Cytotherapy. 2013 Aug;15(8):971-8.

Modulation of glucose and lipid metabolism by porcine adiponectin receptor 1-transgenic mesenchymal stromal cells in diet-induced obese mice.

Lin YY, Chen CY, Lin Y, Chiu YP, Chen CC, Liu BH, Mersmann HJ, Wu SC, Ding ST.

Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan.

 

Abstract

BACKGROUND AIMS:

Obesity and its associated diseases demand better therapeutic strategies. Regenerative medicine combined with gene therapy has emerged as a promising approach in various clinical applications. Adiponectin (ApN) and its receptors have been demonstrated to play beneficial roles in modulating glucose and lipid homeostasis. In the current study, we tested such an approach by transplanting mesenchymal stromal cells (MSCs) from porcine ApN receptor (pAdipoR) 1-transgenic mice into high-fat/sucrose diet (HFSD)-fed mice.

METHODS:

Twenty 6-week-old Friend virus B/NJNarl male mice were randomly assigned into four groups with the control fed a chow diet (chow) and others HFSD for 10 months. The HFSD groups were then intraperitoneally injected once per week for 8 weeks with placebo (200 μL phosphate-buffered saline), wild-type MSC (WT-MSC, 2 × 10(6) cells/200 μL phosphate-buffered saline) or pAdipoR1-transgenic MSC (pR1-tMSC, 2 × 10(6) cells/200 μL phosphate-buffered saline), respectively. Body weights, blood samples, tissue histology, and gene expression and protein levels of metabolism-associated genes were analyzed.

RESULTS:

Both WT-MSC and pR1-tMSC transplantations restored the messenger RNA expression of AdipoR1, with those of glucose transporter 4 and 5′-adenosine monophosphate-activated protein kinase catalytic subunit α-1 and protein levels of pyruvate kinase induced by pR1-tMSC in the muscles of HFSD-fed mice. In the liver, both WT-MSC and pR1-tMSC ameliorated HFSD-induced hepatosteatosis, with the gene expression of lipoprotein lipase and hormone-sensitive lipase upregulated by the latter. Lastly, pR1-tMSC transplantation reduced fatty acid synthase mRNA levels in the adipose tissues of HFSD-fed mice.

CONCLUSIONS:

This study demonstrates the modulatory actions of MSC and pR1-tMSC on genes associated with glucose and lipid metabolism and provides insights into its therapeutic application for obesity-associated metabolic complication.

KEYWORDS: adiponectin receptor 1, diet-induced obesity, gene therapy, mesenchymal stromal cells

PMID: 23732048

 

Supplemental information

Adiponectin and its receptors have been demonstrated to play important roles in regulating glucose and lipid metabolism in mice. Obesity, type II diabetes and cardiovascular disease are highly correlated with down-regulated adiponectin signaling. The availability of our transgenic mice with fluorescent proteins offer great study models to investigate the involvement of adiponectin receptor and their ligand (adiponectin) in the biological processes (Figure 1). We have fed adiponectin receptor 1 (adipoR1) transgenic mice high fat diet for 24 weeks, and found no change in weight gain in transgenic mice (Figure 2).  We further demonstrated that pAdipor1 mice can prevent insulin resistance (1).

In this study, we isolated the wild-type mesenchymal stem cells (WT-MSC) and adiponectin receptor 1-transgenic mesenchymal stem cells (pR1-tMSC) to treat the diet-induced obese (DIO) mice that were also diabetic and insulin insensitive. After once-a-week cell transplantation for 8 weeks, WT-MSC and pR1-tMSC treatments improved fatty acid oxidation and alleviate lipid accumulation in the livers (Figure 3), with pR1-tMSC further enhancing glucose metabolism in DIO mice (Figure 4). Our current study, for the first time, demonstrated the therapeutic application of pR1-tMSC to improve diet-induced metabolic complication (2).

