Hypoxia in Obesity and Diabetes: Potential Therapeutic Effects of Hyperoxia and Nitrate

Abstract

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-1α (HIF-1α) is involved in the regulation of several genes of the metabolic pathways including proinflammatory adipokines, endothelial NO synthase (eNOS), and insulin signaling components. It seems that adipose tissue hypoxia and NO-dependent vascular and cellular dysfunctions are responsible for other consequences linked to obesity-related disorders. Although hyperoxia could reverse hypoxic-related disorders, it increases the production of reactive oxygen species (ROS) and decreases the production of NO. Nitrate can restore NO depletion and has antioxidant properties, and recent data support the beneficial effects of nitrate therapy in obesity and diabetes. Although it seems reasonable to combine hyperoxia and nitrate treatments for managing obesity/diabetes, the combined effects have not been investigated yet. This review discusses some aspects of tissue oxygenation and the potential effects of hyperoxia and nitrate interventions on obesity/diabetes management. It can be proposed that concomitant use of hyperoxia and nitrate is justified for managing obesity and diabetes.

Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

“…In obesity, adipocytes become hypertrophied and the attendant relative reduction in vascularity predisposes them to hypoxia because of limitations in oxygen diffusion from the vasculature through the increased adipocyte mass . Obesity produced by high fat diets, induces expression of adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane uncoupling protein, that increases adipocyte oxygen consumption . This is further evidenced by palmitate, a fatty acid that can produce deleterious effects on cardiomyocytes through increases in ANT2 activity that increases adipocyte oxygen consumption and HIF‐1α expression .…”

“…Obesity produced by high fat diets, induces expression of adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane uncoupling protein, that increases adipocyte oxygen consumption . This is further evidenced by palmitate, a fatty acid that can produce deleterious effects on cardiomyocytes through increases in ANT2 activity that increases adipocyte oxygen consumption and HIF‐1α expression . In humans, HIF‐1α protein levels in visceral and subcutaneous adipose tissue are increased with obesity .…”

“…Obesity‐associated inflammation is mediated by increased M1 macrophage accumulation in adipose tissue in part as a response to adipocyte cell death, which in turn leads to release of IL‐6, MCP‐1, TNF‐α, and IL‐1β . HIF‐1α is integral to proper macrophage function and animal models with macrophage‐specific HIF‐1α knockout exhibit impaired macrophage recruitment .…”

“…Amongst many of its characteristics, obesity has been viewed as a hypoxic state . The chronic hypoxic state can lead to adipose tissue dysfunction, insulin resistance, and inflammation which, in turn, can lead to organ damage that produces the metabolic dysfunction of diabetes mellitus as well as cardiovascular disease . Hypoxia inducible factor 1‐alpha (HIF‐1α), which is activated in tissue hypoxia, is an intriguing factor mediating some of the effects of obesity and the metabolic syndrome (MetS).…”

Inflammation stimulates hypoxia‐inducible factor‐1α regulatory activity in 3T3‐L1 adipocytes with conditioned medium from lipopolysaccharide‐activated RAW 264.7 macrophages

“…The protein stability is negatively regulated by the von Hippel‐Lindau‐dependent ubiquitination and subsequent proteasomal degradation in normoxia (Jaakkola et al, ). HIF‐1 regulates the transcription of numerous genes involved in vascular development, glucose and energy metabolism, iron metabolism, and cell proliferation and viability (Norouzirad et al, ; Semenza, ). Under certain metabolic conditions, the mammalian target of rapamycin (mTOR), a downstream target of AKT, modulates transcriptional activity through the nuclear factor kappa B p65 (NF‐κB), signal transducer and activator of transcription 3 (STAT3), HIF‐1α, and peroxisome proliferator‐activated receptor gamma (PPARγ) pathways in a cell type‐specific manner (Weichhart, Hengstschläger, & Linke, ).…”