Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb;12(1):e1160.
doi: 10.1002/prp2.1160.

The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity

Wen-Dong Xu  1   2   3   4 , Shui-Zheng Lai  1   2   3   4 , Jia Zhao  1   2   3   4 , Shi-Jie Wei  1   2   3   4 , Xue-Ying Fang  1   2   3   4 , Yi-Yi Liu  1   2   3   4 , Xiang-Lu Rong  1   2   3   4 , Jiao Guo  1   2   3   4
Affiliations

The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity

Wen-Dong Xu et al. Pharmacol Res Perspect. 2024 Feb.

Abstract

TGF-β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2-SREBP-1c mice and ob/ob mice, were used. TGF-β pathway showed up-regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF-β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre-administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild-type levels in aP2-SREBP-1c mice. In contrast, TGF-β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF-β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF-β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.

Keywords: TGF-β; adipose atrophy; adipose hypertrophy; adipose tissue; glucolipid metabolism.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Effects of TGF‐β inhibitor on body weight, fat/body weight ratio, and organ mass of aP2‐SREBP‐1c mice and ob/ob mice. Changes in body weight of aP2‐SREBP‐1c mice during treatment (A), Fat to body weight ratio (B), Organ weight (C). Changes in body weight of ob/ob mice during treatment (D), Fat to body weight ratio (E), Organ weight (F). Compared with the WT‐veh group, *p < .05, **p < .01, ***p < .001. Compared with the aP2‐veh/ob‐veh group, #p < .05, ##p < .01, ###p < .001.
FIGURE 2
FIGURE 2
Hematoxylin–Eosin (H&E) stained sections of iWAT in aP2‐SREBP‐1c mice and ob/ob mice. HE staining of iWAT and area of lipid droplet in aP2‐SREBP‐1c mice (A, B) and ob/ob mice (E, F). HE staining of BAT and area of lipid droplet in aP2‐SREBP‐1c mice (C, D) and ob/ob mice (G, H), the pathological section shown here was shot at 20 × scope (n = 3). Compared with the WT‐veh group, *p < .05, **p < .01, ***p < .001. Compared with the aP2‐veh/ob‐vehgroup, #p < .05, ##p < .01, ###p < .001.
FIGURE 3
FIGURE 3
Effects of TGF‐β inhibitor on abnormal Glucolipid metabolism in aP2‐SREBP‐1c mice and ob/ob mice. The fasted plasma Glu (A), TG (B), NEFA (C), Glycerol (D), HDL (E), and TC (F) of aP2‐SREBP‐1c mice and their littermates with or without SB431542 treatment. The fasted plasma Glu (G), TG (H), NEFA (I), Glycerol (J), HDL (K), and TC (L) of ob/ob mice and their littermates with or without SB431542 treatment (n = 4–5 per group). Compared with the WT‐veh group, *p < .05, **p < .01, ***p < .001. Compared with the aP2‐veh/ob‐veh group, #p < .05, ##p < .01, ###p < .001.
FIGURE 4
FIGURE 4
Effects of TGF‐β inhibitor on lipolytic and glucose transporters related genes in aP2‐SREBP‐1c mice and ob/ob mice. Related RNA levels of lipolytic related lipases (A, C) and glucose transporters (B, D), were determined in iWAT (n = 4–5). Compared with the WT‐veh group, *p < .05, **p < .01, ***p < .001. Compared with the aP2‐veh/ob‐veh group, #p < .05, ##p < .01, ###p < .001.
FIGURE 5
FIGURE 5
Effects of TGF‐β inhibitor on Glucolipid levels, glucose transporters, and lipolysis‐related genes of 3T3‐L1 mature adipocyte in vitro. The concentration of SB431542 in 3T3‐L1 mouse embryonic fibroblasts (A). Cell morphology under microscope after lipid formation induction which were captured at 10 × scope and 40 × scope by Inverted microscope (B). The Glycerol (C), TG (D) in the cell supernatant with or without SB431542 treatment. The mRNA level of lipolytic‐related lipases and glucose transporters (E) of 3T3‐L1 mature adipocytes with or without SB431542 treatment (n = 3). Compared with the control group, *p < .05, **p < .01, ***p < .001.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Zick Y. Insulin resistance: a phosphorylation‐based uncoupling of insulin signaling. Trends Cell Biol. 2001;11(11):437‐441. doi:10.1016/s0962-8924(01)02129-8 - DOI - PubMed
    1. Zick Y. Role of ser/Thr kinases in the uncoupling of insulin signaling. Int J Obes Relat Metab Disord. 2003;27(Suppl 3):S56‐S60. doi:10.1038/sj.ijo.0802503 - DOI - PubMed
    1. Morigny P, Boucher J, Arner P, Langin D. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics. Nat Rev Endocrinol. 2021;17(5):276‐295. doi:10.1038/s41574-021-00471-8 - DOI - PubMed
    1. Abel ED, Peroni O, Kim JK, et al. Adipose‐selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature. 2001;409(6821):729‐733. doi:10.1038/35055575 - DOI - PubMed
    1. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133‐2223. doi:10.1152/physrev.00063.2017 - DOI - PMC - PubMed