PMID- 37293734
OWN - NLM
STAT- Publisher
LR  - 20230609
IS  - 0578-1426 (Print)
IS  - 0578-1426 (Linking)
VI  - 62
DP  - 2023 Jun 9
TI  - [Effects of small GTP-binding protein GDP dissociation stimulator on adipocyte 
      hypertrophy and glucose metabolism disorder in mice].
PG  - 833-840
LID - 10.3760/cma.j.cn112138-20230209-00072 [doi]
AB  - Objective: To explore the effect and mechanism of small GTP-binding protein GDP 
      dissociation stimulator (SmgGDS) on the development of obesity. Methods: (1) 
      8-week-old C57BL/6J mice were randomly assigned to normal diet and high fat diet 
      group, with 6 mice in each group. They were fed regular feed and a high fat diet 
      containing 60% fat for 4 months, respectively. The expression of SmgGDS in 
      epididymal adipose tissue (eWAT), liver, and skeletal muscle were measured using 
      Western-blot. (2) 6-week-old wild-type (WT) and SmgGDS knockdown (KD) mice were 
      divided into four groups, each receiving high fat diet for 4 months (7 in each 
      group) and 7 months (9 in each group). Glucose tolerance test (GTT) and insulin 
      tolerance test (ITT) were conducted; The weight, adipose tissue, and liver weight 
      of mice were recorded; HE staining examined adipose tissue structural changes; 
      Western-blot determined extracellular signal-regulated kinase (ERK) 1/2 
      phosphorylation levels in eWAT; Real time fluorescence quantitative polymerase 
      chain reaction (RT-qPCR) was used to detect mRNA levels of CCAAT/enhancer binding 
      protein alpha (C/EBPalpha), C/EBPbeta and peroxisome proliferator activated receptor gamma 
      (PPARgamma) in eWAT. (3) Mouse embryonic fibroblasts (MEFs) extracted from WT and KD 
      mice were induced for differentiation. Oil red O staining and Western-blot were 
      used to detect lipid droplet and expression of SmgGDS and phospho-ERK; C/EBPalpha, 
      C/EBPbeta and PPARgamma mRNA levels were measured using RT-qPCR. (4) 10-week-old 
      C57BL/6J mice were randomly assigned into two groups, with 7 mice in each group. 
      Mice were infected with SmgGDS overexpressing adeno-associated virus (AAV-SmgGDS) 
      or empty vector intraperitoneally, then fed with high fat diet. After 4 weeks, 
      performed GTT and ITT; Recorded the weight and adipose tissue weight of mice; HE 
      staining was used to analyze structural changes of eWAT; Western-blot was used to 
      detect the phosphorylation level of ERK in eWAT. Results: (1) The expression of 
      SmgGDS was significantly upregulated in eWAT of high fat diet fed mice (normal 
      diet group: 0.218+/-0.037, high fat diet group:0.439+/-0.072, t=2.74, P=0.034). (2) 
      At 4 months of high fat diet intervention, the glucose tolerance (60 minutes 
      after glucose injection, WT group: 528 mg/dl+/-21 mg/dl, KD group: 435 mg/dl+/-17 
      mg/dl, t=3.47, P=0.030; 90 minutes, WT group: 463 mg/dl+/-24 mg/dl, KD group: 366 
      mg/dl+/-18 mg/dl, t=3.23, P=0.047;120 minutes, WT group: 416 mg/dl+/-21 mg/dl, KD 
      group: 297 mg/dl+/-16 mg/dl, t=4.49, P=0.005) and insulin sensitivity (15 minutes 
      after insulin injection, WT group: 77.79%+/-3.45%, KD group: 54.30%+/-2.92%, t=3.49, 
      P=0.005; 30 minutes, WT group: 62.27%+/-5.31%, KD group: 42.25%+/-1.85%, t=2.978, 
      P=0.024; 90 minutes, WT group: 85.69%+/-6.63%, KD group: 64.71%+/-5.41%, t=3.120, 
      P=0.016) of KD mice were significantly improved compared to the WT group, with an 
      increase in eWAT weight ratio (WT: 4.19%+/-0.18%, KD: 5.12%+/-0.37%, t=2.28, 
      P=0.042), but a decrease in average adipocyte area (WT group: 5221 mum(2)+/-241 mum(2), 
      KD group: 4410 mum(2)+/-196 mum(2), t=2.61, P=0.026). After 7 months of high fat diet, 
