Disrupted leptin-fatty acid biosynthesis is an early manifestation of metabolic abnormalities in schizophrenia

Abstract

BACKGROUND Insulin resistance (IR) and impaired energy expenditure (IEE) are irreparable metabolic comorbidities in schizophrenia. Although mechanism(s) underlying IR and IEE remains unclear, leptin and fatty acid signaling, which has profound influence on insulin secretion/sensitivity, glucose metabolism and energy expenditure, could be disrupted. However, no association of plasma leptin with erythrocyte membrane fatty acids, body mass index (BMI), and psychotic symptoms in the same cohort of untreated patients with first-episode psychosis (FEP) or medicated patients with chronic schizophrenia (CSZ) is presented before. These studies are crucial for deciphering the role of leptin and fatty acids in the development of IR and IEE in schizophrenia. AIM To determine the association between plasma leptin, erythrocyte membrane fatty acids, particularly, saturated fatty acids (SFAs), BMI and psychotic symptoms in patients with FEP and CSZ. METHODS In this study, twenty-two drug naive patients with FEP, twenty-one CSZ patients treated with atypical antipsychotic drugs, and fourteen healthy control (CNT) subjects were analyzed. Plasma leptin was measured using sandwich mode enzyme-linked immunosorbent assay. Erythrocyte membrane SFAs were measured using ultrathin capillary gas chromatography. BMI was calculated by using the formula: weight (kg)/height (m 2 ). Psychiatric symptoms were evaluated at baseline using brief psychiatric rating scale (BPRS), and positive and negative syndrome scale (PANSS). The total BPRS scores, positive and negative symptom scores (PANSS-PSS and PANSS-NSS, respectively) were recorded. Pearson correlation coefficient ( r ) analyses were performed to find the nature and strength of association between plasma leptin, PANSS scores, BMI and SFAs, particularly, palmitic acid (PA). RESULTS In patients with FEP, plasma leptin not BMI was significantly lower ( P = 0.034), whereas, erythrocyte membrane SFAs were significantly higher ( P < 0.005) compared to the CNT subjects. Further, plasma leptin showed negative correlation with erythrocyte membrane SFAs-PA ( r = −0.4972, P = 0.001), PANSS-PSS ( r = −0.4034, P = 0.028), and PANSS-NSS ( r = −0.3487, P = 0.048). However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-PSS ( r = 0.5844, P = 0.0034) and PANSS-NSS ( r = 0.5380, P = 0.008). In CSZ patients, plasma leptin, BMI, and erythrocyte membrane SFAs, all were significantly higher ( P < 0.05) compared to the CNT subjects. Plasma leptin showed positive correlation with BMI ( ...

Metabolic complications of psychotropic medications in psychiatric disorders: Emerging role of de novo lipogenesis and therapeutic consideration

“…Adipocyte-macrophage inflammatory cascade, involving activated monocytes, could be the primary mediator of adipose tissue abnormalities induced by long-term treatment with psychotropic medications in patients with PDs[ 55 , 77 , 84 , 85 ]. In support of this, several studies including our own, have shown that membrane SFAs, fasting glucose, C-reactive protein, and adipokines including adiponectin and resistin are increased but leptin is decreased in patients with recent onset PDs[ 28 , 39 , 57 , 86 - 89 ]. Evidence suggests that while all fatty acids can inhibit adipokine/leptin production, effect of SAFs could be detrimental[ 12 , 57 , 89 , 90 ].…”

“…In support of this, several studies including our own, have shown that membrane SFAs, fasting glucose, C-reactive protein, and adipokines including adiponectin and resistin are increased but leptin is decreased in patients with recent onset PDs[ 28 , 39 , 57 , 86 - 89 ]. Evidence suggests that while all fatty acids can inhibit adipokine/leptin production, effect of SAFs could be detrimental[ 12 , 57 , 89 , 90 ]. In addition, elevated SAFs in adipocytes and intercalated macrophages can stimulate de novo biosynthesis of ceramides, which can further potentiate inflammatory effect of SFAs in adipose tissue by disrupting adipokine secretion and signaling in patients with PDs[ 21 , 86 , 91 , 92 ].…”

“…In addition to RBCs fatty acids, plasma free fatty acids and TG levels have also been found to be significantly increased after treatment with APs[ 54 - 56 ]. Changes in membrane fatty acids and TGs seem to be the result of enhanced DNL, and not due to binge eating or other confounders because; they showed strong association with cognitive and clinical symptom scores[ 37 - 39 , 57 ].…”

“…Although patients with PDs may have elevated risk for adipose tissue dysfunction from the early stage of illness, obesity usually develops or become more severe after treatment with psychotropic medication[ 72 , 73 , 76 , 77 ]. Adipose tissue is one of the two major sites for DNL under normal conditions, evidence suggests that adipose tissue DNL could be enhanced in patients with PDs[ 12 , 55 , 57 , 60 , 61 , 67 ]. Although adipocytes can synthesize and store excess lipids/fats without being inflammatory, insulin resistance has been associated with adipocyte hypertrophy and secretion of pro-inflammatory cytokines[ 78 - 80 ].…”

“…Even early intervention with psychotropic medications has been shown to trigger the development of various metabolic abnormalities in children and adolescents with PDs[ 124 , 125 ]. The mechanism(s) underlying these metabolic abnormalities remains to be documented; however, as discussed before that DNL dysregulation leading to fatty acid accumulation could be the likely mechanisms involved[ 7 , 12 , 57 ]. In support of this, several studies have shown that the levels of RBC’s SFAs and MUFAs are increased in patients with PDs after treatment with psychotropic medications compared to the untreated patients or control subjects[ 36 , 39 , 58 , 61 ].…”