The prevalence of obesity and diabetes is increasing worldwide. Obesity and diabetes are associated with oxidative stress, inflammation, endothelial dysfunction, insulin resistance, and glucose intolerance. Obesity, a chronic hypoxic state that is associated with decreased nitric oxide (NO) bioavailability, is one of the main causes of type 2 diabetes. The hypoxia-inducible factor-1
Obesity and diabetes, two major health problems worldwide, have shown an increasing trend in their prevalence over time [
There are three types of adipocytes or adipose tissues [
Anatomically, adipose tissues are distributed in central adipose tissues (visceral and upper abdominal subcutaneous fats) and peripheral adipose tissues (hip and gluteofemoral fats) [
Some characteristics of the three types of adipocytes.
White adipocytes | Brown adipocytes | Brite or beige adipocytes | References | |
---|---|---|---|---|
Origin in adulthood | Mesenchymal |
Mesenchymal precursors, |
WAT adipocyte and |
[ |
Transcription factor | Myf5− and Tcf21 | Myf5+ | Tcf21 | [ |
Specific gene expression | Leptin | UCP1 and Zic1 | UCP1 and Hoxc9 | [ |
Number of |
Low | High | High | [ |
Main function | Lipid storage | Heat producer | Heat producer | [ |
Effect on obesity | Obesogenic | Antiobesity | Antiobesity | [ |
Histological phenotype | Large cells with one huge |
Small cells with several lipid |
Small cells with several |
[ |
Anatomical description |
Epididymal, mesenteric, |
Interscapular, axillary, cervical, |
Inguinal, cardiac, and |
[ |
Hoxc9: homeobox9; Myf5: myogenic factor 5; Tcf21: transcription factor 21; UCP 1: uncoupling protein 1; WAT: white adipose tissue; Zic1: zinc finger protein in cerebellum 1.
In humans, the turnover of adipocytes is low, that is, ~10% per year, a rate that does not change in the early stages of obesity [
The functions of adipose tissues vary greatly between obese and lean subjects [
It has been estimated that the amount of adipose tissue macrophage infiltration in lean mice and humans is under 10% [
Some adipose tissue secreted adipokines or cytokines.
Adipo/cytokines | Function | References |
---|---|---|
Adiponectin | Increases |
[ |
Sfrp5 | Is increased by calorie restriction diet and has an anti-inflammatory action. | [ |
Adipolin | Is known as adipose-derived insulin-sensitizing factor, improves glucose metabolism, and decreases insulin resistance and inflammation. | [ |
Apelin | Inhibits diet-induced obesity, due to its improvement of vascular integrity. It is positively correlated with BMI, and it is upregulated by insulin in obesity. | [ |
PPAR |
Induces storage of lipids and adipogenesis and reduces lipotoxicity; it also regulates whole body insulin sensitivity. | [ |
Leptin | Is a cytokine-like hormone, which inhibits food intake and energy expenditure. It impairs NO-mediated component. | [ |
Resistin | Is increased in genetic- and diet-induced obesity models. It is specific for WAT and causes insulin resistance. | [ |
AMPK: adenosine monophosphate-activated protein kinase; BMI: body mass index; eNOS: endothelial nitric oxide (NO) synthase; Sfrp5: soluble (secreted) frizzled-related protein 5; WAT: white adipose tissue.
