Neuropsychiatric disorders and type 2 diabetes (T2D) are major public health concerns proposed to be intimately connected. T2D is associated with increased risk of dementia, neuropsychiatric and mood disorders. Evidences of the involvement of insulin signaling on brain mechanisms related to depression indicate that insulin resistance, a hallmark of type 2 diabetes, could develop in the brains of depressive patients. In this article, we briefly review possible molecular mechanisms associating defective brain insulin signaling with reward system, neurogenesis, synaptic plasticity and hypothalamic-pituitary-adrenal (HPA) stress axis in depression. We further discuss the involvement of tumor necrosis factor α (TNFα) promoting defective insulin signaling and depressive-like behavior in rodent models. Finally, due to the high resistant rate of anti-depressants, novel insights into the link between insulin resistance and depression may advance the development of alternative treatments for this disease.

AMP-activated kinase (AMPK) is a key player in energy sensing and metabolic reprogramming under cellular energy restriction. Several studies have linked impaired AMPK function to peripheral metabolic diseases such as diabetes. However, the impact of neurological disorders, such as Alzheimer disease (AD), on AMPK function and downstream effects of altered AMPK activity on neuronal metabolism have been investigated only recently. Here, we report the impact of Aβ oligomers (AβOs), synaptotoxins that accumulate in AD brains, on neuronal AMPK activity. Short-term exposure of cultured rat hippocampal neurons or human cortical slices to AβOs transiently decreased intracellular ATP levels and AMPK activity, as evaluated by its phosphorylation at threonine residue 172 (AMPK-Thr(P)). The AβO-dependent reduction in AMPK-Thr(P) levels was mediated by glutamate receptors of the -methyl-d-aspartate (NMDA) subtype and resulted in removal of glucose transporters (GLUTs) from the surfaces of dendritic processes in hippocampal neurons. Importantly, insulin prevented the AβO-induced inhibition of AMPK. Our results establish a novel toxic impact of AβOs on neuronal metabolism and suggest that AβO-induced, NMDA receptor-mediated AMPK inhibition may play a key role in early brain metabolic defects in AD.

Leptin regulates energy balance and also exhibits neurotrophic effects during critical developmental periods. However, the actual role of leptin during development is not yet fully understood. To uncover the importance of leptin in early life, the present study restored leptin signaling either at the fourth or tenth week of age in mice formerly null for the leptin receptor (LepR) gene. We found that some defects previously considered irreversible due to neonatal deficiency of leptin signaling, including the poor development of arcuate nucleus neural projections, were recovered by LepR reactivation in adulthood. However, LepR deficiency in early life led to irreversible obesity via suppression of energy expenditure. LepR reactivation in adulthood also led to persistent reduction in hypothalamic Pomc, Cartpt and Prlh mRNA expression and to defects in the reproductive system and brain growth. Our findings revealed that early defects in leptin signaling cause permanent metabolic, neuroendocrine and developmental problems.

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