Role of adipose hypoxia in endocrine alterations: a possible new anti-inflammatory therapeutic target in obesity?

Abstract

Dr Jianping Ye is a Professor at the Pennington Biomedical Research Center, Louisiana State University (LA, USA). He completed his graduate education in the medical school, Beijing University (China) in 1989 and moved to the USA to undertake postdoctoral research in 1992. He conducted research in the role of inflammation in cancer and was an instructor at the Health Science Center at San Antonio, University of Texas (TX, USA) in 1997, and assistant professor in the West Virginia University (WV, USA) in 1999. In 2001, he set up his lab at the Pennington Biomedical Research Center, Louisiana State University, where obesity research is the main focus. His current work, supported by NIH and American Diabetes Association, predominantly focuses on insulin resistance in obesity. Recent work from his lab reported that adipose hypoxia may contribute to chronic inflammation and insulin resistance in obesity. The study was based on the hypoxia effect on the endocrine function of adipocytes in a preliminary study of large adipocytes in his laboratory in 2004. Here, Nicole Nogoy talks to Jianping Ye on the future and current issues in the cellular and molecular mechanisms of insulin resistance.

Insulin resistance is a central pathogenic feature of metabolic disorders, such as obesity and Type 2 diabetes mellitus [1], which poses a healthcare problem due to the increasing morbidity and complications of the two diseases [2]. Until recently, the role of fat tissue itself in the development of obesity and its consequences was considered to be passive, where adipocytes were only considered to be a storage medium for fat [3]. However, research conducted over the last few years has clearly demonstrated that adipocytes also secrete a large number of cytokines and hormones, such as leptin, and proinflammatory cytokines, such as TNF-α, IL-6 and monocyte chemoattractant protein (MCP)-1, which are all upregulated in obesity, and believed to contribute to the development of diabetes and cardiovascular disease [3,4].

Cellular and molecular biology provide a wide range of essential methods for understanding the cellular–molecular mechanisms of insulin resistance in obesity and Type 2 diabetes. Over the last few years, there has been increasing interest in the role of inflammation in insulin resistance and the signaling pathways involved [3].

Dr Jianping Ye is a Professor at the Pennington Biomedical Research Center, Louisiana State University (LA, USA). Dr Ye completed his medical degree in Beijing (China) and obtained postdoctoral research experience in NCI/NIH and the Johns Hopkins University. His main research interest currently revolves around mechanisms of insulin resistance in obesity. His current research is supported by the NIH and the American Diabetes Association. His group has recently reported that adipose hypoxia may contribute to chronic inflammation and insulin resistance in obesity [5]. Here, Dr Ye shares his thoughts on the future and current issues in the cellular and molecular mechanisms of insulin resistance in obesity with an emphasis on new potential therapeutic targets.

• Can you please provide the readers of Expert Review of Endocrinology & Metabolism with a general overview of your work in endocrinology?

The goal of my current research is to understand the cellular and molecular mechanisms of insulin resistance, which links obesity to many chronic diseases, including Type 2 diabetes, cardiovascular disease and cancer. The study focuses on the role of inflammation in the pathogenesis of insulin resistance. We are trying to address two questions: how does inflammation signaling lead to inhibition of the insulin action and what obesity-associated factor(s) induces chronic inflammation in adipose tissue in obesity?

• What led you to this area of research?

I have been interested in inflammation research since 1986, when I began my laboratory research in the Graduate School, Beijing University (China). During my postdoctoral training and junior faculty stage, I conducted research in the role of inflammation in cancer. I was an instructor at the Health Science Center at San Antonio, University of Texas (TX, USA) in 1997, and Assistant Professor in the West Virginia University (WV, USA) in 1999. In 2001, I set up my lab at the Pennington Biomedical Research Center, Louisiana State University, where obesity research is the main focus. In order to develop a research program related to obesity, I decided to investigate inflammation in obesity. Since then, the interaction of inflammation and insulin has been the focus of my research.

In 2004, my group discovered the hypoxia effect on the endocrine function of adipocytes in a preliminary study of large adipocytes. Large adipocytes are known to express more inflammatory cytokines and less adiponectin. It is not clear why the adipocyte size is associated with these characteristics. To address this question, we hypothesized that the mechanical tension in the cell membrane is increased with the cell size. In large adipocytes, such mechanical tension is high enough to generate a stress signal for the endocrine alterations. To test this hypothesis, we conducted an experiment to test mechanical pressure on the cell surface. The high pressure was generated in the cell membrane using a compressed air in a sealed chamber, or by placing cells in a vacuum environment that increased the pressure inside the cells. Adipocytes exhibited a dramatic change in endocrine function under the vacuum condition. Since the vacuum condition is associated with a low level of oxygen, we discovered the hypoxia effect on adipocytes. These preliminary studies led us to identify hypoxia in adipose tissue as described in our paper published in the American Journal of Physiology Endocrinology and Metabolism. We reported the results in several meetings and seminars in 2005 and 2006, before the manuscript was published in 2007.

• Obesity is a rather general term; what areas are you researching specifically?

