The study of hypoxia in adipose tissue in relation to obesity is timely, since some very recent studies have put these topics in a physiological context. In this issue of the British Journal of Nutrition, Trayhurn et al. (Reference Trayhurn, Wang and Wood1) summarise our current knowledge on hypoxia in adipose tissue and isolated adipocytes. Hypoxia can be observed in both physiological and pathological situations. Each tissue in the human body might be more or less normally characterised by lower O2 pressure than in arterial blood, as detailed in the paper by Trayhurn et al. (Reference Trayhurn, Wang and Wood1) In fact, compared with O2 pressure in arterial blood, some organs such as the spleen, thymus and brain seem to be highly hypoxic. As for white adipose tissue, it could be demonstrated that oxygenation is comparable with general tissue oxygenation in lean animals, while obese littermates are characterised by about 60 % lower O2 pressure in fat(Reference Ye, Gao, Yin and He2). In adipose tissue of mice, hypoxia underlies the increased production of adipokines and the development of obesity and the metabolic syndrome(Reference Hosogai, Fukuhara and Oshima3). Furthermore, it could be demonstrated in humans that hypoxia occurs in the obese state(Reference Cancello, Henegar and Viguerie4).
Hypoxia leads to activation of the transcription factor hypoxia inducible factor (HIF)-1α, which is a key player in the adaptive response to low O2 availability in tissues. HIF-1α stimulates the transcription of various genes that affect cell proliferation, angiogenesis, the vascular tone, glucose metabolism and the extracellular matrix(Reference Semenza5). Hypoxia in isolated adipocytes has been studied to a greater extent than in vivo, revealing that hypoxia causes various changes in protein expression and secretion behaviour in this cell type. Isolated adipocytes exposed to hypoxia exhibit the same dysregulation of secretory function as observed in expanded adipose tissue including increased release of IL-6, leptin and vascular endothelial growth factor (VEGF)(Reference Wang, Wood and Trayhurn6). In contrast, the release of adiponectin is decreased in hypoxia, possibly through activation of endoplasmic reticulum (ER) stress(Reference Hosogai, Fukuhara and Oshima3). In addition to adipokines, hypoxia leads to a prominent induction of GLUT1 and increased glucose uptake while it is unclear if hypoxia affects the translocation of the insulin-sensitive GLUT4(Reference Wood, Wang, Lorente-Cebrian and Trayhurn7).
Hypoxia in adipose tissue adds to other mechanisms being involved in the development of obesity and its associated co-morbidities, namely inflammation with increased macrophage infiltration into adipose tissue and ER stress. Over the past few years, increasing evidence has supported the concept of chronic low-grade inflammation in expanding fat as a key step to obesity-associated insulin resistance(Reference Xu, Barnes and Yang8). This process is characterised by macrophages infiltrating adipose tissue(Reference Weisberg, McCann, Desai, Rosenbaum, Leibel and Ferrante9) and an increase in the release of pro-inflammatory adipokines such as TNF-α, monocyte chemotactic protein (MCP)-1 and IL-8(Reference Trayhurn and Wood10). At present, it is not clear if hypoxia initiates or augments the inflammatory response in adipose tissue. Another upcoming mechanism of adipocyte ‘stress’ is ER stress. There are several explanations why ER stress occurs particularly in fat in obesity that include increased protein synthesis due to increased energy availability or even glucose deprivation due to insulin resistance in adipose tissue(Reference Gregor and Hotamisligil11). Hypoxia was also proposed to be a cause of ER stress(Reference Hosogai, Fukuhara and Oshima3). Furthermore, hypoxia and ER stress might be closely related since signalling pathways for both forms of stress merge in common pathways, such as activation of mammalian target of rapamycin or c-Jun N-terminal kinase.
