The Effects of Leptin on Glial Cells in Neurological Diseases

Fujita, Yuki; Yamashita, Toshio

doi:10.3389/fnins.2019.00828

Cited by 41 publications

(36 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to neurons, leptin receptor expression has been reported in glial cells including astrocytes, microglia and oligodendrocytes in the CNS [50]. We too observed leptin and LepR expression in activated astrocytes in both young and old Tg mice.…”

Section: Discussionsupporting

confidence: 57%

“…There was also no difference (t(10) = 9.993, p < 0.081, Cohen's D = 1.21) in neuronal LepR expression ( Figure 2e) between young-WT (M = 8103.67, SD = 1659.65) and young-Tg (M = 6266.98, SD = 1615.97) mice. Although our data presents a marginal reduction in leptin and LepR expression between the WT and 5XFAD mice, there was no significant difference in leptin expression ( Figure 2d (48)(49)(50)(51)(52) week) 5XFAD (Tg) mice and wild-type (WT) controls. Independent t-test analysis of (a) neuronal leptin and (e) LepR expression between the young-WT and young-Tg revealed no significant differences.…”

Section: Quantitative Analysis Of Cortical Neuronal Leptin and Lepr Ementioning

confidence: 52%

See 1 more Smart Citation

Altered Brain Leptin and Leptin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease

Pratap

Holsinger

2020

Pharmaceuticals

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Interestingly, individuals with metabolic syndromes share some pathologies with those diagnosed with AD including neuroinflammation, insulin resistance and cognitive deficits. Leptin, an adipocyte-derived hormone, regulates metabolism, energy expenditure and satiety via its receptor, LepR. To investigate the possible involvement of leptin in AD, we examined the distribution of leptin and LepR in the brains of the 5XFAD mouse model of AD, utilizing immunofluorescent staining in young (10–12-weeks; n = 6) and old (48–52-weeks; n = 6) transgenic (Tg) mice, together with age-matched wild-type (WT) controls for both age groups (young-WT, n = 6; old-WT, n = 6). We also used double immunofluorescent staining to examine the distribution of leptin and leptin receptor expression in astrocytes. In young 5XFAD, young-WT and old-WT mice, we observed neuronal and endothelial expression of leptin and LepR throughout the brain. However, neuronal leptin and LepR expression in the old 5XFAD brain was significantly diminished. Reduced neuronal leptin and LepR expression was accompanied by plaque loading and neuroinflammation in the AD brain. A marked increase in astrocytic leptin and LepR was also observed in old 5XFAD mice compared to younger 5XFAD mice. We postulate that astrocytes may utilize LepR signalling to mediate and drive their metabolically active state when degrading amyloid in the AD brain. Overall, these findings provide evidence of impaired leptin and LepR signalling in the AD brain, supporting clinical and epidemiological studies performed in AD patients.

show abstract

Section: Discussionsupporting

confidence: 57%

Section: Quantitative Analysis Of Cortical Neuronal Leptin and Lepr Ementioning

confidence: 52%

Altered Brain Leptin and Leptin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease

Pratap

Holsinger

2020

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…LepR is also expressed in less defined neurons in the ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), preoptic area (PO), pre-mammillary nucleus (PMv), lateral hypothalamus (LH) and weakly in the paraventricular nucleus (PVN) [11][12][13] , that contribute to leptin's effects on homeostatic functions [14][15][16] . Besides neuronal cells, LepR expression has also been reported in astrocytes 17,18 , tanycytes 19 , endothelial cells 20 , microglia and macrophages 21 , oligodendrocytes 22 and vascular leptomeningeal cells (VLMCs) 23 .…”

Section: Introductionmentioning

confidence: 99%

Single-cell analysis reveals cellular heterogeneity and molecular determinants of hypothalamic leptin-receptor cells

Kakava-Georgiadou

Severens

Jørgensen

et al. 2020

Preprint

View full text Add to dashboard Cite

Hypothalamic nuclei which regulate homeostatic functions express leptin receptor (LepR), the primary target of the satiety hormone leptin. Single-cell RNA sequencing (scRNA-seq) has facilitated the discovery of a variety of hypothalamic cell types. However, low abundance of LepR transcripts prevented further characterization of LepR cells. Therefore, we perform scRNA-seq on isolated LepR cells and identify eight neuronal clusters, including three uncharacterized Trh-expressing populations as well as 17 non-neuronal populations including tanycytes, oligodendrocytes and endothelial cells. Food restriction had a major impact on Agrp neurons and changed the expression of obesity-associated genes. Multiple cell clusters were enriched for GWAS signals of obesity. We further explored changes in the gene regulatory landscape of LepR cell types. We thus reveal the molecular signature of distinct populations with diverse neurochemical profiles, which will aid efforts to illuminate the multi-functional nature of leptin’s action in the hypothalamus.

