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Context: Clinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the collagenopathies) have been reported to be associated with short stature and skeletal dysplasias. Etiological diagnosis of skeletal abnormality-related short stature is challenging, and less is known about recombinant human growth hormone (rhGH) therapy. Objective: This is a single-center cohort study which aims at exploring the genetic architecture of short-stature children with skeletal abnormalities and evaluating the frequency of collagenopathies to determine their phenotype, including the rhGH treatment response. Patients and Methods: One hundred and six children with short stature and skeletal abnormalities were enrolled who were evaluated by next-generation sequencing (NGS) to detect variants in the skeletal collagen genes including COL1A1, COL1A2, COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1 , and COL11A2. The results were evaluated using American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical characteristics and rhGH treatment response were summarized. Results: Twenty-four pathogenic or likely pathogenic variants of collagen genes were found in 26 of 106 (24.5%) short-stature patients with skeletal abnormalities, of which COL2A1 mutations were the most common, accounting for about 57.7%. Other frequent mutations associated with skeletal development include FGFR3 , ACAN , NPR2 , COMP , and FBN1 in 12.2%, 0.9%, 0.8%, 0.4%, and 0.4%, respectively, resulting in significantly different degrees of short stature. An overview of clinical features of collagenopathies showed growth retardation, skeletal abnormalities, and heterogeneous syndromic abnormalities involving facial, eye, hearing, and cardiac abnormalities. The average height of 9 patients who received rhGH treatment improved from a median of -3.2 ± 0.9 SDS to -2.2 ± 1.3 SDS after 2.8 ± 2.1 years. The most significant height improvement of 2.3 SDS and 1.7 SDS was also seen in two patients who had been treated for more than 6 years. Conclusions: A proband-based NGS revealed that distinct genetic architecture underlies short stature in varying degrees and clinical features. Skeletal abnormality-related short stature involving multiple systems should be tested for skeletal collagen gene mutation. Limited rhGH treatment data indicate an improved growth rate and height, and close monitoring of adverse reactions such as scoliosis is required. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the bone turnover markers and bone microarchitecture parameters derived from high-resolution peripheral quantitative computed tomography (HR-pQCT) in active and controlled acromegaly patients. Methods: This cross-sectional study involved 55 acromegaly patients from a tertiary hospital (23 males and 32 females, aged 45.0 ± 11.6 years). Firstly, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and markers for bone turnover were assessed. Next, we derived peripheral bone microstructure parameters and volumetric bone mineral density (vBMD) through HR-pQCT. These parameters were compared between acromegaly patients and 110 healthy controls, as well as between 27 active and 28 controlled acromegaly patients. Moreover, the relationship between GH/IGF-1 and bone microstructure parameters was analyzed through multiple linear regression. Results: As compared with healthy controls, acromegaly patients exhibited elevated cortical vBMD, reduced trabecular vBMD, and increased trabecular inhomogeneity in the distal radius and tibia. While controlled acromegaly patients had slower bone turnover, they did not necessarily have better bone microstructure relative to active patients in intergroup comparison. Nevertheless, multiple regression indicated that higher IGF-1 was associated with lower tibial stiffness and failure load. Additionally, males with higher IGF-1 typically had larger trabecular separation, lower trabecular number, and larger cortical pores in the radius. Moreover, patients with elevated GH typically had