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Fatty Acid Sensor GPR120 (FFAR4) Treatment Target for Anxiety & Neuroinflammation (2023 Study)

In the quest to understand the intricate relationship between our diet, brain, and behavior, scientists are turning their focus to a unique receptor, GPR120.

This protein, known for interacting with long-chain fatty acids like omega-3s, is shedding new light on how our body’s inflammation and metabolism can directly affect our mental health.

By exploring GPR120’s role in the brain, particularly in managing neuroinflammation and its effects on mood and behavior, researchers are opening doors to potential new treatments for a range of neuroinflammatory conditions.


  • GPR120’s Role: GPR120, also known as Ffar4, acts as a receptor for long-chain fatty acids, including omega-3 fatty acids, and mediates their anti-inflammatory and insulin-sensitizing effects.
  • Expression in Microglia: GPR120 mRNA is highly present in both murine and human microglia, especially in the brain’s nucleus accumbens (NAc).
  • Impact on Inflammation: GPR120 activation significantly reduces the expression of proinflammatory markers in response to lipopolysaccharide (LPS) in mouse microglia.
  • Behavioral Effects: Central administration of a GPR120 agonist in mice leads to reduced anxiety-like and sickness behaviors induced by proinflammatory challenges.

Source: Journal of Neuroinflammation (2023)

GPR120 & Neuroinflammation (Links)

GPR120 is emerging as a crucial player in the neuroimmune system.

Known for its interaction with omega-3 fatty acids, it’s gaining attention for its potential to influence brain health.

Its role extends beyond mere fat sensing – it’s a mediator of anti-inflammatory responses, especially in neural tissues.

GPR120 in Microglial Reactivity

The presence of GPR120 in microglia, the brain’s primary immune cells, suggests its significant role in neuroimmune responses.

Microglia are critical in maintaining brain health, and their dysfunction can lead to various neurological and psychiatric disorders.

GPR120’s modulation of microglial reactivity, particularly in response to inflammatory stimuli, places it at the forefront of neuroinflammatory research.

GPR120 in the Nucleus Accumbens

The nucleus accumbens (NAc) plays a pivotal role in regulating mood and motivation.

The high expression of GPR120 in this region underscores its potential impact on emotional and behavioral processes.

This finding links metabolic health directly with neurobehavioral functions, hinting at GPR120’s role in conditions like depression and anxiety.

Activation of Fatty Acid Sensor GPR120: Microglia, Sickness, Anxiety (2023 Study)

Researchers evaluated the impact of GPR120 stimulation on microglial reactivity, neuroinflammation, and the manifestation of sickness- and anxiety-like behaviors following acute proinflammatory insults.

GPR120, a sensor for long-chain fatty acids including omega-3 polyunsaturated fatty acids (n-3 PUFAs), has been shown to mediate anti-inflammatory and insulin-sensitizing effects.

The study aimed to explore the role of GPR120 in regulating neuroimmune responses and behavioral changes in response to inflammation, with a focus on the nucleus accumbens (NAc), a brain region associated with anxiety, motivation, and neuroinflammation-induced mood deficits.

How was the study conducted? (Methods)

  • Animal Models: Adult C57Bl/6J male mice were used for gene expression and behavioral tests.
  • Chemicals and Reagents: Various compounds including LPS, omega-3 fatty acids, and GPR120 agonist (CpdA) were used.
  • Cell Culture Experiments: Primary microglia from mouse forebrains or NAc microdissections were prepared. Various treatments with fatty acids, CpdA, and LPS were conducted.
  • Stereotaxic Surgery: Mice underwent surgery for intracerebroventricular (ICV) cannula implantation.
  • Behavioral Assessment: Behavioral effects of central GPR120 agonism were assessed using elevated-plus maze, light/dark box task, and three-chamber social interaction test.
  • Quantitative PCR: Used for measuring gene expression in cell cultures and brain tissues.
  • Immunochemistry and In Situ Hybridization: Conducted for morphological and expression analysis in cells and brain slices.

What were the results?

  • Expression of GPR120: Found to be enriched in murine and human microglia, especially in the NAc of mice.
  • Impact of GPR120 Agonism on Inflammation: Significantly attenuated LPS-induced proinflammatory marker expression in primary mouse microglia and inhibited nuclear translocation of NFκB.
  • Behavioral Effects: Central administration of CpdA mitigated LPS-induced hypolocomotion and anxiety-like behavior in mice, as well as reducing neuroinflammatory markers in the NAc.
  • Microglia Reactivity and Behavioral Responses: GPR120 agonist pre-treatment reduced NAc microglia reactivity and alleviated sickness-like behaviors caused by central cytokine injection.

