Obesity as a Risk Factor for Alzheimer’s Disease: Implication of Leptin and Glutamate

Lloret, Ana; Monllor, Paloma; Esteve, Daniel; Cervera‐Ferri, Ana; Lloret, Maria-Angeles

doi:10.3389/fnins.2019.00508

Cited by 64 publications

(48 citation statements)

References 107 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Low leptin availability is a risk factor for NCDs in older people [34], and a target for developing supplementation therapies for reducing the progression of NCDs [35]. In line with the above, recent reports indicate a link between leptin and obesity-induced NCD [36]. In another proposed pathogenic link between NHLH2 and NCDs, CNS heat deregulation appears to have a role in the pathogenesis of neurodegeneration, and the NHLH2 gene is induced following cold and torpor [37].…”

Section: Discussionmentioning

confidence: 95%

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

View full text Add to dashboard Cite

Background: Approximately 2% of the human core promoter short tandem repeats (STRs) reach lengths of ≥6 repeats, which may in part be a result of adaptive evolutionary processes and natural selection. A single-exon transcript of the human nescient helix loop helix 2 (NHLH2) gene is flanked by the longest CA-repeat detected in a human protein-coding gene core promoter (Ensembl transcript ID: ENST00000369506.1). NHLH2 is involved in several biological and pathological pathways, such as motivated exercise, obesity, and diabetes. Methods: The allele and genotype distribution of the NHLH2 CA-repeat were investigated by sequencing in 655 Iranian subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 290) and matched controls (n = 365). The evolutionary trend of the CA-repeat was also studied across vertebrates. Results: The allele range was between 9 and 25 repeats in the NCD cases, and 12 and 24 repeats in the controls. At the frequency of 0.56, the 21-repeat allele was the predominant allele in the controls. While the 21-repeat was also the predominant allele in the NCD patients, we detected significant decline of the frequency (p < 0.0001) and homozygosity (p < 0.006) of this allele in this group. Furthermore, 12 genotypes were detected across 16 patients (5.5% of the entire NCD sample) and not in the controls (disease-only genotypes; p < 0.0003), consisting of at least one extreme allele. The extreme alleles were at 9, 12, 13, 18, and 19 repeats (extreme short end), and 23, 24, and 25 repeats (extreme long end), and their frequencies ranged between 0.001 and 0.04. The frequency of the 21-repeat allele significantly dropped to 0.09 in the disease-only genotype compartment (p <

show abstract

Section: Discussionmentioning

confidence: 95%

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

View full text Add to dashboard Cite

show abstract

“…These functions suggest that leptin may have protective functions in neurological diseases and insults. The association of increased leptin levels in obesity and increased risk of neurodegenerative diseases in obese individuals has been widely discussed (Forny-Germano et al, 2018; Lloret et al, 2019). In animal disease models, neurotoxin 1-methyl-4-phenyl-1, 2, 4, 5-tetrahydropyridine (MPTP)- or 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD) model show greater neurodegeneration with obesity compared to littermates fed a normal diet (Choi et al, 2005; Morris et al, 2010).…”

Section: Neuroprotective Roles Of Leptinmentioning

confidence: 99%

The Effects of Leptin on Glial Cells in Neurological Diseases

Fujita

Yamashita

2019

Front. Neurosci.

View full text Add to dashboard Cite

It is known that various endocrine modulators, including leptin and ghrelin, have neuroprotective roles in neurological diseases. Leptin is a hormone produced by adipocytes and was originally identified as a gene related to obesity in mice. The leptin receptors in the hypothalamus are the main target for the homeostatic regulation of body weight. Recent studies have demonstrated that leptin receptors are also expressed in other regions of the central nervous system (CNS), such as the hippocampus, cerebral cortex, and spinal cord. Accordingly, these studies identified the involvement of leptin in the regulation of neuronal survival and neural development. Furthermore, leptin has been shown to have neuroprotective functions in animal models of neurological diseases and demyelination. These observations also suggest that dysregulation of leptin signaling may be involved in the association between neurodegeneration and obesity. In this review, we summarize novel functions of leptin in animal models of neurodegenerative diseases. Specifically, we focus on the emerging evidence for the role of leptin in non-neuronal cells in the CNS, including astrocytes, microglia, and oligodendrocytes. Understanding leptin-mediated neuroprotective signals and molecular mechanisms underlying remyelination will be helpful to establish therapeutic strategies against neurological diseases.

show abstract

“…However, obesity impairs this pathway, and an increase in brain glutamate levels leads to a dysfunction in extrasynaptic NMDA-R, a decrease in long-term potentiation, and mitochondrial dysfunctions. Thus, the slow excitotoxicity shown in Alzheimer’s disease due to overexcitation of NMDA receptors by glutamate can be linked to obesity through leptin resistance as a risk factor for neurological disorders [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

High-fat diet-induced obesity and impairment of brain neurotransmitter pool

Labban

Alfawaz

Almnaizel

et al. 2020

Translational Neuroscience

View full text Add to dashboard Cite

AbstractObesity and the brain are linked since the brain can control the weight of the body through its neurotransmitters. The aim of the present study was to investigate the effect of high-fat diet (HFD)-induced obesity on brain functioning through the measurement of brain glutamate, dopamine, and serotonin metabolic pools. In the present study, two groups of rats served as subjects. Group 1 was fed a normal diet and named as the lean group. Group 2 was fed an HFD for 4 weeks and named as the obese group. Markers of oxidative stress (malondialdehyde, glutathione, glutathione-s-transferase, and vitamin C), inflammatory cytokines (interleukin [IL]-6 and IL-12), and leptin along with a lipid profile (cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein levels) were measured in the serum. Neurotransmitters dopamine, serotonin, and glutamate were measured in brain tissue. Fecal samples were collected for observing changes in gut flora. In brain tissue, significantly high levels of dopamine and glutamate as well as significantly low levels of serotonin were found in the obese group compared to those in the lean group (P > 0.001) and were discussed in relation to the biochemical profile in the serum. It was also noted that the HFD affected bacterial gut composition in comparison to the control group with gram-positive cocci dominance in the control group compared to obese. The results of the present study confirm that obesity is linked to inflammation, oxidative stress, dyslipidemic processes, and altered brain neurotransmitter levels that can cause obesity-related neuropsychiatric complications.

show abstract

Obesity as a Risk Factor for Alzheimer’s Disease: Implication of Leptin and Glutamate

Cited by 64 publications

References 107 publications

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

The Effects of Leptin on Glial Cells in Neurological Diseases

High-fat diet-induced obesity and impairment of brain neurotransmitter pool

Contact Info

Product

Resources

About