more porous cortical bone in the radius and fewer trabeculae in the tibia. However, the compromised bone strength in active patients was partially compensated by increased bone thickness. Furthermore, no significant linkage was observed between elevated GH/IGF-1 and the most important HR-pQCT parameters such as trabecular volumetric bone density. Conclusion: Acromegaly adversely affected bone quality, even in controlled patients. As the deterioration in bone microstructure due to prolonged GH/IGF-1 exposure was not fully reversible, clinicians should be aware of the bone fragility of acromegaly patients even after they had achieved biochemical remission. [ABSTRACT FROM AUTHOR]

Purpose: Laron syndrome (LS) is a severe growth disorder caused by GHR gene mutation or post-receptor pathways defect. The clinical features of these patients collected in our present study were summarized, GHR gene variants were investigated and further in vitro functional verification was carried out. Methods: Four patients with LS were collected, their clinical characteristics were summarized, genomic DNA was extracted, and GHR gene was amplified and sequenced. GHR wild type (GHR-WT) and mutant GHR expression plasmids were constructed, and transiently transfected into HepG2 cells and HEK293T cells to observe the subcellular distribution of the GHR protein by immunofluorescence and to determine the expression of GHR and its post-receptor signaling pathway changes by Western blotting. Results: All of the four patients were male, and the median height was -4.72 SDS. Four GHR gene variants including c.587A>C (p.Y196S), c.766C>T (p.Q256*), c.808A>G (p.I270V) and c.1707-1710del (p.E570Afs*30) were identified, and the latter two were novel mutations. The results of mutant GHR plasmids transfection experiments and immunofluorescence assay showed that the subcellular distribution of GHR-Q256* and GHR-E570Afs*30 mutant proteins in HepG2 and HEK293T cells presented with a unique ring-like pattern, gathering around the nucleus, while GHR-Y196S mutant protein was evenly distributed on HepG2 cell membrane similar to GHR-WT. The GHR protein levels of HepG2 cells transiently transfected with GHR-Y196S, GHR-Q256* and GHR-E570Afs*30 were all significantly lower when compared with cells transfected with GHR-WT (P<0.05). Further mutant GHR post-receptor signal transduction investigation demonstrated that GH induced phosphorylated STAT5 levels of HepG2 cells transfected with three mutant plasmids were all significantly decreased in comparison with that of GHR-WT (P<0.05). Conclusions: Two novel GHR gene mutations (I270V and E570Afs*30) were found in our patients with LS. GHR mutations influenced the subcellular distribution and GHR protein levels, then led to the impaired post-receptor signal transduction, suggesting that the GHR mutations contributed to the pathological condition of LS patients. [ABSTRACT FROM AUTHOR]

Epigenetic factors have been proven to contribute to pituitary adenoma formation. 5-hydroxymethylcytosine (5hmC), which is catalyzed by ten-eleven translocation 2 (TET2), is related to DNA demethylation. In order to explore the pathogenesis of non-functioning pituitary adenomas (NFPAs), we detected genomic 5hmC levels in 57 NFPAs and 5 normal pituitary glands, and TET2 expression, distribution and TET2 alteration. Genomic 5hmC levels in NFPAs were significantly lower than those in normal pituitary glands (0.38‰ (0.24‰, 0.61‰) vs. 2.47‰ (1.56‰, 2.83‰), P < 0.0001). There was positive correlation of 5hmC levels with TET2 total and nuclear expression in NFPAs (r = 0.461, P = 0.018; r = 0.458, P = 0.019). Genomic 5hmC levels in NFPAs with TET2 p.P29R were significantly lower than those in wild type NFPAs (0.33 ± 0.18‰ vs. 0.51 ± 0.25‰, P = 0.021). We found genomic 5hmC loss in human NFPAs for the first time. Genomic 5hmC levels may be affected by TET2 expression, subcellular localization and TET2 mutation. [ABSTRACT FROM AUTHOR]

