Mirtazapine Reduces Adipocyte Hypertrophy and Increases Glucose Transporter Expression in Obese Mice

Abstract

Metabolic syndrome is known to engender type 2 diabetes as well as some cardiac, cerebrovascular, and kidney diseases. Mirtazapine—an atypical second-generation antipsychotic drug with less severe side effects than atypical first-generation antipsychotics—may have positive effects on blood glucose levels and obesity. In our executed study, we treated male high-fat diet (HFD)-fed C57BL/6J mice with mirtazapine (10 mg/kg/day mirtazapine) for 4 weeks to understand its antiobesity effects. We noted these mice to exhibit lower insulin levels, daily food efficiency, body weight, serum triglyceride levels, aspartate aminotransferase levels, liver and epididymal fat pad weight, and fatty acid regulation marker expression when compared with their counterparts (i.e., HFD-fed control mice). Furthermore, we determined a considerable drop in fatty liver scores and mean fat cell size in the epididymal white adipose tissue in the treated mice, corresponding to AMP-activated protein kinase expression activation. Notably, the treated mice showed lower glucose tolerance and blood glucose levels, but higher glucose transporter 4 expression. Overall, the aforementioned findings signify that mirtazapine could reduce lipid accumulation and thus prevent HFD-induced increase in body weight. In conclusion, mirtazapine may be useful in body weight control and antihyperglycemia therapy.

Risperidone Exacerbates Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Renal Impairment in Obese Mice

“…Moreover, the increase in number of large adipocytes due to risperidone treatment may be attributable to the ability of chronic risperidone treatment to suppress energy expenditure through reductions in total resting metabolic rate and nonaerobic metabolism in mice [ 39 ]. Another explanation for this result is risperidone’s promotion of fat adipogenesis, which accords with reported findings that risperidone can increase or activate adipogenic marker gene expression—such as through protein kinases A and C-β, tumor growth factor-β, extracellular signal-related kinase (ERK) 1/2, or hormone-sensitive lipase expression—which in turn influences lipogenesis and HFD-induced adipocyte hypertrophy [ 25 , 40 , 41 , 42 ]. Moreover, the synthesis of leptin, a food intake regulation hormone produced in hypothalamus, predominantly occurs in white adipose tissue (WAT) [ 24 ].…”

“…The serum and hepatic triglyceride levels were 27% ( Figure 5 a) and 28% ( Figure 5 b) in the treated mice than in the control mice. Fatty acid synthase (FASN) is a crucial liver enzyme for lipid homeostasis and triglyceride synthesis [ 23 ], whereas patatin-like phospholipid domain containing protein 3 (PNPLA3) is a pathologic marker for lipogenesis regulation in obesity, nonalcoholic fatty liver disease, and cardiovascular disease [ 25 ]. Western blot analysis ( Figure 5 c) indicated that hepatic FASN and PNPLA3 expression was 42% ( Figure 5 d) and 17% ( Figure 5 e) higher in the treated mice than in the control mice.…”

“…To assess IR and IS, we used the homeostatic model assessment for IR (HOMA-IR) and IS indices, respectively [ 25 , 35 , 36 ]—which demonstrated 71% increase and 36% decreased in the treated mice compared with the control mice, respectively ( Figure 7 a and Figure 7 b, respectively). Evaluation of the effects of risperidone on insulin signaling in muscles indicated reduced Akt activation and glucose transporter 4 (GLUT4) expression after risperidone treatment ( Figure 7 c).…”

“…Fat accumulation in the liver may lead to fatty liver disease and subsequently cause elevations in liver enzymes and hepatic injury markers, such as ALT and AST [ 25 , 47 ]. The degree of liver involvement ranges from simple steatosis to steatohepatitis and finally to cryptogenic cirrhosis [ 47 ].…”

“…Triglycerides have been proposed to potentially be a major factor in IR pathogenesis—the main type 2 diabetes (T2D) predictor [ 24 ]. Moreover, hyperinsulinemia and glucose intolerance, which are commonly observed with IR, may cause intrahepatic triglyceride overproduction in patients with nonalcoholic fatty liver disease [ 25 , 26 ]. Studies have estimated that patients with medication-treated schizophrenia have an approximately threefold higher risk of metabolic syndrome compared with community and clinical samples from the general population and that the prevalence of metabolic syndrome among this population, including IR, rapid weight increase, diabetes, elevated cardiovascular risk, and dyslipidemia, is 14.7–68% [ 27 , 28 ].…”