      the eWAT weight ratio of KD mice decreased (WT: 5.02%+/-0.20%, KD: 3.88%+/-0.21%, 
      t=3.92, P=0.001) and adipocyte size decreased (WT group: 6 783 mum(2)+/-390 mum(2), KD 
      group: 4785 mum(2)+/-303 mum(2), t=4.05, P=0.002). The phospho-ERK1 in eWAT increased (WT 
      group: 0.174+/-0.056, KD group: 0.588+/-0.147, t=2.64, P=0.025), and mRNA level of 
      PPARgamma significantly decreased (WT group: 1.018+/-0.128, KD group: 0.029+/-0.015, 
      t=7.70, P=0.015). (3) The expression of SmgGDS was significantly increased in 
      differentiated MEF (undifferentiated: 6.789+/-0.511, differentiated: 10.170+/-0.523, 
      t=4.63, P=0.010); SmgGDS knock-down inhibited lipid droplet formation in MEF (WT 
      group: 1.00+/-0.02, KD group: 0.88+/-0.02, t=5.05, P=0.007) and increased ERK1 (WT 
      group: 0.600+/-0.179, KD group: 1.325+/-0.102, t=3.52, P=0.025) and ERK2 (WT group: 
      2.179+/-0.687, KD group: 5.200+/-0.814, t=2.84, P=0.047) activity, which can be 
      reversed by ERK1/2 inhibitor. (4) SmgGDS over expression resulted in weight gain, 
      increased eWAT weight (control group: 3.29%+/-0.36%, AAV-SmgGDS group: 4.27%+/-0.26%, 
      t=2.20, P=0.048) and adipocyte size (control group: 3525 mum(2)+/-454 mum(2), AAV-SmgGDS 
      group: 5326 mum(2)+/-655 mum(2), t=2.26, P=0.047), impaired insulin sensitivity(30 
      minutes after insulin injection, control group: 44.03%+/-4.29%, AAV-SmgGDS group: 
      62.70%+/-2.81%, t=3.06, P=0.019), and decreased ERK1 (control group: 0.829+/-0.077, 
      AAV-SmgGDS group: 0.326+/-0.036, t=5.96, P=0.001)and ERK2 (control group: 
      5.748+/-0.287, AAV-SmgGDS group: 2.999+/-0.845, t=3.08, P=0.022) activity in eWAT. 
      Conclusion: SmgGDS knockdown improves obesity related glucose metabolism disorder 
      by inhibiting adipogenesis and adipose tissue hypertrophy, which is associated 
      with ERK activation.
FAU - Xiong, T
AU  - Xiong T
AD  - Department of Cardiology, The Second Xiangya Hospital, Central South University, 
      Changsha 410000, China.
FAU - Wang, T
AU  - Wang T
AD  - Department of Cardiology, The Hospital Affiliated to Medical School of Yangzhou 
      University (Taizhou People's Hospital), Taizhou 225300, China.
FAU - Chen, X W
AU  - Chen XW
AD  - Department of Cardiology, The Hospital Affiliated to Medical School of Yangzhou 
      University (Taizhou People's Hospital), Taizhou 225300, China.
FAU - Yang, Y X
AU  - Yang YX
AD  - Department of Cardiology, The Hospital Affiliated to Medical School of Yangzhou 
      University (Taizhou People's Hospital), Taizhou 225300, China.
FAU - Ma, Z W
AU  - Ma ZW
AD  - Department of Cardiology, the First Affiliated Hospital of Dalian Medical 
      University, Dalian 116044, China.
FAU - Zuo, B Y
AU  - Zuo BY
AD  - Department of Cardiology, The Hospital Affiliated to Medical School of Yangzhou 
      University (Taizhou People's Hospital), Taizhou 225300, China.
FAU - Wang, D X
AU  - Wang DX
AD  - Department of Cardiology, The Hospital Affiliated to Medical School of Yangzhou 
      University (Taizhou People's Hospital), Taizhou 225300, China.
LA  - chi
GR  - 82170508/National Natural Science Foundation of China/
PT  - English Abstract
PT  - Journal Article
DEP - 20230609
PL  - China
TA  - Zhonghua Nei Ke Za Zhi
JT  - Zhonghua nei ke za zhi
JID - 16210490R
SB  - IM
EDAT- 2023/06/09 06:42
MHDA- 2023/06/09 06:42
CRDT- 2023/06/09 04:43
PHST- 2023/06/09 06:42 [medline]
PHST- 2023/06/09 06:42 [pubmed]
PHST- 2023/06/09 04:43 [entrez]
AID - 10.3760/cma.j.cn112138-20230209-00072 [doi]
PST - aheadofprint
SO  - Zhonghua Nei Ke Za Zhi. 2023 Jun 9;62:833-840. doi: 
      10.3760/cma.j.cn112138-20230209-00072.