However, leptin receptors are more widely expressed in the brain suggesting additional, as yet unknown, functions of leptin. Here we show that both embryonic and adult hippocampal neurons express leptin receptors coupled to activation of STAT3 and phosphatidylinositol 3-kinase-Akt signaling pathways. Leptin protects hippocampal neurons against cell death induced by neurotrophic factor withdrawal and excitotoxic and oxidative insults. The neuroprotective effect of leptin is antagonized by the JAK2-STAT3 inhibitor AG-490, STAT3 decoy DNA, and phosphatidylinositol 3-kinase/Akt inhibitors but not by an inhibitor of MAPK. Leptin induces the production of manganese superoxide dismutase and the anti-apoptotic protein Bcl-xL, and stabilizes mitochondrial membrane potential and lessens mitochondrial oxidative stress. Leptin receptor-deficient mice (db/db mice) are more vulnerable to seizure-induced hippocampal damage, and intraventricular administration of leptin protects neurons against seizures. By enhancing mitochondrial resistance to apoptosis and excitotoxicity, our findings suggest that leptin signaling serves a neurotrophic function in the developing and adult hippocampus.Leptin is a 16-kDa protein produced primarily by adipose cells from which it is released into the circulation and transported across the blood-brain barrier. Leptin regulates food intake and energy homeostasis by activating receptors on neurons in the hypothalamus. Mice defective in leptin production or signaling are hyperphagic and obese (1, 2). Leptin also serves functions apart from those related to food intake and energy expenditure in mammals, including regulation of fertility (3-5), immune responses (6, 7), and bone formation (8 -10). Leptin signaling is mediated by the leptin receptor (ObRb), 2 which is a member of the class I cytokine receptor superfamily. Leptin binding to Ob-Rb results in activation of the tyrosine kinase JAK-2, which in turn phosphorylates tyrosine residues on the intracellular domain of the receptor, providing a binding site for STAT3. The activated STAT3 proteins dimerize and translocate to the nucleus, where they regulate transcription of various genes (11). Beyond regulating energy homeostasis and neuroendocrine functions by acting on neuronal targets in the hypothalamus, leptin may have more widespread actions in the brain. Leptin receptors are expressed in the hippocampus, cerebral cortex, and other regions of the adult rodent brain (12, 13), but the function of leptin in these brain regions is unknown. However, it was reported that leptin can modulate the excitability of hippocampal neurons by activating potassium channels (14) and that leptin receptor-deficient rodents have impaired spatial learning ability (15), suggesting that leptin signaling may influence neuronal excitability and synaptic plasticity. Here we show that hippocampal neurons express le...

Exosomes, a group of vesicles originating from the multivesicular bodies (MVBs), are released into the extracellular space when MVBs fuse with the plasma membrane. Numerous studies indicate that exosomes play important roles in cell-to-cell communication, and exosomes from specific cell types and conditions display multiple functions such as exerting positive effects on regeneration in many tissues. It is widely accepted that the therapeutic potential of stem cells may be mediated largely by the paracrine factors, so harnessing the paracrine effects of stem and progenitor cells without affecting these living, replicating, and potentially pluripotent cell populations is an advantage in terms of safety and complexity. Ascending evidence indicated that exosomes might be the main components of paracrine factors; thus, understanding the role of exosomes in each subtype of stem cells is far-reaching. In this review, we discuss the functions of exosomes from different types of stem cells and emphasize the therapeutic potentials of exosomes, providing an alternative way of developing strategies to cure diseases.