Purpose: Oxidative stress plays an important role in the pathogenesis of obesity and its associated disorders. Safflower yellow (SY) and hydroxysafflor yellow A (HSYA), the natural compounds isolated from Carthamus tinctorius L. , has been found to possess antioxidative and anti-obesity properties. The purpose of the present study is to investigate whether SY and its main component HSYA alleviate obesity by the antioxidant effects. Methods: Diet-induced obese (DIO) mice were treated with 200 mg/kg/d SY or HSYA for 10 weeks. Body weight, fat mass, serum biochemical parameters and superoxide dismutase (SOD) activities were measured. Glucose and insulin tolerance tests were performed. The expression of antioxidant enzymes in liver and adipose tissue were measured. In vitro, H2O2-induced oxidative stress HepG2 cells and 3T3-L1 adipocytes were treated with SY and HSYA to investigate the direct effects of SY and HSYA on the expression of antioxidant enzymes. Results: SY and HSYA significantly decreased the body weight gain of DIO mice, and decreased fat mass to 57.8% and 61.6% of the control mice, respectively (P < 0.05). The parameters of glucose metabolism and liver function were improved after SY and HSYA treatment. The hepatic SOD activities and the mRNA levels of antioxidant enzymes in liver and adipose tissue of SY and HSYA treated mice were increased (P < 0.05). Meanwhile, the administration of SY and HSYA on the H2O2-induced oxidative stress HepG2 cells and adipocytes also increased the expression of the antioxidant factor and antioxidant enzymes to 1.2~3.3 folds of the control cells (P < 0.05). Conclusion: SY and its main component HSYA could significantly decrease the fat mass, and improve glucose metabolism and liver function in diet-induced obese mice. The beneficial effects of SY and HSYA on obesity and metabolism may be associated with the increased expression of antioxidant enzymes in liver and adipose tissue. [ABSTRACT FROM AUTHOR]

Background: The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis plays an important role in brain structure and maintenance of brain function. There is a close correlation between serum GH and IGF1 levels and age-related cognitive function. The effects of childhood-onset growth hormone deficiency (GHD)on brain morphology are underestimated so far. Methods: In this cross-sectional study, T1-weighted magnetic resonance imaging was assessed in 17 adult males with childhood-onset GHD and 17 age and gender-matched healthy controls. The cortical thickness was analyzed and compared between the two groups of subjects. Effects of disease status and hormone levels on cortical thickness were also evaluated. Results: Although there was no difference in whole brain volume or gray matter volume between the two groups, there was decreased cortical thickness in the parahippocampal gyrus, posterior cingulate gyrus and occipital visual syncortex in the adult growth hormone deficiency (AGHD) group, and increased cortical thickness in a partial area of the frontal lobe, parietal lobe and occipital visual syncortex in AGHD group. Cortical thickness of the posterior cingulum gyrus was prominently associated with FT3 serum levels only in control group after adjusting of IGF-1 levels. Conclusion: These results suggest that young adult male patients with childhood-onset GHD have alterations in cortical thickness in different brain lobes/regions. [ABSTRACT FROM AUTHOR]

Objective: Ghrelin is a 28-amino-acid peptide that regulates energy hemostasis, glucose and lipid metabolism. We aimed to explore the effects of ghrelin on the proliferation and differentiation of 3T3-L1 and human primary preadipocytes. Methods: 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) spectrophotometry, Oil Red O staining, intracellular glycerol-3-phosphate dehydrogenase (G-3-PDH) assays and semiquantitative reverse transcription polymerase chain reaction were used to investigate the action of ghrelin. Results: Ghrelin (0.01–1000 ng/ml) significantly increased the numbers of 3T3-L1 cells, and the maximum stimulatory effect was observed with the 10 ng/ml ghrelin treatment for 24 h (p < 