Long-term high-fat diet increases glymphatic activity in the hypothalamus in mice

Delle, Christine; Cankar, Neža; Holgersson, Christian Digebjerg; Knudsen, Helle Hvorup; Nielsen, Elise Schiøler; Kjaerby, Celia; Mori, Yutaka; Nedergaard, Maiken; Weikop, Pia

doi:10.1038/s41598-023-30630-y

Cited by 12 publications

(8 citation statements)

References 65 publications

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“…It could also be induced by T2DM-associated insulin resistance, as it is known that the suppression of insulin signalling in astrocytes leads to increased angiogenesis and altered blood flow [ 19 ]. Therefore, similar to what has been suggested for rodents on a long-term obesogenic diet [ 17 ], T2DM-associated insulin resistance may play a role in increased fluid trafficking in the hypothalamus in an Aq4-dependent manner. Another T2DM-associated pathological change that may contribute to the increased demand for clearance are disrupted circadian rhythms and impaired sleep quality, as adequate sleep quality ensures a sufficient removal of potentially neurotoxic waste products that accumulate in the awake central nervous system [ 55 ].…”

Section: Discussionsupporting

confidence: 70%

“…The role of Aq4 in the hypothalamus is still underexplored, although a recent study suggested increased activity of the glymphatic system in the hypothalamus in long-term high fat-fed mice [ 17 ]. Our findings regarding the increased numbers of Aq4-ir astrocytes in the hypothalamus of T2DM subjects may indicate an elevated need for microenvironmental clearance through the glymphatic system.…”

Section: Discussionmentioning

confidence: 99%

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Reduction of oxytocin-containing neurons and enhanced glymphatic activity in the hypothalamic paraventricular nucleus of patients with type 2 diabetes mellitus

Correa-da-Silva,

Kalsbeek,

Gadella

et al. 2023

acta neuropathol commun

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Evidence from animal experiments has shown that the hypothalamic paraventricular nucleus (PVN) plays a key role in regulating body weight and blood glucose levels. However, it is unclear whether neuron populations in the human PVN are involved in the development of type 2 diabetes mellitus (T2DM). To address this, we investigated the neuronal and glial populations in the PVN of 26 T2DM patients and 20 matched controls. Our findings revealed a significant reduction in oxytocin (Oxt) neuron density in the PVN of T2DM patients compared to controls, while other neuronal populations remained unchanged. This suggests that Oxt neurons may play a specific role in the pathophysiology of T2DM. Interestingly, the reduction in Oxt neurons was accompanied by a decreased melanocortinergic input in to the PVN as reflected by a reduction in alpha-MSH immunoreactivity. We also analysed two glial cell populations, as they are important for maintaining a healthy neural microenvironment. We found that microglial density, phagocytic capacity, and their proximity to neurons were not altered in T2DM patients, indicating that the loss of Oxt neurons is independent of changes in microglial immunity. However, we did observe a reduction in the number of astrocytes, which are crucial for providing trophic support to local neurons. Moreover, a specific subpopulation of astrocytes characterized by aquaporin 4 expression was overrepresented in T2DM patients. Since this subset of astrocytes is linked to the glymphatic system, their overrepresentation might point to alterations in the hypothalamic waste clearance system in T2DM. Our study shows selective loss of Oxt neurons in the PVN of T2DM individuals in association with astrocytic reduction and gliovascular remodelling. Therefore, hypothalamic Oxt neurons may represent a potential target for T2DM treatment modalities.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Reduction of oxytocin-containing neurons and enhanced glymphatic activity in the hypothalamic paraventricular nucleus of patients with type 2 diabetes mellitus

Correa-da-Silva,

Kalsbeek,

Gadella

et al. 2023

acta neuropathol commun

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show abstract

“…Present results suggest that transient changes in plasma osmolality due to fluctuating blood glucose levels induce PVS alterations that result in acceleration of glymphatic flow in the long-term. We have recently reported that a long-term high-fat diet in mice inducing severe obesity and hypertension did not alter brain-wide glymphatic fluid transport [ 53 ]. Thus, the glymphatic system may better accommodate chronic rather than repeated transient changes in physiological parameters.…”

