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.

Keywords: O2; PO2; adipose tissue; hypoxic; obesity.

Figure 1

Adipose tissue adaptively remodels to cope with obesity (e.g., cell proliferation and expansion, increased energy metabolism). Angiogenesis is increased to counteract the acute endogenous hypoxic that accompanies adipocyte expansion. With the development of obesity, chronic endogenous hypoxic will induce inflammation, fibrosis of WAT and BAT “whitening”, leading to ectopic lipid accumulation in other organs. This may eventually give rise to metabolic diseases, such as coronary atherosclerosis, sarcopenia and NAFLD.

Figure 2

Changes in adipocyte pathways under different hypoxic interventions. In in vitro studies of cellular responses to hypoxic, 1% O₂ is usually used. This was considered as severe hypoxic, as well as acute irritation to the body. However, this was only an extreme case of the mechanism being used to prove. Usually, the body will adapt to the severe hypoxic, and, meanwhile, different concentrations of O₂ in adipose tissue will induce changes in different signaling pathway with distinct outcomes. Different colors represent different oxygen concentrations.