New study shows intermittent fasting reduces obesity-related brain inflammation and cognitive decline (2024)

New study shows intermittent fasting reduces obesity-related brain inflammation and cognitive decline (1)By Neha MathurJan 5 2024Reviewed by Lily Ramsey, LLM

In a recent article published inNutrients,researchers evaluated the long-term beneficial effects of intermittent fasting (IF) on neuroinflammation, cognitive impairment, and memory deficits in mice fed with high-fat diet (HFD).

In addition, they used HFD-fed mice with blood-brain barrier (BBB) leakage to examine the effects of IF on the crosstalk between adipocyte death-related macrophage accumulation and hippocampal inflammation in diabetic encephalopathy.

New study shows intermittent fasting reduces obesity-related brain inflammation and cognitive decline (2)Study:Intermittent Fasting Reduces Neuroinflammation and Cognitive Impairment in High-Fat Diet-Fed Mice by Downregulating Lipocalin-2 and Galectin-3. Image Credit:vetre/


Obesity and type 2 diabetes (T2D) are well recognised for their damaging effects on cognition and memory. Furthermore, these metabolic dysfunctions increase the permeability of the BBB, which further exacerbates neuroinflammation and memory deficits.

Thus, disruption in hippocampal BBB is considered an early biomarker of diabetes-related memory deficits and cognitive impairment.

Studies have shown that two proteins, lipocalin-2 (LCN2) and galectin-3 (GAL3), might be involved in these neurological manifestations.

The former, a gelatinase-related lipocalin, is secreted by adipocytes, including neutrophils and macrophages, whereas various cells express GAL-3 for immune regulation.

Several previous studies have reported that elevated levels of proinflammatory mediators, such as LCN2 and GAL-3, promote neuroinflammation by triggering detrimental neutrophil/microglia activation in the diabetic brain via BBB leakage.

In other words, these proteins might have a functional relationship with the adipose tissue.

Thus, researchers postulate that LCN2 and GAL3 are associated with obesity and T2D-related chronic inflammation. Upon induction through HFD, circulating LCN2 and GAL3 invade the leaky BBB and activate microglial cells, resulting in local neuroinflammation.

Subsequently, these cells secrete high levels of tumor-necrosis factor-alpha (TNF-α), which exacerbates neuroinflammation, further compromising BBB permeability, which further impairs cognition and memory.

Recently, IF, a dietary modification, has garnered attention for its potential to exert neuroprotective effects among patients with T2D and obesity.

About the study

In the present study, researchers used HFD-fed mice to investigate the exact mechanisms by which chronic IF exerts neuroprotective effects over LCN2 and GAL3-mediated neuroinflammation and adipose tissue macrophage infiltration.

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The team divided all test mice into the normal diet (ND), HFD, and HFD + IF (HIF) groups, with each group having 10, 10, and 12 three-week-old male C57BL/6 mice, respectively. The HFD mice derived 60% of their total energy (measured in kilocalories [kcal]) from fat.

For the mice in ND and HFD groups, study protocol mandated that mice were fed a ND/HFD for 30 weeks, and the HIF group mice were first fed an HFD for eight weeks and then switched to IF protocol wherein they were alternatingly fed and subjected to fasting for 24 hours for 22 weeks.

The team measured food and energy intake every alternate day for 16 weeks after the completion of the IF regimen. They sacrificed all mice aged 34 weeks.

Other tests performed on mice tissues were EchoMRI, which quantified their body fat mass, insulin tolerance test (ITT), and glucose tolerance test (GTT), which helped determine their blood glucose levels.

Likewise, an enzyme-linked immunosorbent assay (ELISA) helped assess serum protein levels of all mice, specifically LCN2, GAL3, and matrix metalloproteinase 9 (MMP9).

In addition, the researchers used the Terminal Deoxynucleotidyl Transferase Dutp Nick end Labeling (TUNEL)assay to measure the extent of in situ apoptosis in mice white adipose tissues (WATs).

The team counted the number of crown-like structures (CLSs), characterizing WAT apoptosis and macrophage infiltration, TUNEL-positive cells, and extravascular albumin, an indicator of BBB leakage in hippocampal tissue specimens.

They also performedWestern Blot Analysis and Double/Triple Immunofluorescencesonfrozen WATs and hippocampi specimens of three to four mice per group, and theMorris Water Maze (MWM)test for five days among seven mice per group.

Finally, the researchers determined groupwise differences by ANOVA followed by Tukey’s tests. They presented results as the standard error of the mean (SEM), considering ap-value < 0.05 statistically significant.


Mice in the HFD group had higher body weights (BW) and body fat mass; additionally, they had an impaired glucose tolerance.

Histological analysis revealed that these mice had many CLSs and TUNEL-positive cells in their WATs, indicating HFD-induced adipocyte death and macrophage infiltration.

