Role of Sirtuins in Modulating Neurodegeneration of the Enteric Nervous System and Central Nervous System.

Neurodegeneration of the central and enteric nervous systems is a common feature of aging and aging-related diseases, and is accelerated in individuals with metabolic dysfunction including obesity and diabetes. The molecular mechanisms of neurodegeneration in both the CNS and ENS are overlapping. Sirtuins are an important family of histone deacetylases that are important for genome stability, cellular response to stress, and nutrient and hormone sensing. They are activated by calorie restriction (CR) and by the coenzyme, nicotinamide adenine dinucleotide (NAD+). Sirtuins, specifically the nuclear SIRT1 and mitochondrial SIRT3, have been shown to have predominantly neuroprotective roles in the CNS while the cytoplasmic sirtuin, SIRT2 is largely associated with neurodegeneration. A systematic study of sirtuins in the ENS and their effect on enteric neuronal growth and survival has not been conducted. Recent studies, however, also link sirtuins with important hormones such as leptin, ghrelin, melatonin, and serotonin which influence many important processes including satiety, mood, circadian rhythm, and gut homeostasis. In this review, we address emerging roles of sirtuins in modulating the metabolic challenges from aging, obesity, and diabetes that lead to neurodegeneration in the ENS and CNS. We also highlight a novel role for sirtuins along the microbiota-gut-brain axis in modulating neurodegeneration

Treatment of Obesity Through Glial Cell-Derived Neurotrophic Factor Lipid Nanoparticle Delivery in Mice

Background and Aims: The overexpression of glial cell-derived neurotrophic factor (GDNF) in the liver and adipose tissues offers strong protection against high-fat diet (HFD)-induced obesity in mice. We hypothesize that sustainably enhancing GDNF expression in the liver may provide a therapeutic effect that can prevent the progression of HFD-induced obesity in mice. Methods: Expression lentivector encoding mouse GDNF (GDNF(pDNA) or empty vector (pDNA, control) were encapsulated in lipid nanoparticles (LNPs) using the thin-film hydration method. Mice were fed with regular diet (RD) or HFD for 20 weeks prior to injection and the GDNF and control vector-loaded LNPs were administered by intravenous (IV) injection to mice once weekly for 5 weeks. Changes in body weight were monitored and mice tissues were collected and imaged for fluorescence using an IVIS in vivo imaging system. Post-treatment abdominal fat weight, colon length, and spleen weight were obtained. GDNF protein levels in the liver and serum were quantified by enzyme-linked immunosorbent assay, while liver AKT serine/threonine kinase and AMP-activated protein kinase phosphorylation levels were evaluated by Western blotting. Results: IV-injected GDNF(pDNA)-loaded LNPs targeted the liver and remained in there for up to 15 days postinjection. A single injection of GDNF(pDNA)-loaded LNPs significantly increased GDNF expression for 7 days and consequently increased the levels of phosphorylated AKT serine/threonine kinase and AMP-activated protein kinase. Once weekly injections of GDNF(pDNA)-loaded LNPs for 5 weeks slowed increase in body weight, reduced abdominal fat, and modulated the gut microbiota toward a healthier composition in HFD-fed mice. Conclusion: GDNF(pDNA)-loaded LNPs could potentially be developed as a therapeutic strategy to reverse weight gain in obese patients