Abstract
Insulin resistance–as observed in aging, diabetes, obesity, and other pathophysiological situations, affects brain function, for insulin signaling is responsible for neuronal glucose transport and control of energy homeostasis and is involved in the regulation of neuronal growth and synaptic plasticity. This study investigates brain metabolism and function in a liver-specific Phosphatase and Tensin Homologue (Pten) knockout mouse model (Liver-PtenKO), a negative regulator of insulin signaling. The Liver-PtenKO mouse model showed an increased flux of glucose into the liver–thus resulting in an overall hypoglycemic and hypoinsulinemic state–and significantly lower hepatic production of the ketone body beta-hydroxybutyrate (as compared with age-matched control mice). The Liver-PtenKO mice exhibited increased brain glucose uptake, improved rate of glycolysis and flux of metabolites in the TCA cycle, and improved synaptic plasticity in the hippocampus. Brain slices from both control- and Liver-PtenKO mice responded to the addition of insulin (in terms of pAKT/AKT levels), thereby neglecting an insulin resistance scenario. This study underscores the significance of insulin signaling in brain bioenergetics and function and helps recognize deficits in diseases associated with insulin resistance.
Highlights
The human brain consumes about 25% of the body’s resting state glucose
A liver specific deletion of Phosphatase and Tensin Homologue (Pten) resulted in improved liver insulin signaling activity leading to higher glucose absorption in the liver, and increased glycogen synthesis, whereas the levels triglyceride, leptin, insulin, and fasting glucose levels to be decreased in the plasma of the PtenloxP/loxP;Alb-Cre+ mutant mice
The Liver-PtenKO model in this study entails a relatively hypoglycemic and hypoinsulinemic state that may force the brain to become more insulin- or glucose-sensitive, it may be surmised that the Liver-PtenKO phenotype will directly improve synaptic plasticity and function in the mutant mice
Summary
The human brain consumes about 25% of the body’s resting state glucose. Neuronal brain glucose uptake occurs mostly through the insulin-sensitive glucose transporter GLUT4 [1]. The subsequent AKT-dependent phosphorylation of several targets results in translocation of GLUT4 from the intracellular storage compartment to the plasma membrane [2]. Glucose is metabolized via glycolysis and in the tricarboxylic acid cycle, in which the intermediate oxoglutarate can be converted into neurotransmitters, such as glutamate and GABA, rendering synaptic plasticity susceptible to the bioenergetic state of the brain [3]. The sensitivity of the brain towards insulin determines its ability to meet the bioenergetic and functional demands of neurons. Insulin has been shown to influence synaptic transmission by modulating the cell membrane expression of NMDA (N-methyl-D-aspartic acid)
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