Role of de novo lipogenesis in insulin resistance in first-episode psychosis and therapeutic options

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

“…Palmitic acid and stearic acid can be further elongated and desaturated to give higher MUFAs including nervonic acid as the terminal product[ 33 - 35 ]. Although under normal physiological conditions DNL is a tightly regulated process, enhanced DNL has been associated with various metabolic diseases[ 35 ], which could be a likely scenario in patients with PDs treated with psychotropic medications[ 12 ].…”

“…Evidence suggests that DNL is essential for brain and peripheral tissue development and metabolic homeostasis[ 40 - 43 ]. However; enhanced DNL has been associated with inflammation and various metabolic abnormalities including insulin resistance/diabetes, obesity, and NAFLD[ 12 , 13 , 34 , 35 , 44 - 48 ]. Since psychotropic medi-cations have been shown to induce or exaggerate these metabolic abnormalities, enhanced DNL could be a major mediator.…”

“…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 ].…”

“…While psychotropic medications including antipsychotic drugs (APs) and antidepressants (ADs) can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce the development or exacerbate various pre-existing metabolic abnormalities including insulin resistance, adiposity/obesity and non-alcoholic fatty liver disease (NAFLD)[ 5 - 8 ]. Evidence suggests that oxidative stress and inflammation could be the major risk factors associated with various metabolic abnormalities in PDs; however, the underlying mechanisms remain(s) unclear[ 8 - 12 ]. Finding the underlying mechanism(s) could play a crucial role in developing effective therapies/drugs for minimizing the development of various metabolic abnormalities and improving treatment outcome and the quality of life in patients with PDs.…”

“…Over the years several mechanisms have been sown to induce oxidative stress and inflammation and associated metabolic abnormalities, they are triggered initially by the accumulation of intracellular fatty acids synthesized via de novo pathway/ de novo lipogenesis (DNL)[ 12 - 19 ]. Although DNL produces both saturated fatty acids (SAFs) and monounsaturated fatty acids (MUFAs), evidence suggest that effect of SAFs on metabolic abnormalities could be detrimental as they increase oxidative stress and inflammation by disrupting calcium homeostasis, endoplasmic reticulum (ER) and mitochondrial function, whereas, MUFAs can induce metabolic abnormalities, specially, insulin resistance even without increasing oxidative stress and inflammation[ 17 - 21 ].…”