show abstract

“…Leptin signaling in hypothalamic astrocytes is important for synaptic plasticity and neuroendocrine control of feeding by leptin [187]. Moreover, leptin receptor expression on other glial cells (microglia, macrophages, oligodendrocytes and OPCs) suggests that leptin has a neuroprotective role and it is involved in remyelination, as suggested in literature [190]. With SCENIC analysis we detected 38 active gene regulatory networks which recapitulated the distribution of cell types among clusters and identified regulons that discriminated cell types from each other, such as Fli1 and Bclaf1 which determined Agrp neurons.…”

Section: Discussionmentioning

confidence: 75%

“…LepR is also expressed in less defined neurons in the ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), preoptic area (PO), pre-mammillary nucleus (PMv), lateral hypothalamus (LH) and weakly in the paraventricular nucleus (PVN) [45], [100], [185], that contribute to leptin's effects on homeostatic functions [98], [99], [101]. Besides neuronal cells, LepR expression has also been reported in astrocytes [186], [187], tanycytes [188], endothelial cells [189], microglia and macrophages [190], oligodendrocytes [191] and vascular leptomeningeal cells (VLMCs) [192]. Thus, the hypothalamic LepR population of cells is highly diverse, but a full description of the diversity of their transcriptomes remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

Molecular profiling and targeting of brain cells and circuits related to energy balance and food reward

Georgiadou¹

View full text Add to dashboard Cite

In the great, grand scheme of things, we're just tiny specks that will one day be forgotten. So it doesn't matter what we did in the past or how we'll be remembered. The only thing that matters is right now, this moment. This one spectacular moment we are sharing together. Molecular profiling and genetic targeting of brain cells RNA sequencing for molecular profiling and classification of brain cells A popular and reliable method to investigate brain heterogeneity is RNA sequencing, which provides information about the whole transcriptome and can be applied to a brain region, a specific cell population or at the single cell level. Many different cell dissociation protocols and sequencing technologies exist, the application of which can vary depending on the brain region, cell abundance, developmental stage and the desired sequencing depth. For example, when researchers desire to sequence a particular cell type, they can use a transgenic animal expressing a fluorescent protein in the cell population of interest, Targeting neural subtypes and circuits with viral vectors Molecular profiling of cells is very useful for identifying novel cell types and gaining insights into their molecular makeup and transcriptional responses to cues. Nevertheless, in order to understand cell types better, we need to gain genetic access to them. A popular method for gene delivery into the brain in order to map cells, visualize brain connectivity and study the function of cell populations and circuits is viral vector technology. Viral vectors are used to target genetic information into cells of choice. To this end, either wild-type or engineered viral capsids are used to "package" the genetic information (transgene) designed in a way to facilitate proper expression of RNA or protein. Few of the most commonly used viral vectors in neuroscience are the adeno-associated virus (AAV), lentivirus (LV), canine adenovirus 2 (Cav2) and rabies. The two former are mostly used for anterograde targeting, while the two latter are used for retrograde targeting of neurons and are extremely useful for brain mapping of circuits. In this thesis we use AAV and Cav2, therefore we will discuss those. Adeno-associated viral vectors (AAVs) AAV is the most popular viral vector system used in neuroscience and gene therapy. The first gene therapy drug, which treats retinal dystrophy, was approved in 2017, while there are at least 20 approved gene therapy treatments available and at least 4000 ongoing clinical trials [25], [26]. Besides the fact that the AAV capsid has limited capacity and can accommodate only up to 5.2 kb of DNA, their use has a lot of advantages. Genes delivered by AAVs do not incorporate into the host genome and rather stay episomal [27], therefore they do not cause insertional mutations that could lead to toxic consequences. AAV capsids Hypothalamus, energy balance and leptin In this thesis we mostly focus on cells located in the hypothalamus (Chapters 1-3) and profile leptin receptor-expressing cells (Chapters 1 & 2). The hypothalamus is loc...

show abstract

The Effects of Leptin on Glial Cells in Neurological Diseases

Cited by 41 publications

References 112 publications

Altered Brain Leptin and Leptin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease

Altered Brain Leptin and Leptin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease

Single-cell analysis reveals cellular heterogeneity and molecular determinants of hypothalamic leptin-receptor cells

Molecular profiling and targeting of brain cells and circuits related to energy balance and food reward

Contact Info

Product

Resources

About