Through the secretion of various adipokines, adipocytes may influence other cell types in adipose tissue referred to as the stromavascular fraction. The issue of increased VEGF release by hypoxic adipocytes and macrophages is of special interest(Reference Ye, Gao, Yin and He2, Reference Wang, Wood and Trayhurn6). This adipokine might stimulate endothelial cells and lead to neovascularisation. Furthermore, adipose tissue-residing macrophages are involved in the process of neovascularisation(Reference Khmelewski, Becker, Meinertz and Ito12) possibly through MCP-1 signalling from adipocytes, further contributing to the prevention of hypoxia in adipose tissue. This would be an example of macrophages exerting positive effects in adipose tissue, besides inflammation.
Hypoxia does not only play a role in pathological states, but occurs also in normal physiology, for example during exercise. Both hypoxia in obesity and hypoxia in exercise activate 5′AMP-activated protein kinase (AMPK). Acute activation of AMPK in exercise leads to increased insulin sensitivity, namely in skeletal muscle and adipose tissue where glucose uptake and fatty acid oxidation increase(Reference Daval, Foufelle and Ferre13). Pharmacological activation of AMPK is an interesting drug target for type 2 diabetes. In the obese state, hypoxia in adipose tissue is a chronic effect and may therefore be distinct from acute hypoxia observed in exercise. It may also be speculated that AMPK activation may differ somehow in both situations, explaining why hypoxia may exert such differential effects. So, it must be noticed that hypoxia is not always ‘bad’ per se. However, hypoxia in adipose tissue might also be deleterious in other circumstances than obesity. Namely, one very recent study revealed that obstructive sleep apnoea syndrome patients are characterised by lower adiponectin levels, indicating that repetitive intermittent hypoxia might influence adipocyte secretion and function(Reference Nakagawa, Kishida and Kihara14).
In summary, hypoxia occurs in expanding adipose tissue where it contributes together with inflammatory processes and ER stress to the altered secretory function of this tissue. Understanding hypoxic events in adipose tissue might be helpful to better understand the pathophysiology of obesity and to target involved pathways for the treatment of obesity-related diseases.
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The study of hypoxia in adipose tissue in relation to obesity is timely, since some very recent studies have put these topics in a physiological context. In this issue of the British Journal of Nutrition, Trayhurn et al. (Reference Trayhurn, Wang and Wood1) summarise our current knowledge on hypoxia in adipose tissue and isolated adipocytes. Hypoxia can be observed in both physiological and pathological situations. Each tissue in the human body might be more or less normally characterised by lower O2 pressure than in arterial blood, as detailed in the paper by Trayhurn et al. (Reference Trayhurn, Wang and Wood1) In fact, compared with O2 pressure in arterial blood, some organs such as the spleen, thymus and brain seem to be highly hypoxic. As for white adipose tissue, it could be demonstrated that oxygenation is comparable with general tissue oxygenation in lean animals, while obese littermates are characterised by about 60 % lower O2 pressure in fat(Reference Ye, Gao, Yin and He2). In adipose tissue of mice, hypoxia underlies the increased production of adipokines and the development of obesity and the metabolic syndrome(Reference Hosogai, Fukuhara and Oshima3). Furthermore, it could be demonstrated in humans that hypoxia occurs in the obese state(Reference Cancello, Henegar and Viguerie4).
Hypoxia leads to activation of the transcription factor hypoxia inducible factor (HIF)-1α, which is a key player in the adaptive response to low O2 availability in tissues. HIF-1α stimulates the transcription of various genes that affect cell proliferation, angiogenesis, the vascular tone, glucose metabolism and the extracellular matrix(Reference Semenza5). Hypoxia in isolated adipocytes has been studied to a greater extent than in vivo, revealing that hypoxia causes various changes in protein expression and secretion behaviour in this cell type. Isolated adipocytes exposed to hypoxia exhibit the same dysregulation of secretory function as observed in expanded adipose tissue including increased release of IL-6, leptin and vascular endothelial growth factor (VEGF)(Reference Wang, Wood and Trayhurn6). In contrast, the release of adiponectin is decreased in hypoxia, possibly through activation of endoplasmic reticulum (ER) stress(Reference Hosogai, Fukuhara and Oshima3). In addition to adipokines, hypoxia leads to a prominent induction of GLUT1 and increased glucose uptake while it is unclear if hypoxia affects the translocation of the insulin-sensitive GLUT4(Reference Wood, Wang, Lorente-Cebrian and Trayhurn7).