Section: Discussionmentioning

confidence: 99%

Transient but not chronic hyperglycemia accelerates ocular glymphatic transport

Delle,

Wang,

Giannetto

et al. 2024

Fluids Barriers CNS

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Glymphatic transport is vital for the physiological homeostasis of the retina and optic nerve. Pathological alterations of ocular glymphatic fluid transport and enlarged perivascular spaces have been described in glaucomatous mice. It remains to be established how diabetic retinopathy, which impairs vision in about 50% of diabetes patients, impacts ocular glymphatic fluid transport. Here, we examined ocular glymphatic transport in chronic hyperglycemic diabetic mice as well as in healthy mice experiencing a daily transient increase in blood glucose. Mice suffering from severe diabetes for two and four months, induced by streptozotocin, exhibited no alterations in ocular glymphatic fluid transport in the optic nerve compared to age-matched, non-diabetic controls. In contrast, transient increases in blood glucose induced by repeated daily glucose injections in healthy, awake, non-diabetic mice accelerated antero- and retrograde ocular glymphatic transport. Structural analysis showed enlarged perivascular spaces in the optic nerves of glucose-treated mice, which were absent in diabetic mice. Thus, transient repeated hyperglycemic events, but not constant hyperglycemia, ultimately enlarge perivascular spaces in the murine optic nerve. These findings indicate that fluid transport in the mouse eye is vulnerable to fluctuating glycemic levels rather than constant hyperglycemia, suggesting that poor glycemic control drives glymphatic malfunction and perivascular enlargement in the optic nerve.

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“…However, a previous study found that the expression of AQP4 was significantly different in the cortex and hippocampus during postnatal and adulthood [ 60 ]. Meanwhile, long-term HFD challenge could increase AQP4 density and polarization in the hypothalamus, but not in the hippocampus [ 61 ]. Considering that there was no change in the number and area of astrocytes in the hippocampal region in PDGFB cTG and WT mice fed with CHD and HFD, different responses may occur in different brain subareas with respect to HFD challenge and persistent PDGF-BB elevation.…”

Section: Discussionmentioning

confidence: 99%

Bone-derived PDGF-BB enhances hippocampal non-specific transcytosis through microglia-endothelial crosstalk in HFD-induced metabolic syndrome

Liu,

Shu,

Chen

et al. 2024

J Neuroinflammation

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Background It is well known that high-fat diet (HFD)-induced metabolic syndrome plays a crucial role in cognitive decline and brain-blood barrier (BBB) breakdown. However, whether the bone-brain axis participates in this pathological process remains unknown. Here, we report that platelet-derived growth factor-BB (PDGF-BB) secretion by preosteoclasts in the bone accelerates neuroinflammation. The expression of alkaline phosphatase (ALPL), a nonspecific transcytosis marker, was upregulated during HFD challenge. Main body Preosteoclast-specific Pdgfb transgenic mice with high PDGF-BB concentrations in the circulation recapitulated the HFD-induced neuroinflammation and transcytosis shift. Preosteoclast-specific Pdgfb knockout mice were partially rescued from hippocampal neuroinflammation and transcytosis shifts in HFD-challenged mice. HFD-induced PDGF-BB elevation aggravated microglia-associated neuroinflammation and interleukin-1β (IL-1β) secretion, which increased ALPL expression and transcytosis shift through enhancing protein 1 (SP1) translocation in endothelial cells. Conclusion Our findings confirm the role of bone-secreted PDGF-BB in neuroinflammation and the transcytosis shift in the hippocampal region during HFD challenge and identify a novel mechanism of microglia-endothelial crosstalk in HFD-induced metabolic syndrome.

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Long-term high-fat diet increases glymphatic activity in the hypothalamus in mice

Cited by 12 publications

References 65 publications

Reduction of oxytocin-containing neurons and enhanced glymphatic activity in the hypothalamic paraventricular nucleus of patients with type 2 diabetes mellitus

Reduction of oxytocin-containing neurons and enhanced glymphatic activity in the hypothalamic paraventricular nucleus of patients with type 2 diabetes mellitus

Transient but not chronic hyperglycemia accelerates ocular glymphatic transport

Bone-derived PDGF-BB enhances hippocampal non-specific transcytosis through microglia-endothelial crosstalk in HFD-induced metabolic syndrome

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