Cordycepin, a 3-deoxyadenosine, is the predominant functional component of the fungus Cordyceps militaris, a traditional Chinese medicine. Previous studies investigating the inhibition of cancer cells by cordycepin identified that it not only promotes cell apoptosis, but also controls cell proliferation. Furthermore, studies have elucidated the molecular mechanisms of inhibiting cell proliferation by cordycepin binding the A3 adenosine receptor, activating G protein, inhibiting cAMP formation, decreasing glycogen synthase kinase-3β/β-catenin activation and suppressing cyclin D1 and c-myc expression. The most significant signaling pathway in which cell apoptosis is induced by cordycepin is the caspase pathway. Cordycepin induces cell apoptosis via binding the DR3 receptor and consequently activating caspase-8/-3. Taken together, these studies demonstrate that cordycepin may be used as a natural medicine, as it can not only control tumor cell proliferation, but also induce cancer cell apoptosis.

To investigate the effects of hypoxic exercise training on microRNA (miRNA) expression and the role of miRNA expression in regulating lipid metabolism, 20 dietary-induced obese SD rats were divided into a normoxic sedentary group (N, n=10) and a hypoxic exercise training group (H, n=10). After four weeks, measurements were taken of body weight, body length, fat mass, serum lipid concentration, miRNAs differentially expressed in rat liver, and gene and protein expression levels of peroxisome proliferator activated receptor α (PPARα), fatty acid synthetase (FAS), and carnitine palmitoyl transferase 1A (CPT1A) in rat liver. Body weight, Lee’s index, fat mass, fat/weight ratio, and serum levels of total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) were all significantly lower in the H group than in the N group (P<0.01). Six miRNAs expressed significantly differently in the liver (P<0.05). Specifically, expression levels of miR-378b were significantly lower in the H group than in the N group (P<0.05). Compared with the normoxic sedentary group, hypoxic exercise training resulted in a lower ratio of FAS mRNA to CPT1A mRNA (P<0.05), as well as lower CPT1A protein levels (P<0.01), while a higher ratio of FAS to CPT1A protein levels (P<0.01) was observed. In conclusion, hypoxic training may elevate the resistance of high fat diet induced obesity in rats by reducing the expression of miR-378b, and decrease the fatty acid mitochondrial oxidation in obese rat livers by decreasing the protein expression of CPT1A and increasing the protein expression ratio of FAS/CPT1A.

Hypoxic exercise may represent a novel therapeutic strategy to reduce and prevent obesity through the regulation of lipid metabolism. During hypoxic exercise, the targeting of peroxisome proliferator-activated receptor gamma (PPARγ) by miR-27b has been proposed to be one of the mechanisms involved in the modulation of lipid metabolism. We have previously shown that miR-27b can repress PPARγ and lipid metabolism-associated factors, thereby affecting lipid metabolism during hypoxic exercise in a rat model of obesity. In the current study, we aimed to confirm the role of miR-27b in the regulation of lipid metabolism. First, miR-27b expression was either upregulated or downregulated through the injection of adeno-associated virus (AAV) 9 containing a miR-27b expression cassette or miR-27b-3p inhibitor, respectively, into the right gastrocnemius muscle of obese rats. The rats were then subjected to a 4-week program of hypoxic exercise, and a series of parameters related to lipid metabolism were systematically evaluated, including body composition, blood lipid levels, miR-27b RNA levels, and mRNA and protein levels of PPARγ and those of its downstream lipid metabolism-associated factors. No significant differences were found in body composition between rats expressing different levels of miR-27b. However, regarding blood lipids, miR-27b overexpression led to increased concentrations of triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and free fatty acids (FFAs), while inhibition of miR-27b decreased the total cholesterol (TC) level and increased that of high-density lipoprotein cholesterol (HDL-C). At the mRNA level, miR-27b overexpression downregulated the expression of Pparγ, but upregulated that of lipid metabolism-associated factors such as heart-type fatty acid-binding protein (H-FABP), fatty acid transport protein 1 (FATP1), adipose triglyceride lipase (ATGL), and lipoprotein lipase (LPL), whereas miR-27b inhibition elicited the opposite effect; however, inhibition of miR-27b led to elevated cholesterol 7 alpha-hydroxylase (CYP7A1) and fatty acid translocase 36 (CD36) levels. Similarly, at the protein level, miR-27b overexpression promoted a decrease in the concentration of PPARγ, whereas miR-27b inhibition led to an increase in PPARγ levels, as well as those of CYP7A1, CD36, ATGL, and LPL. Overall, our results indicated that hypoxic exercise regulates lipid metabolism via the miR-27b/PPARγ pathway and modulates ATGL and LPL expression through inducing their post-transcriptional modifications.

Background: Hypobaric hypoxia results in weight loss in obese individuals, and exercise training is advocated for the treatment of obesity and its related metabolic dysfunctions. The purpose of this study was to investigate the effects of hypoxic living and exercise training on obesity and adipose tissue leptin/leptin receptor in dietary-induced obese rats. Methods: One hundred and thirty high-fat diet fed Sprague-Dawley rats were assigned into one of the following groups (n=10 each): control, sedentary hypoxic living for 1 to 4 weeks (SH1, SH2, SH3, and SH4), living and exercise training in normoxic conditions for 1 to 4 weeks (TN1, TN2, TN3, and TN4), and living and exercise training in hypoxic conditions for 1 to 4 weeks (TN1, TN2, TN3, and TN4). Epididymal adipose tissue expression levels of leptin and leptin receptor were determined. Results: Compared to hypoxic living and living and exercise training in normoxic conditions, living and exercise training in hypoxic conditions for 3-4 weeks resulted in lower Lee index (P<0.05 to P<0.01), and higher expression of leptin and leptin receptor (P<0.05 to P<0.01) in adipose tissue. Conclusion: In a rodent model of altitude training, living and exercise training in hypoxic conditions resulted in greater alterations in obesity and adipose tissue leptin/leptin receptor than hypoxic living alone and living and exercise training in normoxic conditions.

The aim of the present study was to investigate the role of miR‑92a in lipid metabolism in hypoxic rats. Microarray analysis and reverse transcription‑quantitative (RT‑q)PCR were used to detect changes in the mRNA expression levels of miR‑92a in the epididymal fat of hypoxic and normoxic rats. The downstream target mRNA of miR‑92a was predicted using bioinformatics analysis and verified using a dual luciferase reporter assay. Changes in the expression of frizzled (Fzd)10 and c‑Myc in the epididymal fat were detected using RT‑qPCR and western blotting. Microarray analysis and RT‑qPCR results showed that the expression of miR‑92a was significantly lower in the fat tissues of the hypoxic rats compared with the normoxic rats. The results of the dual luciferase reporter assay showed that the target gene of miR‑92a was Fzd10, which is an acceptor in the Wnt pathway. Fzd10 expression was upregulated in the hypoxic rats. The mRNA expression levels of c‑Myc, which is located downstream of the Wnt pathway, was increased significantly. The increase in the mRNA and protein expression levels of Fzd10 and c‑Myc may be associated with miR‑92a downregulation. Downregulation of miR‑92a in‑turn may result in lipolysis through the regulation of the Wnt/β‑catenin signaling pathway, and thus weight loss in the rats.