Hypoxia in adipose tissue adds to other mechanisms being involved in the development of obesity and its associated co-morbidities, namely inflammation with increased macrophage infiltration into adipose tissue and ER stress. Over the past few years, increasing evidence has supported the concept of chronic low-grade inflammation in expanding fat as a key step to obesity-associated insulin resistance(Reference Xu, Barnes and Yang8). This process is characterised by macrophages infiltrating adipose tissue(Reference Weisberg, McCann, Desai, Rosenbaum, Leibel and Ferrante9) and an increase in the release of pro-inflammatory adipokines such as TNF-α, monocyte chemotactic protein (MCP)-1 and IL-8(Reference Trayhurn and Wood10). At present, it is not clear if hypoxia initiates or augments the inflammatory response in adipose tissue. Another upcoming mechanism of adipocyte ‘stress’ is ER stress. There are several explanations why ER stress occurs particularly in fat in obesity that include increased protein synthesis due to increased energy availability or even glucose deprivation due to insulin resistance in adipose tissue(Reference Gregor and Hotamisligil11). Hypoxia was also proposed to be a cause of ER stress(Reference Hosogai, Fukuhara and Oshima3). Furthermore, hypoxia and ER stress might be closely related since signalling pathways for both forms of stress merge in common pathways, such as activation of mammalian target of rapamycin or c-Jun N-terminal kinase.
Through the secretion of various adipokines, adipocytes may influence other cell types in adipose tissue referred to as the stromavascular fraction. The issue of increased VEGF release by hypoxic adipocytes and macrophages is of special interest(Reference Ye, Gao, Yin and He2, Reference Wang, Wood and Trayhurn6). This adipokine might stimulate endothelial cells and lead to neovascularisation. Furthermore, adipose tissue-residing macrophages are involved in the process of neovascularisation(Reference Khmelewski, Becker, Meinertz and Ito12) possibly through MCP-1 signalling from adipocytes, further contributing to the prevention of hypoxia in adipose tissue. This would be an example of macrophages exerting positive effects in adipose tissue, besides inflammation.
Hypoxia does not only play a role in pathological states, but occurs also in normal physiology, for example during exercise. Both hypoxia in obesity and hypoxia in exercise activate 5′AMP-activated protein kinase (AMPK). Acute activation of AMPK in exercise leads to increased insulin sensitivity, namely in skeletal muscle and adipose tissue where glucose uptake and fatty acid oxidation increase(Reference Daval, Foufelle and Ferre13). Pharmacological activation of AMPK is an interesting drug target for type 2 diabetes. In the obese state, hypoxia in adipose tissue is a chronic effect and may therefore be distinct from acute hypoxia observed in exercise. It may also be speculated that AMPK activation may differ somehow in both situations, explaining why hypoxia may exert such differential effects. So, it must be noticed that hypoxia is not always ‘bad’ per se. However, hypoxia in adipose tissue might also be deleterious in other circumstances than obesity. Namely, one very recent study revealed that obstructive sleep apnoea syndrome patients are characterised by lower adiponectin levels, indicating that repetitive intermittent hypoxia might influence adipocyte secretion and function(Reference Nakagawa, Kishida and Kihara14).
In summary, hypoxia occurs in expanding adipose tissue where it contributes together with inflammatory processes and ER stress to the altered secretory function of this tissue. Understanding hypoxic events in adipose tissue might be helpful to better understand the pathophysiology of obesity and to target involved pathways for the treatment of obesity-related diseases.