**4. Discussion**

An increasing amount of evidence confirms the role of abnormal lipid metabolism in the pathobiology and clinical course of schizophrenia [2–4]. Despite the fact that research concerning fatty acid metabolism is going on for a long time, there is an insufficient amount of evidence to determine the mechanism and all pathways engaged in lipid disturbances related to schizophrenia [23]. Differences in PUFA levels between patients suffering from schizophrenia and healthy individuals were also reported [4]. Until now there are no guidelines for the routine assessment of serum FA levels or concentrations in patients with psychiatric illness.

In our study, there were no differences in GPR120 levels between patients and healthy individuals. Nevertheless, the negative relationship between GPR120 serum concentration and DHA and ALA concentration was detected only among healthy individuals. We did not find any correlation between GPR120 receptor concentration and FA serum concentration in the SZ group. This phenomenon suggests that patients suffering from schizophrenia may manifest a GPR120 insensitivity with activation becoming impossible (see Figure 3). The revealed relationships were found to be insignificant after Bonferroni correction for multiple comparisons. To some extent, the small sample size could have also affected the lack of relationship after performing multiple comparisons. Further studies with a larger sample size are required.

**Figure 3.** The proposed mechanism of the connection between GPR120 insensitivity and impaired lipid metabolism in schizophrenia. In healthy individuals, GPR120 activation leads to anti-inflammatory effects. Natural ligands (DHA and ALA) stimulate GPR120–β-arrestin complex formation and drive phospholipase A2 (PLA2) activation. Pro-/anti-inflammatory homeostasis is maintained. In schizophrenia patients, GPR120 insensitivity leads to pro/anti-inflammatory imbalance. Natural ligands (DHA and ALA) are unable to stimulate GPR120–β-arrestin complex formation. Overactivity of PLA2 causes a switch to inflammatory pathway stimulation. Pro-/anti-inflammatory homeostasis is disturbed.

It is still unclear whether GPR120 concentration in the serum reflects the expression of the receptor and cell signaling. We decided to examine the serum concentration of GPR120 for some reasons. Firstly, this type of sample is more stable during storage in low temperatures compared to RNA [24]. Gene testing is essential to confirm the results of our study. Introducing serum sample collection in clinical practice from a population health perspective is more convenient and accessible compared to RNA samples. Thus, serum samples may be a more favorable material used as a biomarker of fatty acid metabolism disturbances in further clinical practice [17,25].

In a population of children, lower GPR120 plasma levels were associated with negative outcomes, i.e., insulin resistance and higher BMI [26]. In our study, we did not find any relationship between BMI and GPR120, and lower GPR120 serum concentration was related to the higher concentration of PUFAs in the HC group. It is possible that a higher concentration of PUFAs in serum increases anti-inflammatory status, and GPR120 activation (to restore balance) is not required. On the other hand, an activated GPR120 forms a complex with β-arrestin, which may lead to a reduction in free GPR120 blood concentration [10].

The mechanism linked with GPR120 disruption in schizophrenia may be related to PLA2 activity. According to Horrobin's theory of schizophrenia, PLA2 excess activity is linked with an abnormal skin reaction in the niacin test in schizophrenia patients [27]. PUFAs are able to activate PLA2 via the GPR120 receptor, leading to the production of prostaglandin. This pathway is involved in the anti-inflammatory DHA effects in macrophages [28].

GPR120 activation mediates downstream signaling mechanisms and prevents the expression of proinflammatory cytokines. Thus, GPR120 has the potential to diminish systemic inflammation and manage metabolic functions [10,12]. There is a suggestion that several beneficial effects of omega-3 do not require GPR120. However, GPR120 function is essential to regulate vascular inflammation and neointimal hyperplasia [29]. Disruption of the anti-inflammatory GPR120-related pathway could affect the persistent proinflammatory state in schizophrenia and may be involved in a higher risk of cardiometabolic conditions in the psychiatric population [30]. However, GPR120 participation in dyslipidemia observed in schizophrenia patients remains unclear.

