Insulin modulates emotional behavior through a serotonin-dependent mechanism

Martin, Hugo; Bullich, Sébastien; Martinat, Maud; Chataigner, Mathilde; Miceli, Mathieu Di; Simon, Vincent; Clark, Samantha; Butler, Jasmine; Schell, Mareike; Chopra, Simran; Chaouloff, Francis; Kleinridders, André; Cota, Daniela; Deurwaerdère, Philippe De; Pénicaud, Luc; Layé, Sophie; Guiard, Bruno P.; Fioramonti, Xavier

doi:10.1038/s41380-022-01812-3

Cited by 19 publications

(30 citation statements)

References 53 publications

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“…This is also further substantiated by animal models showing that insulin receptor deletion in the amygdala also led to impaired glucose metabolism 64 . Hence, it is postulated that impaired insulin sensitivity in the amygdala is critical for the development of T2D and mood disorders 64,65 . Whether insulin sensitivity in the amygdala is a joint feature between peripheral metabolism and emotional behaviours in humans needs to be further investigated.…”

Section: Discussionmentioning

confidence: 95%

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Brain insulin responsiveness is linked to age and peripheral insulin sensitivity

Wagner

Veit

Kübler

et al. 2023

Diabetes Obesity Metabolism

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Aims: Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear. Materials and Methods:We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo-controlled within-subject design in 110 participants (54 women, body mass index 18-49 kg/m 2 , age 21-74 years). Cerebral blood flow was measured before and after nasal spray application to assess brain insulin action. Peripheral insulin sensitivity was assessed by a five-point oral glucose tolerance test. Linear regressions were used to investigate associations between age and peripheral insulin sensitivity with brain insulin action in predefined region of interests (i.e. insulin-sensitive brain regions).Results: We found significant negative associations between age and insulin action in the hippocampus (β = -0.215; p = .017) and caudate nucleus (β = -0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (β = -0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (β = -0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward-related brain regions. Conclusion:We could show a region-specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.

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Section: Discussionmentioning

confidence: 95%

“…64 Hence, it is postulated that impaired insulin sensitivity in the amygdala is critical for the development of T2D and mood disorders. 64,65 Whether insulin sensitivity in the amygdala is a joint feature between peripheral metabolism and emotional behaviours in humans needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Brain insulin responsiveness is linked to age and peripheral insulin sensitivity

Wagner

Veit

Kübler

et al. 2023

Diabetes Obesity Metabolism

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“…15 Thus, DR 5-HT neurons may detect changes in glucose or insulin levels since they express the glucokinase, a key enzyme involved in the glucose-sensing machinery 16 ; or the insulin receptor. 17 These data suggest that the serotonergic system may detect insulin-hypoglycemia and be involved in the regulation of CRR. Thus, we hypothesized that DR 5-HT neurons are activated in response to insulin and/or decreased glucose level to modulate the CRR to insulin-induced hypoglycemia.…”

Section: Introductionmentioning

confidence: 85%

“…Pet1-cre-mCherry mice were obtained by crossing Pet1-cre mice with B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J mice (Jackson Laboratory, Bar Harbor, Maine, USA) as previously described. 17…”

Section: Animalsmentioning

confidence: 99%

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Serotonergic neurons are involved in the counter‐regulatory response to hypoglycemia

Martin,

Coursan,

Lallement

et al. 2023

J Neuroendocrinology

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ObjectivesIntensive insulin therapy provides optimal glycemic control in patients with diabetes. However, intensive insulin therapy causes so‐called iatrogenic hypoglycemia as a major adverse effect. The ventromedial hypothalamus (VMH) has been described as the primary brain area initiating the counter‐regulatory response (CRR). Nevertheless, the VMH receives projections from other brain areas which could participate in the regulation of the CRR. In particular, studies suggest a potential role of the serotonin (5‐HT) network. Thus, the objective of this work is to determine the contribution of 5‐HT neurons in CRR control.MethodsComplementary approaches have been used to test this hypothesis in quantifying the level of 5‐HT in several brain areas by HPLC in response to insulin‐induced hypoglycemia, measuring the electrical activity of dorsal Raphe (DR) 5‐HT neurons in response to insulin or decreased glucose level by patch‐clamp electrophysiology; and measuring the CRR hormone glucagon as an index of the CRR to the modulation of the activity of 5‐HT neurons using pharmacological or pharmacogenetic approaches.ResultsHPLC measurements show that the 5HIAA/5HT ratio is increased in several brain regions including the VMH in response to insulin‐induced hypoglycemia. Patch‐clamp electrophysiological recordings show that insulin, but not decreased glucose level, increases the firing frequency of DR 5‐HT neurons in the DR. In vivo, both the pharmacological inhibition of 5‐HT neurons by intraperitoneal injection of the 5‐HT1A receptor agonist 8‐OH‐DPAT or the chemogenetic inhibition of these neurons reduce glucagon secretion, suggesting an impaired CRR.ConclusionTaken together, these data highlight a new neuronal network involved in the regulation of the CRR. In particular, this study shows that DR 5‐HT neurons detect iatrogenic hypoglycemia in response to the increased insulin level and may play an important role in the regulation of CRR.This article is protected by copyright. All rights reserved.

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