Obesity and aging have both seen dramatic increases in prevalence throughout society. This review seeks to highlight common pathologies that present with obesity, along with the underlying risk factors, that have remarkable similarity to what is observed in the aged. These include skeletal muscle dysfunction (loss of quantity and quality), significant increases in adiposity, systemic alterations to autonomic dysfunction, reduction in nitric oxide bioavailability, increases in oxidant stress and inflammation, dysregulation of glucose homeostasis, and mitochondrial dysfunction. This review is organized by the aforementioned indices and succinctly highlights literature that demonstrates similarities between the aged and obese phenotypes in both human and animal models. As aging is an inevitability and obesity prevalence is unlikely to significantly decrease in the near future, these two phenotypes will ultimately combine as a multidimensional syndrome (a pathology termed sarcopenic obesity). Whether the pre-mature aging indices accompanying obesity are additive or synergistic upon entering aging is not yet well defined, but the goal of this review is to illustrate the potential consequences of a double aged phenotype in sarcopenic obesity. Clinically, the modifiable risk factors could be targeted specifically in obesity to allow for increased health span in the aged and sarcopenic obese populations.
BACKGROUND/OBJECTIVES-The cellular and extracellular matrix (ECM) interactions that regulate adipose tissue homeostasis are incompletely understood. Proteoglycans (PGs) and their sulfated glycosaminoglycans (GAGs) provide spatial and temporal signals for ECM organization and interactions with resident cells by impacting growth factor and cytokine activity. Therefore, PGs and their GAGs could be significant to adipose tissue homeostasis. The purpose of this study was to determine the role of ECM sulfated GAGs in adipose tissue homeostasis.METHODS-Adipose tissue and metabolic homeostasis in mice deficient in xylosyltransferase 2 (Xylt2−/−) were examined by histologic analyses, gene expression analyses, whole body fat composition measurements, and glucose tolerance test. Adipose tissue inflammation and adipocyte precursors were characterized by flow cytometry and in vitro culture of mesenchymal stem cells.RESULTS-Xylt2−/− mice have low body weight due to overall reductions in abdominal fat deposition. Histologically, the adipocytes are reduced in size and number in both gonadal and mesenteric fat depots of Xylt2−/− mice. In addition, these mice are glucose intolerant, insulin resistant, and have increased serum triglycerides as compared to Xylt2+/+ control mice. Furthermore, the adipose tissue niche has increased inflammatory cells and enrichment of proinflammatory factors IL6 and IL1β, and these mice also have a loss of adipose tissue vascular endothelial cells. Lastly, xylosyltransferease-2 (XylT2) deficient mesenchymal stem cells from gonadal adipose tissue and bone marrow exhibit impaired adipogenic differentiation in vitro. CONCLUSIONS-DecreasedGAGs due to the loss of the key GAG assembly enzyme XylT2 causes reduced steady state adipose tissue stores leading to a unique lipodystrophic model. Accumulation of an adipocytic precursor pool of cells is discovered indicating an interruption in differentiation. Therefore, adipose tissue GAGs are important in the homeostasis of adipose tissue 4 Corresponding Author.
Increased fluid shear stress (FSS) is a key initiating stimulus for arteriogenesis, the outward remodeling of collateral arterioles in response to upstream occlusion. Placental growth factor (PLGF) is an important arteriogenic mediator. We previously showed that elevated FSS increases PLGF in a reactive oxygen species (ROS)-dependent fashion both in vitro and ex vivo. Heme oxygenase 1 (HO-1) is a cytoprotective enzyme that is upregulated by stress and has arteriogenic effects. In the current study, we used isolated murine mesentery arterioles and co-cultures of human coronary artery endothelial cells (EC) and smooth muscle cells (SMC) to test the hypothesis that HO-1 mediates the effects of FSS on PLGF. HO-1 mRNA was increased by conditions of increased flow and shear stress in both co-cultures and vessels. Both inhibition of HO-1 with zinc protoporphyrin and HO-1 knockdown abolished the effect of FSS on PLGF. Conversely, induction of HO-1 activity increased PLGF. To determine which HO-1 product upregulates PLGF, co-cultures were treated with a CO donor (CORM-A1), biliverdin, ferric ammonium citrate (FAC), or iron-nitrilotriacetic acid (iron-NTA). Of these FAC and iron-NTA induced an increase PLGF expression. This study demonstrates that FSS acts through iron to induce pro-arteriogenic PLGF, suggesting iron supplementation as a novel potential treatment for revascularization.