0.05). Ghrelin also promoted the proliferation of human primary preadipocytes from 24 h (p < 0.05) to 48 h (p < 0.05) at a concentration of 1000 ng/ml. Further investigation showed that IGF-1 levels were notably increased in ghrelin-treated 3T3-L1 and human preadipocytes, and IGF-1 antibody was capable to attenuate this stimulatory action of ghrelin (all p < 0.05). Additionally, ghrelin significantly suppressed the differentiation of 3T3-L1 and human primary preadipocytes; 10 ng/ml ghrelin notably downregulated G-3-PDH activities in 3T3-L1 cells on day 3 and in human cells from days 4 to 12 following differentiation (all p < 0.05), and the intracellular lipoprotein lipase mRNA levels were lower than that of the controls (p < 0.05). Further investigation showed that the mRNA levels of peroxisome proliferator-activated receptor γ2 (PPARγ2) and CCAAT/enhancer binding protein α (C/EBPs) were also suppressed in ghrelin-treated human differentiating adipocytes. Conclusion: Ghrelin promotes the proliferation of 3T3-L1 and human primary preadipocytes by increasing the expression of IGF-1. Ghrelin inhibits murine and human adipocyte differentiation by downregulating PPARγ2 and C/EBPα levels, consequently leading to decreased lipid accumulation and lipogenic enzymes expression. [ABSTRACT FROM AUTHOR]

Objectives: To explore serum zinc-α2-glycoprotein (ZAG) changes in patients with or without premature coronary artery disease (PCAD) and its association with several cardiovascular risk factors. Methods: A total of 3,364 patients who were undergone coronary angiography in Peking Union Medical College Hospital were screened. According to the degree of coronary artery stenosis, the number of 364 patients with PCAD (age <55 years in males and <65 years in females) and 126 age and gender matched patients without premature coronary artery disease (NPCAD) were recruited in our present study. In addition, 182 age and gender matched healthy controls were also enrolled. Serum ZAG levels were determined by enzyme-linked immunosorbent assay (ELISA) method. Results: Serum ZAG were significantly lower in the PCAD (8.03 ± 1.01 vs. 8.78 ± 1.89 μg/mL, p < 0.05) and NPCAD groups (8.28 ± 1.61 vs. 8.78 ± 1.89 μg/mL, p < 0.05), respectively, when compared with the controls. Multiple regression analysis showed that PCAD was independently associated with serum ZAG levels (B = −0.289, p = 0.002). The probability of PCAD in subjects with low tertile ZAG levels was 2.48-fold higher than those with high tertile levels after adjusting for other confounders [OR = 3.476, 95% CI 1.387–8.711, p = 0.008]. This phenomenon was more likely to be observed in male subjects with BMI <24 kg/m2. The receiver operating curve (ROC) analysis showed a weak diagnostic performance of serum ZAG for PCAD (AUC = 0.659, 95% CI 0.612–0.705, p < 0.05). At the cutoff value of 7.955 μg/mL serum ZAG, the sensitivity and specificity for differentiating patients with PCAD from controls were 50.5 and 78.0%, respectively. The combination of ZAG with other clinical variables including age, gender, BMI, SBP, FBG, TC, HDL-C, Cr, and Urea had significantly improved the diagnosis accuracy with a sensitivity of 82.6%, a specificity of 95.0%, and AUC of 0.957 (95% CI, 0.940–0.975, p < 0.05). Conclusion: Serum ZAG levels were firstly found to be decreased in Chinese PCAD patients. Subjects with lower ZAG levels were more likely to have PCAD, especially for male subjects with BMI <24 kg/m2. ZAG might be the potential diagnostic biomarkers for PCAD patients, and the combination of ZAG and clinical variables had higher discriminative performance. [ABSTRACT FROM AUTHOR]