Obesity is known to increase the risk for many chronic diseases. Since my research is to understand inflammation in the development of these chronic diseases in the obese conditions, the role of IκB kinase (IKK)/nuclear factor (NF)-κB signaling pathway is a focus in our research. IKK/NF-κB represents a dominant signaling pathway in inflammation. Activation of this pathway is required for expression and action of many inflammatory cytokines (e.g., TNF-α, MCP-1 and IL-1). It is clear that this pathway is involved in inflammation in obese conditions. Inhibition of this pathway by gene modification in transgenic mice or by aspirin in human was shown to improve insulin sensitivity in many reports. However, it is not clear what factors lead to activation of this pathway in obesity. Our study suggests that hypoxia is an initial factor for activation of NF-κB in adipose tissue in obese conditions. We believe that adipose hypoxia has at least two major effects on obesity-associated chronic inflammation. The first is induction of adipocyte expression of cytokines (e.g., MIF and MCP-1), which promotes macrophage infiltration in the adipose tissue. The second is to provide a hypoxic environment for macrophages, which are much more active than adipocytes in the production of inflammatory cytokines (e.g., TNF-α and IL-1) in hypoxia.

• A key feature of your recently published paper (in American Journal of Physiology Endocrinology & Metabolism) was on the possible contribution of hypoxia to endocrine alterations in adipose tissue; what particular evidence has led to this possibility?

This paper provides systematic experimental evidence to support the role of hypoxia in the chronic inflammation in adipose tissue. First, hypoxia was demonstrated with three approaches in the adipose tissue in the obese condition in mice; second, the hypoxia was associated with chronic inflammation, such as macrophage infiltration and inflammation cytokine expression, in the adipose tissue; third, hypoxia reduced the inflammatory response in adipocytes and macrophages in cell culture; furthermore, hypoxia inhibited adiponectin (an adipocyte-specific cytokine) expression in adipocytes. These results suggest that adipose hypoxia is a potential initial factor for chronic inflammation and endocrine disorders in adipose tissue in obesity. This hypothesis explains what induces inflammation and what reduces adiponectin expression in obesity. The study may provide a new approach for the prevention and treatment of obesity-associated diseases.

• Are there other factors involved in hypoxia-induced endocrine alteration & inflammation?

The hypoxia response may increase lipolysis that leads to release of free fatty acids (FFA) from adipocytes. FFA may be involved in the endocrine alteration and inflammation through activation of several signaling pathways, such as the Toll-like receptor 4 pathway and diacylglycerol–PKC pathway. In addition, hypoxia may lead to the endocrine alteration and chronic inflammation through induction of endoplasmic reticulum stress and inhibition of protein synthesis. It is known that hypoxia induces these responses in cells.

• What effects does chronic inflammation have in obesity & Type 2 diabetes?

Chronic inflammation has many side effects. The following are some examples:

•	Inflammation inhibits insulin sensitivity through suppression of insulin signaling molecules, such as insulin receptor substrate proteins (IRSs) and PPAR-γ [6]. The effect is mediated by proinflammatory cytokines, such as TNF-α and IL-1;
•	Chronic inflammation induces metabolic disorder in fatty acids and glucose. Inflammation stimulates hydrolysis of triglycerides in adipocytes and increases FFA levels in blood. A high level of plasma FFA may contribute to the development of fatty liver, increased lipid deposit in muscle and pancreatic β-cell islets. In the liver, insulin resistance may lead to overproduction of glucose, which contributes to hyperglycemia;
•	In the β-cell islets, chronic inflammation may induce β-cell apoptosis and induce degeneration in the islet. This will contribute to dysfunction of the β-islet that make Type 2 diabetes even worse;
•	Chronic inflammation also increases the risk of cancer, atherosclerosis and cardiovascular diseases in obese subjects. Inflammation stimulates the formation and metastasis of tumors. Inflammation induces hyperinsulinemia through insulin resistance. The high level of insulin promotes tumor growth and metastasis directly through activation of the PI3K–Akt pathway. In addition, the high level of insulin may promote angiogenesis in solid tumors. Angiogenesis is required for nutrient and oxygen supply to the tumor cells. Furthermore, inflammation promotes the formation of atherosclerosis.

• What are the potential therapeutic implications of these results for obesity & Type 2 diabetes patients?

Our results may explain why obese patients with sleep apnea have a high risk of insulin resistance. Sleep apnea leads to systemic intermittent hypoxia. Given the increased mass of adipose tissue in obesity, the hypoxia response in adipose tissue may lead to elevation of inflammatory cytokines in the plasma and, thus, induce systemic inflammation. The inflammation may account for the pathogenesis of insulin resistance in the patients.

Our results explain the beneficial effects of physical exercise on insulin sensitivity in a new platform. Physical exercise is able to improve insulin sensitivity through several known mechanisms, such as activation of AMP-activated protein kinase in skeletal muscle, consumption of extra lipid in the body and improvement of blood supply to skeletal muscle. Physical exercise also increases blood supply to adipose tissue, and thus may reduce hypoxia-induced inflammation in obesity.

The improvement of oxygenation in adipose tissue may be a new strategy in the treatment of obesity-associated inflammation and insulin resistance.

• What is needed to further understand the role of hypoxia & its effects on inflammation & endocrine alteration, & how will you focus your future research efforts over the next 5 years?

The hypothesis of adipose hypoxia remains to be further tested in animals using transgenic approaches. It also needs to be tested in the human body.

I intend to investigate the mechanisms underlying the adipose hypoxia. I will also make an effort to test the hypothesis using transgenic mice. The result may help us to understand the physiology of adipose tissue and to identify more target molecules for therapeutic intervention of obesity and Type 2 diabetes.