Clinical trials showed the ability of omega-3 PUFAs to reduce clinical symptoms of schizophrenia [31,32]. We did not find any differences in PUFA concentration and intake between schizophrenia patients and healthy individuals. The pharmacological treatment of schizophrenia increases the sterol regulatory element-binding protein type 1 (SREBP1) which regulates the expression of genes related to fatty acid synthesis [33]. This phenomenon to a certain degree may explain the lack of difference in serum FAs between SZ and HC groups. Antipsychotic medication increases the expression and activity of enzymes involved in PUFA metabolism, and changes in the blood plasma lipidome are suggested as a treatment response in psychiatric disorders [5]. On the other hand, in our study, the nutritional assessment concerned short-term omega-3 intake. This short period of dietary habit analysis was performed due to the evaluation of serum as a biomarker of PUFAs. We hypothesize that the severity of symptoms will be more linked to long-term omega-3 intake. However, in patients suffering from schizophrenia, especially those who experienced psychotic symptoms recently, examining long-term intake will be a challenge. People with schizophrenia commonly experience cognitive impairment, lack of motivation, and poor compliance; thus, misreporting could be expected, especially regarding long-term food intake assessment [34,35].

Adequate intake of omega-3 fatty acids plays an important role in maintaining mental health. DHA and EPA are structurally integrated via phospholipid molecules and they ensure the proper structure of neuronal cell membranes [3]. FAs regulate the expression of genes, as well as changes in protein concentration, which could be blocked to some extent in SZ patients [36].

Each omega-3 PUFA has various molecular effects, and EPA levels are several hundred-fold lower than DHA levels [37]. Studies confirmed the anti-inflammatory potential of DHA. However, DHA formulas did not improve schizophrenia symptoms, which suggest an abnormal or lack of response to its supplementation [38]. GPR120 insensitivity and changes in FAs metabolism could, to some extent, explain the better efficacy of EPA in SZ. In our study, we found numerous correlations between the intake of EPA and the concentration of blood PUFAs in patients, which we did not notice in the HC group. These findings may be the result of a different utilization of FAs in metabolic pathways.

Increasing ALA while simultaneously decreasing LA intake is effective in improving omega-3 PUFA status [39]. The scientific community suggests that the dietary ratio of omega-6/omega-3 PUFAs should be from 2:1 to 4:1; however, in the Western diet, the ratio ranges from 15:1 to 17:1 [39]. In our study, 85% of patients and 80% of healthy individuals had a ratio higher than 4:1, and the median ratio was 6.23:1 in the SZ group and 5.23:1 in the HC group. Taking into consideration the variation PUFA metabolism between patients and healthy subjects, it is possible that individuals with psychiatric disorders require a higher intake or different proportions of omega-3/omega-6 FAs for health benefits. The different recommended intake of PUFAs in the psychiatric population should be considered [40]. No differences in the intake of PUFAs between persons with schizophrenia and healthy volunteers was revealed. Nevertheless, we found improper intake of DHA and EPA in 97.5% of the SZ group and 97.5% of the HC group.

## **5. Conclusions**

Our consistent findings report lipid disturbances in schizophrenia patients. Interestingly, no changes in serum FAs or related markers were found. However, our results indicate different transformations and responses to FAs in schizophrenia. Based on our results, it is suggested that a diminished anti-inflammatory response could be a component connecting GPR120 insensitivity with schizophrenia. The interplay involving the inflammatory processes confirmed in psychiatric diseases, the limited ability to extinguish them, and the imbalance in PUFA diet could lead to the worsening course of schizophrenia, with increasing metabolic complication risk.

Further work should concentrate on finding lipid-based biomarkers and lipid-related interventions in patients suffering from schizophrenia. The modulation of lipid homeostasis is a promising target in managing psychiatric disorders.