Objectives: To explore the activating transcription factor 3 (ATF3) and fibronectin type III domain-containing protein 5 (FNDC5)/irisin protein levels in serum and mRNA levels in subcutaneous and visceral white adipose tissue (sWAT and vWAT) in normal-weight (NW) and overweight/obese (OW/OB) patients with colorectal cancer (CRC). Methods: 76 CRC patients and 40 healthy controls were recruited. Serum ATF3 and irisin levels were detected by using ELISA kits, and the mRNA expression levels in sWAT and vWAT were measured by performing RT-qPCR. Results: The serum ATF3 levels were greater by 37.2%, whereas the irisin levels were lower by 23.3% in NW+CRC patients compared with those in healthy controls. CRC was independently associated with both ATF3 and irisin levels. The probability of CRC greater by 22.3-fold in individuals with high ATF3 levels compared with those with low ATF3 levels, whereas the risk of CRC in subjects with high irisin levels was lower by 78.0% compared to the risk in those with low irisin levels after adjustment for age, gender, BMI, and other biochemical parameters. Serum ATF3 and irisin could differentiate CRC patients from controls with receiver operating characteristic (ROC) curve areas of 0.745 (95% CI, 0.655–0.823) and 0.656 (95% CI, 0.561–0.743), respectively. The combination of ATF3 and irisin exhibited improved diagnosis value accuracy with ROC curve areas of 0.796 (95% CI, 0.710–0.866) as well as 72.6% sensitivity and 80.0% specificity. Conclusion: Increased ATF3 and reduced irisin levels were observed in sera from CRC patients. Individuals with high ATF3 and low irisin levels were more likely to have CRC. ATF3 and irisin represent potential diagnostic biomarkers for CRC patients. [ABSTRACT FROM AUTHOR]

Objectives: To explore zinc-α2-glycoprotein (ZAG), leptin, high-molecular-weight adiponectin (HMW-ADPN), and tumor necrosis factor-alpha (TNF-α) levels in serum and subcutaneous and visceral white adipose tissue (sWAT and vWAT) among normal weight (NW) and overweight/obese (OW/OB) patients with colorectal cancer (CRC). Methods: A total of 76 Chinese CRC patients (42 NW + CRC, 34 OW/OB + CRC) and 40 healthy controls were recruited. Serum levels of the adipokines of interest were measured by an enzyme-linked immunosorbent assay method, and their mRNA levels in sWAT and vWAT were determined by reverse transcription quantitative PCR methods. results: Serum ZAG levels in the NW + CRC group were significantly increased by 11.7% compared with the healthy controls. Serum leptin levels in the OW/OB + CRC group were found to be increased by 57.7%, while HMW-ADPN levels were decreased by 23.5% when compared with the NW + CRC group of CRC patients. Additionally, ZAG mRNA levels in sWAT were significantly reduced by 78.8% in OB + CRC in comparison with NW + CRC patients. ZAG mRNA levels were negatively associated with body mass index (BMI) in sWAT but positively correlated with BMI in vWAT. TNF-α mRNA levels in vWAT of OB + CRC patients were significantly increased by 2.8-fold when compared with NW + CRC patients. In particular, CRC was independently associated with serum ZAG levels. The risk of CRC in participants with high tertile serum ZAG levels was 5.84-fold higher than in those with low tertile ZAG levels after adjusting for age, gender, and other confounders [odds ratio (OR) = 6.84, 95% confidence interval (CI) 1.70--27.54, P = 0.03]. The CRC risk in participants with high tertile leptin levels was only 10.7% of those with low tertile leptin levels (OR = 0.11, 95% CI 0.01--0.89, P = 0.04). The area under the receiver operating characteristic (ROC) curve of ZAG was 0.66 (95% CI 0.54--0.77, P < 0.05). At the cutoff value of 1.42 μg/mL serum ZAG, the sensitivity and specificity for differentiating patients with CRC from controls were 62.2 and 69.2%, respectively. Conclusion: Serum ZAG levels were significantly increased in CRC patients. Subjects with higher circulating ZAG and lower leptin levels were more likely to have CRC than those with lower ZAG and higher leptin levels. Serum ZAG might be a potential diagnostic biomarker for CRC in the Chinese population. [ABSTRACT FROM AUTHOR]

