Insulin resistance is associated with smaller brain volumes in a preliminary study of depressed and obese children

Phillips, Owen R.; Onopa, Alexander; Zaiko, Yevgeniya V.; Singh, Manpreet K.

doi:10.1111/pedi.12672

Cited by 11 publications

(7 citation statements)

References 46 publications

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“…Although the neurobiological mechanisms underlying the relationship between IR and depression have yet to be identified, impairments of brain plasticity have been incriminated. In humans, associations between the severity of IR and the reduction of brain volume have been unveiled (Last et al, 2007;Phillips et al, 2018). In keeping with these results, mice or rats developing IR display deficits in adult hippocampal neurogenesis (Lindqvist et al, 2006;Stranahan et al, 2008;Lang et al, 2009;Park et al, 2010) in a manner similar to that observed in animal models of depression (Surget et al, 2008;David et al, 2009).…”

Section: Introductionmentioning

confidence: 74%

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

et al. 2019

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Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic-and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic-and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.

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Section: Introductionmentioning

confidence: 74%

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

et al. 2019

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“…As obesity is a complex phenomenon, it is important to explore which obesity associated factors are particularly relevant to the brain alterations found in obese/overweight participants. These may include low-grade systemic inflammation ( 43 – 45 ), HPA dysfunctions ( 46 , 47 ), leptin-resistance ( 48 ), insulin resistance ( 49 – 51 ), or ceramide-induced DNA methylation ( 52 ). Our findings provide the strongest support for the role of dyslipidemia and systemic inflammation in these brain alteration.…”

Section: Discussionmentioning

confidence: 99%

Higher Body-Mass Index and Lower Gray Matter Volumes in First Episode of Psychosis

et al. 2020

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Background Neurostructural alterations are often reported in first episode of psychosis (FEP), but there is heterogeneity in the direction and location of findings between individual studies. The reasons for this heterogeneity remain unknown. Obesity is disproportionately frequent already early in the course of psychosis and is associated with smaller brain volumes. Thus, we hypothesized that obesity may contribute to brain changes in FEP. Method We analyzed MRI scans from 120 participants with FEP and 114 healthy participants. In primary analyses, we performed voxel-based morphometry (VBM) with small volume corrections to regions associated with FEP or obesity in previous meta-analyses. In secondary analyses, we performed whole-brain VBM analyses. Results In primary analyses, we found that when controlling for BMI, FEP had lower GM volume than healthy participants in a) left fronto-temporal region (pTFCE = 0.008) and b) left postcentral gyrus (pTFCE = 0.043). When controlling for FEP, BMI was associated with lower GM volume in left cerebellum (pTFCE < 0.001). In secondary analyses, we found that when controlling for BMI, FEP had lower GM volume than healthy participants in the a) cerebellum (pTFCE = 0.004), b) left frontal (pTFCE = 0.024), and c) right temporal cortex (pTFCE = 0.031). When controlling for FEP, BMI was associated with lower GM volume in cerebellum (pTFCE = 0.004). Levels of C-reactive protein, HDL and LDL-cholesterol correlated with obesity related neurostructural alterations. Conclusions This study suggests that higher BMI, which is frequent in FEP, may contribute to cerebellar alterations in schizophrenia. As previous studies showed that obesity-related brain alterations may be reversible, our ﬁndings raise the possibility that improving the screening for and treatment of obesity and associated metabolic changes could preserve brain structure in FEP.

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“…VBM and was positively correlated with insulin sensitivity independent of age, sex, depression severity, and several other clinical factors. 41 In addition, these teenager patients with greater IR index also showed reduced hippocampal and anterior cingulate cortex (ACC) volumes, which were associated with more severe depressive symptoms. 42 These results in teenager studies provided additional information that insulin also play important roles in developing brain and emotional behaviors.…”

Section: Ir and Volumetric Alterationsmentioning

confidence: 99%

“…Adiposity‐related IR was found to be associated with lower cortical thickness across the globe, with the strongest associations locating in the lateral frontal, parietal, and superior temporal cortices. In a group of 46 depressed and obese children, whole brain volume was calculated using VBM and was positively correlated with insulin sensitivity independent of age, sex, depression severity, and several other clinical factors 41 . In addition, these teenager patients with greater IR index also showed reduced hippocampal and anterior cingulate cortex (ACC) volumes, which were associated with more severe depressive symptoms 42 .…”

Section: Brain Atrophymentioning

confidence: 99%

Insulin Resistance and Cognitive Impairment: Evidence From Neuroimaging

Cui

Tang

et al. 2022

Magnetic Resonance Imaging

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Insulin is a peptide well known for its role in regulating glucose metabolism in peripheral tissues. Emerging evidence from human and animal studies indicate the multifactorial role of insulin in the brain, such as neuronal and glial metabolism, glucose regulation, and cognitive processes. Insulin resistance (IR), defined as reduced sensitivity to the action of insulin, has been consistently proposed as an important risk factor for developing neurodegeneration and cognitive impairment. Although the exact mechanism of IR‐related cognitive impairment still awaits further elucidation, neuroimaging offers a versatile set of novel contrasts to reveal the subtle cerebral abnormalities in IR. These imaging contrasts, including but not limited to brain volume, white matter (WM) microstructure, neural function and brain metabolism, are expected to unravel the nature of the link between IR, cognitive decline, and brain abnormalities, and their changes over time. This review summarizes the current neuroimaging studies with multiparametric techniques, focusing on the cerebral abnormalities related to IR and therapeutic effects of IR‐targeting treatments. According to the results, brain regions associated with IR pathophysiology include the medial temporal lobe, hippocampus, prefrontal lobe, cingulate cortex, precuneus, occipital lobe, and the WM tracts across the globe. Of these, alterations in the temporal lobe are highly reproducible across different imaging modalities. These structures have been known to be vulnerable to Alzheimer's disease (AD) pathology and are critical in cognitive processes such as memory and executive functioning. Comparing to asymptomatic subjects, results are more mixed in patients with metabolic disorders such as type 2 diabetes and obesity, which might be attributed to a multifactorial mechanism. Taken together, neuroimaging, especially MRI, is beneficial to reveal early abnormalities in cerebral structure and function in insulin‐resistant brain, providing important evidence to unravel the underlying neuronal substrate that reflects the cognitive decline in IR. Evidence Level 5 Technical Efficacy Stage 2

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Insulin resistance is associated with smaller brain volumes in a preliminary study of depressed and obese children

Abstract: There may be a significant cost for developing insulin resistance on the developing brain. Disentangling the precise relationship between the insulin resistance and the developing brain is critical.

Cited by 11 publications

References 46 publications

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

Higher Body-Mass Index and Lower Gray Matter Volumes in First Episode of Psychosis

Insulin Resistance and Cognitive Impairment: Evidence From Neuroimaging

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