Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress.

Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer's model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an ex-vivo model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated ex-vivo slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention.

PPARγ activation improves the molecular and functional components of I(to) remodeling by angiotensin II.

Patients with diabetes exhibit significantly altered renin-angiotensin system (RAS) control. Recently, it has been determined that hyperglycemic conditions induce an increase in angiotensin II (AT II) expression; specifically by cardiomyocytes. Altered RAS has been shown to be associated with an increase in oxidative stress and cardiac dysfunction leading to the development of cardiac hypertrophy. The transient outward potassium current (I(to)) in cardiac myocytes is mainly mediated by members of the Kv subfamily of voltage gated potassium channels and has been shown to be altered in cellular localization and expression during the development of cardiac hypertrophy. However it is not clear as to how AT II affects the pore forming complex at the cell membrane and thus directly affects the I(to) current. In the current study, we explored the protective effect of PPARγ ligands on cardiomyocyte I(to) by preventing NADPH Oxidase activation and the ensuing ROS formation. Furthermore, short term PPARγ activation in diabetic leptin deficient db/db mice displayed improvements in the membrane association of the molecular components of I(to) as well as prolonged QT interval. These findings demonstrate that PPARγ agonists have the potential to attenuate cardiomyocyte dysfunction associated with diabetes.

The cardio-protective signaling and mechanisms of adiponectin.

Adiponectin is an endogenous insulin-sensitizing hormone which has been found to regulate energy metabolism throughout the body, including the heart. However, low levels of adiponectin are found in patients with diabetes, hypertension and cardiovascular diseases. Thus it has been suggested to be an independent predictor for cardiovascular risk. Paradoxically, recent studies have also determined that adiponectin has cardioprotective effects against various cardiac related pathologies which lead to heart failure. These cardioprotective effects of adiponectin are attributed to its anti-inflammatory, anti-oxidant and anti-apoptotic properties. Further findings suggest that locally produced adiponectin in cardiomyocytes are functional and biologically significant. This ectopic derived adiponectin exerts its protective effects through an autocrine mechanism. These data suggest adiponectin may serve as a potential therapeutic target against the development of pathologies which develop into heart failure. The current manuscript has summarized the key findings to date which explore the cardioprotective mechanisms of adiponectin against various cardiac pathologies. Further we explore the roles of both circulating and endogenous heart specific adiponectin and their physiological importance in various heart diseases.