Objective: Ileal transposition (IT) surgery has been reported to improve glucose and lipid metabolism, and fibroblast growth factor 21 (FGF21) is a powerful metabolic regulator. In the present study, we aimed to investigate the effects of IT surgery on metabolism and its possible relationship with the FGF21 signaling pathway in diabetic Goto-Kakizaki (GK) rats. Methods: Ten-week-old male GK rats were subjected to IT surgery with translocation of a 10 cm ileal segment to the proximal jejunum (IT group) or sham surgery without the ileum transposition (Sham-IT group). Rats in the no surgery group did not receive any surgical intervention. Six weeks later, body weight, fat mass, fasting blood glucose (FBG), and serum levels of FGF21 and leptin were measured. The expression of the FGF21 signaling pathway and white adipose tissue (WAT) browning-related genes in the WAT and liver were evaluated by real-time reverse transcription polymerase chain reaction (RT-qPCR) and western blot. Results: IT surgery significantly decreased the body weights and FBG levels and increased the insulin sensitivity of GK rats. The total WAT mass of the IT rats showed a 41.5% reduction compared with the Sham-IT rats, and serum levels of FGF21 and leptin of the IT rats decreased by 26.3 and 61.7%, respectively (all P < 0.05). The mRNA levels of fibroblast growth factor receptor 1 (FGFR1) and its co-receptor b klotho (KLB) in the perirenal WAT (pWAT) of the IT rats were 1.4- and 2.4-fold that of the Sham-IT rats, respectively, and the FGFR1 protein levels were 1.7-fold of the Sham-IT rats (all P < 0.05). In accordance with the pWAT, the protein levels of FGFR1 and KLB in the epididymal WAT (eWAT) of the IT rats notably increased to 3.0- and 3.9-fold of the Sham-IT rats (P < 0.05). Furthermore, uncoupling protein 1 (UCP1) protein levels in the eWAT and pWAT of the IT rats also increased to 2.2- and 2.3-fold of the Sham-IT rats (P < 0.05). However, the protein levels of FGFR1 and KLB in the subcutaneous WAT (sWAT) of the IT rats decreased by 34.4 and 72.1%, respectively, compared with the Sham-IT rats (P < 0.05). In addition, the protein levels of FGF21 and KLB in the livers of IT rats were 3.9- and 2.3-fold of the Sham-IT rats (all P < 0.05). Conclusions: IT surgery significantly decreased fat mass and improved glucose metabolism in diabetic GK rats. These beneficial roles of IT surgery were probably associated with its stimulatory action on the expression of FGFR1 and KLB in both the eWAT and the pWAT, thereby promoting UCP1 expression in these tissues. [ABSTRACT FROM AUTHOR]

Zinc-α2-glycoprotein (ZAG) plays an important role in the regulation of body weight, body fat, and glucose metabolism. In this study, we first measured ZAG levels in serum and ZAG mRNA levels in subcutaneous white adipose tissue (sWAT) among overweight/obese patients and lean control subjects. Second, we investigated the effects of ZAG administration on the body weight, body fat and glucose metabolism of high-fat diet (HFD)-induced obese ICR mice and the possible mechanisms involved. The results showed that serum ZAG and mRNA levels in sWAT were significantly decreased in overweight/obese patients and that both showed a negative association with body mass index (BMI) and body weight after adjustment for age and sex. Further partial correlation analysis found that ZAG mRNA expression was positively related with several WAT browning-related genes, including uncoupling protein 1 (UCP1) (r = 0.67) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1a) (r = 0.60), in the sWAT of all subjects. Additionally, intraperitoneal injection of a ZAG expression plasmid (5 µg/injection, four times a week) in HFD-induced obese mice for 8 weeks demonstrated that ZAG overexpression significantly decreased body weight and WAT mass, and greatly increased the glucose tolerance of obese mice, as shown by the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT). The staining of UCP1-positive adipocytes was significantly stronger in the sWAT of ZAG-treated obese mice than in that of obese control mice. The mRNA and protein levels of PGC1α in sWAT were significantly increased to 2.2- and 5.3-fold, respectively, compared with HFD obese mice, and there was a strong positive correlation between the expression levels of Zag and Pgc1α in mouse sWAT (r = 0.74). A similar phenomenon was also observed in visceral white adipose tissue (vWAT): the mRNA and protein levels of PGC1α were increased to 1.9- and 3.6-fold, respectively, when obese mice were treated with ZAG. In conclusion, ZAG levels in both sWAT and serum are inversely related with BMI and body weight in Chinese subjects. The action of ZAG on body weight, fat mass and glucose metabolism may be realized through activating PGC1α expression in sWAT and vWAT, then promoting WAT browning in obese mice. [ABSTRACT FROM AUTHOR]