Limitations to consider…

  • Species Specificity: The study predominantly used murine models, which may not fully replicate human physiological responses.
  • Behavioral Tests: Some tests, like the elevated-plus maze, did not show significant differences in certain aspects (e.g., time spent in open arms), indicating variability in behavioral responses.
  • Focus on Specific Brain Region: While the study concentrated on the NAc, the role of GPR120 in other brain regions remains less explored.

Potential implications…

  • Neuroimmune Regulation: GPR120 in microglia plays a crucial role in modulating neuroimmune responses, potentially contributing to the neuroprotective effects of n-3 PUFAs.
  • Therapeutic Potential: GPR120 agonists might offer new therapeutic strategies for treating neuroinflammatory conditions, especially those related to mood and behavior disorders.

Future Research Directions

  • Broader Application: Investigate the role of GPR120 in other brain regions and its overall impact on the central nervous system.
  • Human Studies: Conduct clinical trials to assess the efficacy and safety of GPR120 agonists in human subjects, especially in the context of mood disorders and neuroinflammation.
  • Mechanistic Insights: Further research to understand the molecular mechanisms underlying GPR120-mediated neuroprotection and its interaction with other neuroimmune pathways.
  • Long-Term Effects: Study the long-term effects of GPR120 stimulation, particularly in chronic neuroinflammatory conditions.
  • Comorbidity with Metabolic Disorders: Explore the role of GPR120 in the intersection of metabolic and psychiatric disorders, given the link between obesity, diet, and neuroinflammation.

Protective Role of GPR120 Against Neuroinflammation (Mechanisms)

Combating Inflammatory Markers

GPR120 shows remarkable abilities in countering inflammation.

Its activation leads to a significant reduction in proinflammatory markers like TNF-α and IL-1β, particularly in response to lipopolysaccharide (LPS), a known inducer of inflammation.

This action is akin to or even surpasses the effects of omega-3 fatty acids, known for their anti-inflammatory properties.

Behavioral Impacts of GPR120 Activation

GPR120’s influence extends to behavioral aspects. Its activation in the brain blunts behaviors associated with sickness and anxiety, which are often induced by inflammatory challenges.

This effect is particularly evident in response to LPS exposure, which typically leads to reduced locomotion and increased anxiety-like behaviors in animal models.

GPR120’s Modulation of Neuroinflammation

The agonism of GPR120 significantly reduces the reactivity of microglia in the NAc, a key brain region implicated in mood regulation.

This reduction in microglial reactivity is associated with decreased sickness-like behaviors and an improved mood state in animal models.

This suggests GPR120’s potential as a therapeutic target for conditions where neuroinflammation plays a key role, such as depression and anxiety disorders.

GPR120 & Neuropsychiatric Disorders

GPR120 and Depression

Chronic inflammation has been consistently linked to depression.

Inflammatory cytokines can alter brain chemistry and neuroplasticity, often leading to depressive symptoms.

GPR120’s ability to modulate microglial activation and inflammatory responses in the brain, especially in regions like the nucleus accumbens, directly relates to this.

By controlling the inflammatory cascade, GPR120 could potentially mitigate the neurochemical changes associated with depression, offering a new avenue for treatment strategies, particularly for individuals whose depression is resistant to conventional therapies.

Anxiety Disorders and GPR120

Anxiety disorders often co-occur with heightened states of bodily inflammation.

The role of GPR120 in reducing neuroinflammation and its behavioral manifestations, such as anxiety-like behaviors in animal models, is particularly relevant here.

The receptor’s presence in key brain areas involved in mood regulation suggests that modulating GPR120 activity could help in balancing the neural circuits that go awry in anxiety disorders.

GPR120 and Neurodegenerative Disorders

While not traditionally classified under mental health, neurodegenerative diseases like Alzheimer’s and Parkinson’s often have psychiatric manifestations such as mood disturbances and anxiety.

The neuroinflammatory processes in these diseases are a key area of concern.

GPR120’s anti-inflammatory actions could provide neuroprotective benefits, potentially slowing disease progression and alleviating some of the associated psychiatric symptoms.

GPR120 and Stress-Related Disorders

Stress is a well-known trigger for both neuroinflammation and mental health disorders.

The ability of GPR120 to counteract inflammation-induced by stressors suggests its potential role in managing stress-related disorders.

This includes conditions like PTSD, where dysregulated immune responses in the brain are evident.

Takeaway: GPR120 for Neuroinflammation & Psychiatric Disorders

The exploration of GPR120 is a critical step in understanding the complex interplay between diet, brain inflammation, and mental health.

As research continues to unravel the mysteries of this unique receptor, the potential for developing new treatments for a range of neuroinflammatory and mental health conditions grows.

The journey of understanding GPR120 is not just about a single receptor; it’s about piecing together a larger puzzle of how our body’s physical processes intertwine with our mental well-being.


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