The insulin signaling pathways have been previously reported in detail by several authors [
Insulin resistance in obesity. Obesity is associated with hypoxia, inflammation, and lipolysis. These conditions can lead to insulin resistance by impairment of insulin receptor substrate (IRS)/phosphatidyl inositol-3 kinase (PI3K)/AKT pathway. The c-Jun amino-terminal kinase (JNK), Toll-like receptors (TLRs), Akt substrate of 160 kDa (AS160), and AKT/serine (Ser)-1177 are the sensing points that hypoxia and inflammatory factors can inhibit insulin signaling. It should be noted that not all the above signaling occurs in every cell. GLUT: glucose transporter; IKKB: I
Circulating levels of inflammatory factors including free fatty acids and TNF-
In obesity, the overproduction of ROS leads to adipocyte dysfunction. Increased substrates of the electron transport chain and an increased potential of the mitochondrial inner membrane are the main reasons for increased ROS, in particular the superoxide anion [
The enlargement of adipocytes leads to increase in protein synthesis, causing endoplasmic reticulum (ER) stress due to inappropriate folding. In addition, chronic high free fatty acid levels can also cause ER stress [
Oxygenation of adipocytes is different depending on their location and types [
Hypoxia can increase cell necrosis and apoptosis in humans and mice. Yin et al. have reported that in vitro hypoxia (1% oxygen for 16 hours) causes 75% cell death in 3T3-L1 adipocytes via increased necrosis (40%) and apoptosis (35%) [
Hypoxia affects cellular pathways by stimulation of lipolysis, inhibition of adipogenesis, and adipocyte differentiation [
Hypoxia-inducible factor-1
Hypoxia-inducible factor-1
Factors influencing HIF-1
Effectors | HIF-1 |
HIF-1 |
References |
---|---|---|---|
Oxygen | ✓ | [ | |
2-OG (2-oxoglutarate) | ✓ | [ | |
Hypoxia | ✓ | [ | |
Hyperoxia | ✓ |
[ | |
iNOS-derived NO | ✓ | [ | |
RACK1 | ✓ | [ | |
HSP90 | ✓ | [ | |
ROS | ✓ | [ |
HIF-1
Collectively, the overall function of HIF-1
NO contributes to vasodilation, vascular remodeling, angiogenesis, and glucose metabolism, as well as playing a protective role in cardiovascular disease [
Exogenously delivered NO (sodium nitroprusside as a NO donor) stimulates uptake and transendothelial transport (TET) of insulin by inhibition of protein tyrosine phosphatase 1B (PTP1B) via S-nitrosylation; PTP1B dephosphorylates the IRS-1 and IRS-2 tyrosines, as well as inhibiting insulin signaling and TET [
Despite previous reports on the carcinogenic effect of dietary nitrate/nitrite [
Elevated free fatty acids in obesity and hypoxia [
To summarize, obesity and hypoxia cause oxidative stress and NO depletion, leading to endothelial dysfunction, and consequent obesity disorders. Inorganic nitrate/nitrite apart from replenishing decreased NO bioavailability has antioxidant properties; inorganic nitrite reduces superoxide anion bioavailability and iNOS activity [
Normobaric and hyperbaric oxygen therapies (NBOT and HBOT, resp.) have been used in medicine. NBOT has beneficial therapeutic effects on severe acute ischemic stroke [
Obesity is a chronic hypoxic state, which causes several deleterious changes such as adipose tissue dysfunction, insulin resistance, inflammation, and organ damage, changes which can lead to other metabolic disorders including cardiovascular disease and diabetes. In recent years, to prevent the adverse effects of obesity, some interventions have been suggested, such as drugs, exercise, and healthier diet patterns [
Recent data support the beneficial effects of a nutritional-based nitrate/nitrite therapy in obesity and diabetes [
The proposal for this study was approved by the ethics committee of our institute.
No competing interests are declared by the authors.
The study was conceived by all authors. Reza Norouzirad and Asghar Ghasemi drafted the manuscript; Reza Norouzirad, Asghar Ghasemi, and Pedro González-Muniesa critically revised the manuscript. All of the authors read and approved the final manuscript.
The authors acknowledge Ms. Niloofar Shiva, an academic faculty member of Research Institute for Endocrine Sciences, for critical editing of the English grammar and syntax of the manuscript. This study has been extracted from a part of the thesis written by Reza Norouzirad, Ph.D. candidate, Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, and was funded and supported by the Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.