Table 1.
Mechanisms of SGA-induced metabolic side effects.
| Reference | Experimental model | Molecular mechanism | Main effects |
|---|---|---|---|
| (18) | L6 rat skeletal muscle cell line | ↓ Insulin-stimulated IRS-1-associated PI3K activity↓ Phosphorylation of AKT and GSK-3 | ↑ Glycogen synthesis |
| (41) | 3T3-L1 cells | ↓ The maximal insulin-stimulated glucose transport and lipolysis rate | Insulin resistance and alterated lipogenesis and lipolysis |
| (42) | Male Sprague-Dawley rats (Adipocytes INWAT and SCWAT) | ↓ HSL and ↑ FAS expression | ↓ Lipolytic activity |
| (43) | In vitro ligand binding assays | Affinities for anorexigenic (bombesin receptor subtype 3, calcitonin gene-related peptide receptor, cholecystokinin receptor, melanocortin-4 receptor, neurotensin receptor 1) or orexigenic (cannabinoid receptor 1, galanin 1 receptor) and high affinity for 5-HT, 5-HT2A, 5-HT2C and 5-HT6, muscarinic M1, and H1Rs | Weight gain |
| (44) | Human pre-adipocytes and rat muscle-derived stem cells | Activation kinase C-β (PKC-β) | Weight gain for influence adipogenic events |
| (45–47) | Female Sprague-Dawley rats (Arc and DVC)34 male patientsFemale Sprague-Dawley rats (coronal hypothalamic sections) | ↓ Levels of POMC and ↑ NPY | Weight gain is associated with reduced appetite-inhibiting |
| (48) | Female Sprague-Dawley rats (Hypothalamus) | ↑ Phosphorylation levels of AMPK | Weight gain and hyperphagia |
| (49, 50) | Female Sprague-Dawley rats (coronal sections brains) | Blockade acetylcholine (ACh) muscarinic M3 receptor (M3R) | Inhibit the acetylcholine pathway for insulin secretion |
| (51) | Young male patients | ↑ Leptin and NPY levels | Weight gain |
| (52) | Male Sprague-Dawley rats (liver tissue) | ↓ IRS2 levels, ↓ phosphorylation of GSK3α, and ↑ phosphorylation of GSK3β | Disturbances of glucose homeostasis (suggest an increased activity of glycogen synthase, and therefore, an increased insulin sensitivity) |
| (53) | Male 6-week-old ICR mice (hypothalamus) | Activates hypothalamic AMPK by antagonizing H1Rs, dopamine D2 receptors and α1-adrenoceptors | Hyperglycemia |
| (54) | Female Sprague-Dawley rats (liver or perirenal WAT) | ↑ mRNA expression of SREBP-2 and target genes for cholesterol synthesis and transports. ↑ mRNA expression of SREBP-1c and its targeted fatty acid-related genes | Dyslipidemia |
| (55) | The glucose transporter from Staphylococcus epidermidis (GlcPSe) | The glucose transporter from Staphylococcus epidermidis (GlcPSe) | ↓ Glucose transport |
| (56, 57) | Female Sprague-Dawley rats (brain; hypothalamus) | ↑ Expression of HDC mRNA and ↑ the hypothalamic H1R binding; activates AMPK by blocking the H1Rs | Hyperphagia and weight gain |
| (58) | Female Sprague-Dawley rats (liver) | ↓ AKT/GSK phosphorylation and upregulate muscarinic M3 receptors. ↑ The protein levels of SREBPs | Disturbances negative in glucose-lipid metabolic independent of weight gain |
| (59) | Primary human peripheral blood mononuclear cells | ↓ Glucose uptake accompanied by downregulation AMPK. ↑ GLUT1 protein expression, ↓ GLUT1 mRNA expression, and GLUT1 promoter was hypermethylated. ↓ PDH complex activity | ↓ Glucose uptake and affect energy metabolism |
| (60) | Female C57BL/6—Htr2c-null mice | Interaction with HTR2C in C57bL/6 and no interaction in Htr2c-null mice | Hyperphagia and weight gain |
IRS, insulin receptor substrate (60); PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; AMPK, 5′ adenosine monophosphate-activated protein kinase; AKT, protein kinase B; GSK-3, glycogen synthase kinase 3; HSL, hormone-sensitive lipase; FAS, fatty acid synthase; 5-HT, serotonin or 5-hydroxytryptamine; POMC, pro-opiomelanocortin; NPY, neuropeptide Y; SREBPs, sterol regulatory element-binding proteins; HDC, histidine decarboxylase; H1R, histamine H1 receptor; PDH, pyruvate dehydrogenase; HTR2C, encodes the 5-HT 2C receptor; SGA, Second generation antipsychotic.