Furthermore, triple immunofluorescence showed the presence of LCN2- and GAL3-positive neutrophils and macrophages in the WAT of HFD mice.

Interrupting the HFD regimen with IF caused dramatic weight loss and attenuated IR and adipocyte death in mice of the HIF group.

IF also significantly attenuated HFD-induced IR to correct impaired glucose tolerance and reduced the upregulated MMP9 expression in the hippocampus of mice in the HIF group. Immunofluorescence analysis revealed that IF also weakened macrophage infiltration in HFD mice to improve IR.

Furthermore, IF significantly attenuated the HFD-induced increase in serum LCN2, circulating, and macrophage-derived GAL3 protein levels in WATs of HIF mice, which reduced BBB leakage, neuroinflammation, and memory deficits.

It also reversed the HFD-induced increases in proinflammatory cytokines, such as TNF-α and interleukin-6 (IL-6). Finally, in the hippocampus of HFD mice, IF reduced astrocytic LCN2 and microglial GAL3 expression.


Together, the study results suggest that IF, an alternative to continuous caloric restriction, may improve IR, and reduce WAT inflammation by inhibiting macrophage infiltration and adipocyte death to correct metabolic dysfunction(s) in HFD mice.

Thus, further research should focus on testing and validating the use of IF as a drug replacement therapy to improve cognitive impairment due to HFD-induced neuroinflammation and BBB disruption in chronic low-grade inflammatory conditions, such as T2D and obesity.

Further studies could help establish the exact mechanisms by which IF protects against obesity and T2D-related cognitive impairment and memory deficits with more precision.

Journal reference:

  • Lee, J., An, H. S., Shin, H. J., Jang, H. M., Im, C. O., Jeong, Y., Eum, K., Yoon, S., Lee, S. J., Jeong, E. A., Kim, K. E., & Roh, G. S. (2024). Intermittent Fasting Reduces Neuroinflammation and Cognitive Impairment in High-Fat Diet-Fed Mice by Downregulating Lipocalin-2 and Galectin-3.Nutrients,16(1), 159. doi:

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Regarding the concepts mentioned in this article, here is some information:

Intermittent Fasting (IF):

Intermittent fasting is a dietary pattern that involves alternating periods of fasting and eating. It has gained attention for its potential health benefits, including neuroprotective effects among patients with type 2 diabetes (T2D) and obesity. IF has been studied for its effects on neuroinflammation and cognitive impairment in mice fed with a high-fat diet (HFD).

Neuroinflammation and Cognitive Impairment:

Neuroinflammation refers to inflammation in the brain, which can contribute to various neurological disorders. Cognitive impairment refers to a decline in cognitive function, including memory deficits. Obesity and T2D are known to have damaging effects on cognition and memory, and they can increase the permeability of the blood-brain barrier (BBB), leading to neuroinflammation and memory deficits.

Lipocalin-2 (LCN2) and Galectin-3 (GAL3):

LCN2 and GAL3 are proteins that have been implicated in neuroinflammation and cognitive impairment. LCN2 is secreted by adipocytes, including neutrophils and macrophages, while GAL3 is expressed by various cells for immune regulation. Elevated levels of LCN2 and GAL3 have been associated with neuroinflammation by triggering detrimental neutrophil/microglia activation in the diabetic brain via BBB leakage.

High-Fat Diet (HFD):

A high-fat diet refers to a diet that is high in fat content, often associated with obesity and metabolic dysfunctions. In the study mentioned, mice were fed with a high-fat diet to induce obesity and T2D-related chronic inflammation.

Blood-Brain Barrier (BBB):

The blood-brain barrier is a protective barrier that separates the blood circulation from the brain tissue. It regulates the passage of substances between the blood and the brain. Disruption in the BBB can lead to increased permeability, allowing harmful substances to enter the brain and contribute to neuroinflammation and cognitive impairment.

Adipocyte Death and Macrophage Infiltration:

Adipocyte death refers to the death of fat cells, which can occur in conditions such as obesity. Macrophage infiltration refers to the accumulation of macrophages, a type of immune cell, in adipose tissue. In the study, HFD-induced adipocyte death and macrophage infiltration were observed in mice fed with a high-fat diet.

Morris Water Maze (MWM) Test:

The Morris Water Maze test is a commonly used behavioral test to assess spatial learning and memory in rodents. It involves placing the mice in a pool of water and measuring their ability to find a hidden platform using spatial cues. This test was used in the study to evaluate the effects of intermittent fasting on cognitive impairment in mice.

These are some of the key concepts mentioned in the article. If you have any specific questions or would like more information on a particular topic, feel free to ask!

New study shows intermittent fasting reduces obesity-related brain inflammation and cognitive decline (2024)
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