Chronic Intermittent Hypoxia Exposure Alternative to Exercise Alleviates High-Fat-Diet-Induced Obesity and Fatty Liver

Abstract

Obesity often concurs with nonalcoholic fatty liver disease (NAFLD), both of which are detrimental to human health. Thus far, exercise appears to be an effective treatment approach. However, its effects cannot last long and, moreover, it is difficult to achieve for many obese people. Thus, it is necessary to look into alternative remedies. The present study explored a noninvasive, easy, tolerable physical alternative. In our experiment, C57BL/6 mice were fed with a high-fat diet (HFD) to induce overweight/obesity and were exposed to 10% oxygen for one hour every day. We found that hypoxia exerted protective effects. First, it offset HFD-induced bodyweight gain and insulin resistance. Secondly, hypoxia reversed the HFD-induced enlargement of white and brown adipocytes and fatty liver, and protected liver function. Thirdly, HFD downregulated the expression of genes required for lipolysis and thermogenesis, such as UCP1, ADR3(beta3-adrenergic receptor), CPT1A, ATGL, PPARα, and PGC1α, M2 macrophage markers arginase and CD206 in the liver, and UCP1 and PPARγ in brown fat, while these molecules were upregulated by hypoxia. Furthermore, hypoxia induced the activation of AMPK, an energy sensing enzyme. Fourthly, our results showed that hypoxia increased serum levels of epinephrine. Indeed, the effects of hypoxia on bodyweight, fatty liver, and associated changes in gene expression ever tested were reproduced by injection of epinephrine and prevented by propranolol at varying degrees. Altogether, our data suggest that hypoxia triggers stress responses where epinephrine plays important roles. Therefore, our study sheds light on the hope to use hypoxia to treat the daunting disorders, obesity and NAFLD.

Short-Term Mild Hypoxia Modulates Na,K-ATPase to Maintain Membrane Electrogenesis in Rat Skeletal Muscle

“…Lipid metabolism plays a major role in cell physiology, and its changes, which are part of hypoxic adaptation, remain poorly understood [ 56 , 57 ]. The activity of Na,K-ATPase is regulated by the lipid environment, which is realized through direct protein–lipid interactions and/or by influencing the physical properties of the lipid bilayer [ 45 , 46 ].…”

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

“…Hypoxic induces expression of factors such as UCP1, ADR3 (β3-adrenergic receptor), CPT1A, adipose triglyceride lipase (ATGL), PPARα and PGC1α, and arginase in liver. Moreover, the M2 macrophage marker, CD206 and recombinant PPARγ in liver and and UCP1 in brown fat were upregulated [ 230 ]. In contrast, in ApoE knockout mice, 6.5% hypoxic intervention increased adipose Angptl4 levels, inhibited adiponectin lipase, increased fasting plasma triglyceride and very low-density lipoprotein cholesterol levels and increased the size of atherosclerotic plaques [ 231 ].…”

Intermittent hypoxia conditioning as a potential prevention and treatment strategy for ischemic stroke: Current evidence and future directions

“…The specific mechanism by which hypoxia improves glucose and lipid metabolism remains unclear. Animal studies have shown that the regulatory mechanism of IH on metabolism may be related to hypoxia-induced epinephrine (Luo et al, 2022), ameliorating insulin resistance via the HIF-insulin signaling pathway (Tian et al, 2016) recovery of mitochondrial activity (Trzepizur et al, 2015; Table 2).…”

“…HIFs are the major regulators of the hypoxic transcriptional response, and the O 2 -sensitive prolyl/aspartate hydroxylase (PHDs/FIH) regulates HIF activity in the transition between normoxia and hypoxia conditions (Kaelin and Ratcliffe, 2008). Under various pathological conditions, hypoxia conditioning serves to improve the clinical outcome of the disease by regulating the cellular environment (Taylor and Colgan, 2017), thereby enhancing mitochondrial metabolism, enhancing antioxidant and antiinflammatory capacity, and promoting the repair process to reduce the extent of neurological and vascular damage (Walshe and D'Amore, 2008;Tsai et al, 2013;Qiao et al, 2015;Ryou et al, 2017;Manukhina et al, 2018;Pietrogrande et al, 2019;Ren et al, 2020;Li et al, 2022;Luo et al, 2022). Since the underlying cellular and molecular mechanisms are unclear, more relevant research evidence is needed.…”