Increased fluid shear stress (FSS) is a key initiating stimulus for arteriogenesis, the outward remodeling of collateral arterioles in response to upstream occlusion. Placental growth factor (PLGF) is an important arteriogenic mediator. We previously showed that elevated FSS increases PLGF in a reactive oxygen species (ROS)-dependent fashion both in vitro and ex vivo. Heme oxygenase 1 (HO-1) is a cytoprotective enzyme that is upregulated by stress and has arteriogenic effects. In the current study, we used isolated murine mesentery arterioles and cocultures of human coronary artery endothelial cells (EC) and smooth muscle cells (SMC) to test the hypothesis that HO-1 mediates the effects of FSS on PLGF. HO-1 mRNA was increased by conditions of increased flow and shear stress in both cocultures and vessels. Both inhibition of HO-1 with zinc protoporphyrin and HO-1 knockdown abolished the effect of FSS on PLGF. Conversely, induction of HO-1 activity increased PLGF. To determine which HO-1 product upregulates PLGF, cocultures were treated with a CO donor (CORM-A1), biliverdin, ferric ammonium citrate (FAC), or iron-nitrilotriacetic acid (iron-NTA). Of these FAC and iron-NTA induced an increase PLGF expression. This study demonstrates that FSS acts through iron to induce pro-arteriogenic PLGF, suggesting iron supplementation as a novel potential treatment for revascularization.
In coronary artery disease, atherosclerosis chronically reduces blood flow. Placental growth factor (PLGF), a protein produced by endothelial cells (EC), can promote collateral artery remodeling to increase blood flow. However, collateral growth is impaired in people with type II diabetes. Our group has previously demonstrated that PLGF levels are reduced in a mouse model of diet‐induced type II diabetes. However, the mechanism for this reduction remains to be defined. Inflammatory cytokines and advanced glycation end products (AGE) are implicated in diabetic vascular dysfunction. We therefore hypothesized that AGE and TNFα signaling would inhibit PLGF expression in EC. Human coronary artery EC were treated with AGE, bovine serum albumin (BSA, as a control for AGE), or TNFα. AGE had no direct effect on PLGF in EC; however, TNFα reduced PLGF in EC (P<0.001). Next, murine macrophages (RAW cell line) were treated with AGE or BSA. RAW media was then transferred to murine endothelial cells (EOMA cell line). Treatment with both RAW‐BSA and RAW‐AGE media significantly reduced PLGF levels in EOMA cells compared with control RAW media (BSA, 481.75 ±21.00 pg/mL; AGE, 631.29 ±41.88 pg/mL; control, 1022.48 ±115 pg/mL; P<0.001, n=4). However, TNFα levels were only increased in RAW‐AGE media compared to RAW‐BSA media and RAW‐control media (AGE, 811.11 ±48.37 pg/mL; BSA, 305.68 ±13.95 pg/mL; control, 276.07 ± 10.40 pg/mL; P< 0.001, n=3). This finding suggests that cytokines other than TNFα may also be inhibitory for PLGF. Analysis of RAW media using a Multiplex Pro mouse 6‐panel cytokine assay revealed that TNFα was increased in RAW‐AGE media compared to RAW‐BSA and RAW‐control media (P<0.007). There was also a trend towards increased IL‐10 and IFN‐γ with AGE treatment, which approached significance (P<0.06), suggesting that these cytokines may also be important targets for future investigation. Identifying signaling pathways by which AGE and inflammatory mediators affect PLGF will give new insights into the pathology of diabetic cardiovascular disease. Support or Funding Information NIH R56 HL084494 (PL), OSU CVM
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