Loss of brain energy metabolism control as a driver for memory impairment upon insulin resistance

Abstract

The pathophysiological mechanisms intersecting metabolic and neurodegenerative disorders include insulin resistance, which has a strong involvement of environmental factors. Besides central regulation of whole-body homeostasis, insulin in the central nervous system controls molecular signalling that is critical for cognitive performance, namely signalling through pathways that modulate synaptic transmission and plasticity, and metabolism in neurons and astrocytes. This review provides an overview on how insulin signalling in the brain might regulate brain energy metabolism, and further identified molecular mechanisms by which brain insulin resistance might impair synaptic fuelling, and lead to cognitive deterioration.

Density of Sphingosine-1-Phosphate Receptors Is Altered in Cortical Nerve-Terminals of Insulin-Resistant Goto-Kakizaki Rats and Diet-Induced Obese Mice

“…In turn, putatively increased S1PR2 signaling due to higher S1P concentrations in HFD-fed mice could also dampen synaptic insulin signaling. Loss of tonic insulin receptor signaling in nerve terminals is believed to contribute to memory impairment [ 33 , 46 ].…”

“…Diabetes impacts synapses with negative consequences for brain function, including memory performance [ 26 ]. Furthermore, rodent models of diabetes show altered neuromodulation systems operated by adenosine [ 27 – 29 ], ATP [ 30 ], or endocannabinoids [ 31 , 32 ], which control synaptic activity and brain energy metabolism, and might interact with brain insulin signaling [ 33 ]. These systems can also afford neuroprotection.…”

Brain energy metabolism: A roadmap for future research

“…The field needs clear, physiologically obtained data on brain interstitial insulin levels across regions (most obviously, within the hippocampus) and across neural states (in particular, at baseline and during cognitive challenge): such data will permit understanding of the mechanisms by which insulin modulates metabolism and cognition and the ways in which these mechanisms are impaired in disease states, likely leading to novel therapeutic avenues. Metabolic regulation by insulin is expected to be particularly complex due to the compartmentalized nature of brain energy metabolism, and the interaction with other neuromodulation systems ( Duarte, 2023 ) including that operated by adenosine (see Section 9.1 ).…”

Microgliosis driven by palmitate exposure alters energy metabolism and extracellular vesicles release that impact behavior and systemic metabolism

“…Excessive consumption of diets rich in saturated fat leads to obesity that, together with its metabolic complications and comorbidities, impacts the brain (Hartmann et al ., 2020; Hoscheidt et al ., 2022; Duarte, 2023). In animal models, metabolic syndrome upon diet-induced obesity (DIO) has been reported to trigger hippocampal metabolic alterations, synaptic dysfunction, and impairments in learning and memory processes (reviewed in García-Serrano & Duarte, 2020).…”