Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Effet protecteur de la néoglucogenèse intestinale sur le développement de l’obésité et du diabète

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Rôle de la néoglucogenèse intestinale dans le développement de l’obésité et de la stéatose hépatique

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La NGI protège des altérations du métabolisme du tissu adipeux associées à l’obésité

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La néoglucogenèse intestinale active la thermogenèse du tissu adipeux brun en mobilisant le système nerveux sympathique

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Post-translational regulation of the glucose-6-phosphatase complex by cyclic adenosine monophosphate is a crucial determinant of endogenous glucose production and is controlled by the glucose-6-phosphate transporter

© 2016 American Chemical Society.The excessive endogenous glucose production (EGP) induced by glucagon participates in the development of type 2 diabetes. To further understand this hormonal control, we studied the short-term regulation by cyclic adenosine monophosphate (cAMP) of the glucose-6-phosphatase (G6Pase) enzyme, which catalyzes the last reaction of EGP. In gluconeogenic cell models, a 1-h treatment by the adenylate cyclase activator forskolin increased G6Pase activity and glucose production independently of any change in enzyme protein amount or G6P content. Using specific inhibitors or protein overexpression, we showed that the stimulation of G6Pase activity involved the protein kinase A (PKA). Results of site-directed mutagenesis, mass spectrometry analyses, and in vitro phosphorylation experiments suggested that the PKA stimulation of G6Pase activity did not depend on a direct phosphorylation of the enzyme. However, the temperature-dependent induction of both G6Pase activity and glucose release suggested a membrane-based mechanism. G6Pase is composed of a G6P transporter (G6PT) and a catalytic unit (G6PC). Surprisingly, we demonstrated that the increase in G6PT activity was required for the stimulation of G6Pase activity by forskolin. Our data demonstrate the existence of a post-translational mechanism that regulates G6Pase activity and reveal the key role of G6PT in the hormonal regulation of G6Pase activity and of EGP

Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric bypass but not after gastric lap-band in mice.

Unlike the adjustable gastric banding procedure (AGB), Roux-en-Y gastric bypass surgery (RYGBP) in humans has an intriguing effect: a rapid and substantial control of type 2 diabetes mellitus (T2DM). We performed gastric lap-band (GLB) and entero-gastro anastomosis (EGA) procedures in C57Bl6 mice that were fed a high-fat diet. The EGA procedure specifically reduced food intake and increased insulin sensitivity as measured by endogenous glucose production. Intestinal gluconeogenesis increased after the EGA procedure, but not after gastric banding. All EGA effects were abolished in GLUT-2 knockout mice and in mice with portal vein denervation. We thus provide mechanistic evidence that the beneficial effects of the EGA procedure on food intake and glucose homeostasis involve intestinal gluconeogenesis and its detection via a GLUT-2 and hepatoportal sensor pathway

Adaptation of Hepatic, Renal and Intestinal Gluconeogenesis During Food Deprivation

International audienceThe maintenance of plasma glucose is a vital necessity in all situations. Multiple adaptations permitting endogenous glucose production from the liver, kidneys, and gut take place during starvation. The mobilization of liver glycogen stores is the more rapid process to tune blood glucose from the moment where glucose availability from food starts to lack. Increased lipolysis from the adipose depots plays a crucial role to provide energy to the whole body and especially to allow the liver to carry out gluconeogenesis from lactate and alanine, which is an endergonic process. Proteolysis from skeletal muscles then supplies carbon skeletons to build glucose from amino acids released in blood. Among the exquisite late adaptations of gluconeogenesis taking place after the exhaustion of liver glycogen stores, the progressive replacement of hepatic gluconeogenesis by renal and intestinal gluconeogenesis (from glutamine) is essential, since it permits to maintain plasma glucose and in the same time to preserve energy balance of the body. Gluconeogenesis from glutamine, indeed, is an exergonic process. The late blunting in hepatic GNG paralleling the increase in intestinal GNG in late starvation allows the liver to store glycogen again, which might be a key adaptation for survival