Hypoxia as a Double-Edged Sword to Combat Obesity and Comorbidities

Abstract

The global epidemic of obesity is tightly associated with numerous comorbidities, such as type II diabetes, cardiovascular diseases and the metabolic syndrome. Among the key features of obesity, some studies have suggested the abnormal expansion of adipose-tissue-induced local endogenous hypoxic, while other studies indicated endogenous hyperoxia as the opposite trend. Endogenous hypoxic aggravates dysfunction in adipose tissue and stimulates secretion of inflammatory molecules, which contribute to obesity. In contrast, hypoxic exposure combined with training effectively generate exogenous hypoxic to reduce body weight and downregulate metabolic risks. The (patho)physiological effects in adipose tissue are distinct from those of endogenous hypoxic. We critically assess the latest advances on the molecular mediators of endogenous hypoxic that regulate the dysfunction in adipose tissue. Subsequently we propose potential therapeutic targets in adipose tissues and the small molecules that may reverse the detrimental effect of local endogenous hypoxic. More importantly, we discuss alterations of metabolic pathways in adipose tissue and the metabolic benefits brought by hypoxic exercise. In terms of therapeutic intervention, numerous approaches have been developed to treat obesity, nevertheless durability and safety remain the major concern. Thus, a combination of the therapies that suppress endogenous hypoxic with exercise plans that augment exogenous hypoxic may accelerate the development of more effective and durable medications to treat obesity and comorbidities.

Chronic Intermittent Hypoxia-Induced Dysmetabolism Is Associated with Hepatic Oxidative Stress, Mitochondrial Dysfunction and Inflammation

“…Indeed, different studies report that hyperglycemia inhibits the expression and activity of HIFs in different tissues even in conditions of hypoxia, namely pancreatic β-cells and the retina [41,42], and that HIF-2α is usually activated slower and for a longer time [42]. As previously discussed in this manuscript, this effect could potentially result from a delicate balance between hypoxia and angiogenesis [29][30][31]. It is plausible that the lack of significant alterations in HIF levels in the HFIH group might be attributed to a compensatory angiogenic response triggered by an initial hypoxia induced by the consumption of a HF diet.…”

“…It is consensual that high-fat diet promotes hypoxia and inflammation; however, it is also known that hypoxia activates angiogenesis [29]. Knowing that in adipose tissue, increased angiogenesis attenuates the negative effects of hypoxia (for a review, see [30]) and that tumor hypoxia is alleviated by vascular normalization (for a review, see [31]), we can postulate that activated hepatic angiogenesis in HF-diet-fed animals may prevent the exacerbation of dysmetabolic states with 2 weeks of CIH.…”

Comparison of urine proteome between obese people and normal weight people

“…These biological processes related to nutrition and metabolism, such as: response to hypoxia, which has been shown to exacerbate adipose tissue dysfunction and stimulate the secretion of inflammatory molecules, which can lead to obesity [35], ADP catabolic process, cellular response to nutrient levels, lipid transport and cholesterol metabolic process, UDP-N-acetylglucosamine biosynthetic process, adipose tissue UDP-N-acetylglucosamine was significantly positively correlated with BMI that inhibits UDP-N-acetylglucosamine biosynthesis, leading to reduced glucose-stimulated leptin release in cultured adipocytes [36]. Some studies have shown that dysregulation of glucose metabolism associated with obesity, diabetes or cancer correlates with increased levels of the enzyme in this process.…”