Short stature, skeletal abnormalities, collagenopathies, next-generation sequencing, growth hormone treatment Also, in the B Results b , subsection " I Comparison of Collagen Gene-Related Short Stature With Other Short Stature Genes and Growth Response to rhGH Treatment i ", final paragraph, incorrect height Z scores were presented. Keywords: short stature; skeletal abnormalities; collagenopathies; next-generation sequencing; growth hormone treatment EN short stature skeletal abnormalities collagenopathies next-generation sequencing growth hormone treatment 1 1 1 04/08/22 20220406 NES 220406 In the B Results b , subsection " I Comparison of Collagen Gene-Related Short Stature With Other Short Stature Genes and Growth Response to rhGH Treatment i ", paragraph 2 as published originally, B Table 4 b was incorrectly cited. [Extracted from the article]

Purposes: Nuciferine, a main aporphine alkaloid component found in lotus leaf (Nelumbo nucifera), has been demonstrated to possess the property of reducing fat mass and alleviating dyslipidemia in vivo. The purpose of this study is to explore the effects of nuciferine on the proliferation and differentiation of 3T3-L1 cells and further investigate the possible underlying molecular mechanisms. Methods: 3T3-L1 preadipocytes were treated with 0∼20 μM nuciferine for 24∼120 h, the cell viability was assessed using CCK8. 3T3-L1 preadipocytes and human primary preadipocytes were then induced differentiation and the effects of nuciferine on the lipid metabolism in differentiating and fully differentiated adipocytes were observed by the methods of intracellular triglyceride (TG) assay, Oil Red O staining, RT-qPCR and western blot. Transient transfection and dual luciferase reporter gene methods were used to assess the effects of nuciferine on FAS promoter activities. Results: Nuciferine inhibited the proliferation of 3T3-L1 preadipocytes in a dose- and time-dependent manner. 20 μM nuciferine significantly attenuated lipid accumulation and reduced intracellular TG contents by 47.2, 59.9 and 55.4% on the third, sixth and ninth day of preadipocytes differentiation, respectively (all p < 0.05). Moreover, the mRNA levels of PPARγ, C/EBPα, C/EBPβ, FAS, ACC, HSL and ATGL were notably decreased by 39.2∼92.5% in differentiating preadipocytes when treated with 5∼20 μM nuciferine (all p < 0.05). In fully differentiated adipocytes treated with 20 μM nuciferine for 48 h, the mRNA levels of FAS, ACC and SREBP1 were remarkably downregulated by 22.6∼45.2% compared with the controls (0 μM) (all p < 0.05), whereas the expression of adipokines FGF21 and ZAG were notably promoted by nuciferine. Similarly, in fully differentiated human primary adipocytes, the mRNA levels of FAS, ACC, SREBP1 were decreased and the expression of FGF21 and ZAG were elevated after treated with nuciferine (all p < 0.05). Further mechanism studies showed that 2.5∼20 μM nuciferine significantly decreased FAS promoter activities in 3T3-L1 preadipocytes. Conclusion: Nuciferine inhibited the proliferation and differentiation of 3T3-L1 preadipocytes. The inhibitory effects of nuciferine on adipogenesis might be due to the downregulation of PPARγ, C/EBPα and C/EBPβ, which led to the reduction of intracellular lipid accumulation in 3T3-L1 cells and by downregulating the expression of critical lipogenic enzymes, especially of FAS, which was achieved by inhibiting the FAS promoter activities. Besides, nuciferine promoted the expression of adipokines in fully differentiated adipocytes. [ABSTRACT FROM AUTHOR]