Hypothalamic serotonin–insulin signaling cross-talk and alterations in a type 2 diabetic model

Papazoglou, Ioannis; Berthou, Flavien; Vicaire, Nicolas; Rouch, Claude; Markaki, Evangelia N.; Bailbé, Danielle; Portha, Bernard; Taouis, Mohammed; Gerozissis, Kyriaki

doi:10.1016/j.mce.2011.12.007

Cited by 28 publications

(16 citation statements)

References 38 publications

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“…Furthermore, the fact that subgranular neurons express 5-HT [22], leptin [44] and insulin receptors [45] as well as their substrates [45,46] could indicate the existence of a cross talk between these factors in this neuronal population. This hypothesis is strengthened by our previous results evidencing such an interaction in the rat hypothalamus and in human neuroblastoma cells via PI3K/Akt [47]. Thus, the central resistance to leptin and/or insulin could alter mood not only directly but also indirectly through the impairment of 5-HT signaling at the level of GSK3β in the subgranular neurons.…”

Section: Discussionmentioning

confidence: 62%

Hippocampal GSK3β as a Molecular Link Between Obesity and Depression

et al. 2014

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Obesity is considered as a risk factor for mood disorders including depression. Nevertheless, the mechanisms underlying this association are not clearly understood. To address this issue, we investigated the impact of high-fat (HF)-diet-induced obesity on depressive-like behavior and on serotonin (5-HT)-dependent Akt/glycogen synthase kinase 3β (GSK3β) signaling in the dentate gyrus (DG) of the hippocampus, which has been associated with mood regulation. We first showed that a HF diet induced significant overweight and hyperglycemia as well as a depressive-like behavior in adult Wistar rats. By using an ex vivo approach on brain slices, we demonstrated that 5-HT activates the Akt/GSK3β cascade in the DG of control chow (C) diet-fed animals and that a 16-week HF diet feeding abolishes this activation, concurrently with a desensitization of leptin and insulin signaling in the same region. Furthermore, depressive-like behavior inversely correlated with 5-HT-induced phosphorylation of GSK3β in the subgranular neurons of the DG. Interestingly, a substitution of HF with C diet for 6 weeks induced a total loss of depressive symptoms, whereas body weight and glycemia remained significantly higher compared to control rats. In addition, food restoration led to a recovery of the Akt/GSK3β signaling pathway activation in the DG. In parallel, we observed a negative correlation between body weight and cell proliferation in the subgranular zone of the DG. To conclude, we provide evidence for a desensitization of 5-HT-induced Akt/GSK3β signaling and an impaired cell proliferation in the DG by HF diet, suggesting novel molecular mechanisms linking obesity to depression.

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Section: Discussionmentioning

confidence: 62%

Hippocampal GSK3β as a Molecular Link Between Obesity and Depression

et al. 2014

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“…In support of this hypothesis is the finding that SERT KO mice exhibit an attenuated insulin-induced increase of pAKT (Chen et al, 2012). Furthermore, a recent study showed that insulin-resistance rendered normal serotonin-dependent phosphorylation of Akt in the hypothalamus nonfunctional (Papazoglou et al, 2012). Thus, our data underscores the importance of an intact central insulin-serotonergic signaling axis under physiologic conditions.…”

Section: Discussionmentioning

confidence: 99%

Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function

Saunders

Siuta

Robertson

et al. 2014

Neurochemistry International

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The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. Here, we examined whether phosphorylation of Akt, a key regulator of the insulin signaling pathway, controls serotonin (5-HT) signaling. To explore how impairment in Akt function regulates 5-HT homeostasis, we used a brain-specific rictor knockout (KO) mouse model of impaired neuronal phosphorylation of Akt at Ser473. Cortical 5-HT1A and 5-HT2A receptor binding was significantly elevated in rictor KO mice. Concomitant with this elevated receptor expression, the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) led to an increased hypothermic response in rictor KO mice. The increased cortical 5-HT1A receptor density was associated with higher 5-HT1A receptor levels on the cortical cell surface. In contrast, rictor KO mice displayed significantly reduced head-twitch response (HTR) to the 5-HT2A/C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), with evidence of impaired 5-HT2A/C receptor signaling. In vitro, pharmacological inhibition of Akt significantly increased 5-HT1A receptor expression and attenuated DOI-induced 5-HT2A receptor signaling, thereby lending credence to the observed in vivo cross-talk between neuronal Akt signaling and 5-HT receptor regulation. These data reveal that defective central Akt function alters 5-HT signaling as well as 5-HT-associated behaviors, demonstrating a novel role for Akt in maintaining neuronal 5-HT receptor function.

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“…Under a diabetic situation, an impairment of the serotonergic signaling in the hypothalamus is observed. Moreover, hypothalamic impairment of the serotonin induced-PI3K/Akt pathway can modify downstream signaling cascades, leading to symptoms of type 2 diabetes [135]. These observations suggest the existence of a cross talk between serotonin and insulin in the central nervous system.…”

Section: Other Gpcrs Crosstalk With Insulin Signaling Pathwaymentioning

confidence: 99%

Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors

Shi²,

West

et al. 2017

Journal of Cardiovascular Pharmacology

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Summary Diabetes is a major risk factor for the development of heart failure. One of the hallmarks of diabetes is insulin resistance associated with hyperinsulinemia. The literature shows that insulin and adrenergic signaling is intimately linked to each other; however, whether and how insulin may modulate cardiac adrenergic signaling and cardiac function remains unknown. Notably, recent studies have revealed that insulin receptor and β2 adrenergic receptor (β2AR) forms a membrane complex in animal hearts, bringing together the direct contact between two receptor signaling systems, and forming an integrated and dynamic network. Moreover, insulin can drive cardiac adrenergic desensitization via PKA and GRK phosphorylation of the β2AR, which compromises adrenergic regulation of cardiac contractile function. In this review, we will explore the current state of knowledge linking insulin and GPCR signaling, especially βAR signaling in the heart, with emphasis on molecular insights regarding its role in diabetic cardiomyopathy (DCM).

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Hypothalamic serotonin–insulin signaling cross-talk and alterations in a type 2 diabetic model

Cited by 28 publications

References 38 publications

Hippocampal GSK3β as a Molecular Link Between Obesity and Depression

Hippocampal GSK3β as a Molecular Link Between Obesity and Depression

Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function

Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors

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