Obesity as a premature aging phenotype - implications for sarcopenic obesity.

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.

Fluid shear stress regulates placental growth factor expression via heme oxygenase 1 and iron.

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.

Placental growth factor levels in quadriceps muscle are reduced by a Western diet in association with advanced glycation end products.

In peripheral artery disease (PAD), atherosclerotic occlusion chronically impairs limb blood flow. Arteriogenesis (collateral artery remodeling) is a vital adaptive response to PAD that protects tissue from ischemia. People with type II diabetes have a high risk of developing PAD and would benefit from arteriogenesis. However, arteriogenesis is suppressed in people with diabetes by a multifaceted mechanism which remains incompletely defined. Upregulation of placental growth factor (PLGF) is a key early step in arteriogenesis. Therefore, we hypothesized that metabolic dysfunction would impair PLGF expression in skeletal muscle. We tested this hypothesis in C57BL/6J and ApoE-/- mice of both sexes fed a Western diet (WD) for 24 wk. We first assessed baseline levels of PLGF, vascular endothelial growth factor (VEGF-A), and VEGF receptor 1 (VEGFR1) protein in hindlimb skeletal muscle. Only PLGF was consistently decreased by the WD. We next investigated the effect of 24 wk of the WD on the response of PLGF, VEGF-A, VEGFR1, and monocyte chemoattractant protein-1 (MCP-1) to the physiological stimulus of vascular occlusion. Hindlimb ischemia was induced in mice by gradual femoral artery occlusion using an ameroid constrictor. Growth factor levels were measured 3-28 days postsurgery. In C57BL/6J mice, the WD decreased and delayed upregulation of PLGF and abolished upregulation of VEGF-A and VEGFR1 but had no effect on MCP-1. In ApoE-/- mice fed either diet, all factors tested failed to respond to occlusion. Metabolic phenotyping of mice and in vitro studies suggest that an advanced glycation end product/TNFα-mediated mechanism could contribute to the effects observed in vivo.NEW & NOTEWORTHY In this study, we tested the effect of a Western diet on expression of the arteriogenic growth factor placental growth factor (PLGF) in mouse skeletal muscle. We provide the first demonstration that a Western diet interferes with both baseline expression and hindlimb ischemia-induced upregulation of PLGF. We further identify a potential role for advanced glycation end product/TNFα signaling as a negative regulator of PLGF. These studies provide insight into one possible mechanism by which type II diabetes may limit collateral growth.

Glial Growth Factor 2 Regulates Glucose Transport in Healthy Cardiac Myocytes and During Myocardial Infarction via an Akt-Dependent Pathway.

Neuregulin (NRG), a paracrine factor in myocytes, promotes cardiac development via the ErbB receptors. NRG-1ß also improves cardiac function and cell survival after myocardial infarction (MI), although the mechanisms underlying these cardioprotective effects are not well elucidated. Increased glucose uptake has been shown to be cardio-protective during MI. We hypothesized that treatment with a recombinant version of NRG-1ß, glial growth factor 2 (GGF2), will enhance glucose transport in the healthy myocardium and during MI. Cardiac myocytes were isolated from MI and healthy adult rats, and subsequently incubated with or without insulin or GGF2. Glucose uptake was measured using a fluorescent D-glucose analog. The translocation of glucose transporter (GLUT) 4 to the cell surface, the rate-limiting step in glucose uptake, was measured using a photolabeled biotinylation assay in isolated myocytes. Similar to insulin, acute in vitro GGF2 treatment increased glucose uptake in healthy cardiac myocytes (by 40 and 49%, respectively, P = 0.002). GGF2 treatment also increased GLUT4 translocation in healthy myocytes by 184% (P < 0.01), while ErbB 2/4 receptor blockade (by afatinib) abolished these effects. In addition, GGF2 treatment enhanced Akt phosphorylation (at both threonine and serine sites, by 75 and 139%, respectively, P = 0.029 and P = 0.01), which was blunted by ErbB 2/4 receptor blockade. GGF2 treatment increased the phosphorylation of AS160 (an Akt effector) by 72% (P < 0.05), as well as the phosphorylation of PDK-1 and PKC (by 118 and 92%, respectively, P < 0.05). During MI, cardiac GLUT4 translocation was downregulated by 44% (P = 0.004) and was partially rescued by both in vitro insulin and GGF2 treatment. Our data demonstrate that acute GGF2 treatment increased glucose transport in cardiac myocytes by activating the ErbB 2/4 receptors and subsequent key downstream effectors (i.e., PDK-1, Akt, AS160, and PKC). These findings highlight novel mechanisms of action of GGF2, which warrant further investigation in patients with heart failure.

Adipose tissue loss and lipodystrophy in xylosyltransferase II deficient mice.

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 IL1ß, 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: Decreased GAGs 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 by mediating control of adipose precursor development, tissue inflammation, and vascular development.