Recently, our group found that AdipoR1 enhances fatty acid metabolism and cell viability in palmitate-treated HepG2 cells partially by activating AKT signaling. Therefore, AdipoR1 has therapeutic potential in the treatment of nonalcoholic fatty liver disease (3). Furthermore, AdipoR1 overexpression reduces lipid accumulation and hypertrophy in the heart of diet-induced obese mice (4). After receiving a high fat and high sucrose (HF/HS) diet for 24 weeks, AdipoR1-transgenic mice did not become obese, nor did they develop heart hypertrophy. The AdipoR1 transgene decreased the elevating cardiac troponin I expression caused by the obesity inducing diet. While the HF/HS induced mRNA expression of CD36 and CPTI, AdipoR1 reversed it. Suppression of cardiac SOD mRNA expression by the HF/HS was also improved by the AdipoR1 transgene. The HF/HS caused a higher autophagic gene expression of Beclin 1 and Lamp 2A in the heart, whereas the AdipoR1 transgene ameliorated them.  The AdipoR1 transgene enabled mice to resist diet-induced obesity while decreasing lipid accumulation, oxidative stress, and autophagic damage. Therefore, there is a great opportunity to take advantage of the genetically modified stem cell therapies to treat cardiovascular or heart failure-related diseases.

Shinn-Chih Wu-1Figure 1. The mouse on the right is a homologous AdipoR1 transgenic mouse expressing also red fluorescent protein whereas the far left one is a wild type mouse.

 

Shinn-Chih Wu-2Figure 2. The mouse on the right is a homologous AdipoR1 transgenic mouse fed with high fat and high sucrose diet for 24 weeks whereas the left one is a wild type mouse.

 

Shinn-Chih Wu-3Figure 3. Effects of pR1-tMSC transplantation on hepatic lipid droplet accumulation in HF/HS-fed mice. (A) Representative histological analyses of liver sections from control (a, chow diet) and HF/HS-fed mice treated with (b) PBS, (c) WT-MSC and (d) pR1-tMSC. Sections were stained with hematoxylin and eosin and viewed at X400 magnification with scale bars indicating 20 μm. (B) Quantification of the area of lipid droplets in histological sections of livers as determined by ImageJ software. Data are expressed as mean ± SEM (n = 6). Different letters indicate statistical significance, P≦ 0.05.

 

Shinn-Chih Wu-4

Figure 4. Effects of pR1-tMSC transplantation on body weight and blood glucose levels of HF/HS-fed mice. (A) Body weight, (B) fasting blood glucose levels, (C) glucose tolerance test and (D) total area under the curve were measured and calculated as described in the text. Mice fed a HF/HS were treated with PBS, WT-MSC or pR1-tMSC for 8 weeks, whereas the control was fed a chow diet. Data are expressed as mean ± SEM. Different letters indicate statistical significance, P ≦ 0.05 (PBS versus MSC, n = 6). *P ≦ 0.05.

 

Reference:

  1. Liu BH, Lin YY, Wang YC, Huang CW, Chen CC, Wu SC, Mersmann HJ, Cheng WT, Ding ST. Porcine adiponectin receptor 1 transgene resists high-fat/sucrose diet-induced weight gain, hepatosteatosis and insulin resistance in mice. Exp Anim2013;62(4):347-60.
  2. Lin YY, Chen CY, Lin Y, Chiu YP, Chen CC, Liu BH, Mersmann HJ, Wu SC, Ding ST. Modulation of glucose and lipid metabolism by porcine adiponectin receptor 1-transgenic mesenchymal stromal cells in diet-induced obese mice. Cytotherapy2013 Aug;15(8):971-8.
  3. Chou IP, Lin YY, Ding ST, Chen CY. Adiponectin receptor 1 enhances fatty acid metabolism and cell survival in palmitate-treated HepG2 cells through the PI3 K/AKT pathway. Eur J Nutr2013 Oct 16.
  4. Chou IP, Chiu, YP, Ding ST, Liu, BH, Lin YY, Chen CY. Adiponectin receptor 1 overexpression reduces lipid accumulation and hypertrophy in the heart of diet-induced obese mice. — Possible involvement of oxidative stress and Autophagy. Endocrin. Res. (In press)
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