Astragalus polysaccharide prevents heart failure-induced cachexia by alleviating excessive adipose expenditure in white and brown adipose tissue

Abstract

Background Astragalus polysaccharide (APS) is a key active ingredient isolated from Astragalus membranaceus that has been reported to be a potential treatment for obesity and diabetes by regulating lipid metabolism and adipogenesis, alleviating inflammation, and improving insulin resistance. However, whether APS regulates lipid metabolism in the context of cachexia remains unclear. Therefore, this study analysed the effects of APS on lipid metabolism and adipose expenditure in a heart failure (HF)-induced cardiac cachexia rat model. Methods A salt-sensitive hypertension-induced cardiac cachexia rat model was used in the present study. Cardiac function was detected by echocardiography. The histological features and fat droplets in fat tissue and liver were observed by H&E staining and Oil O Red staining. Immunohistochemical staining, Western blotting and RT‒qPCR were used to detect markers of lipolysis and adipose browning in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Additionally, sympathetic nerve activity and inflammation in adipose tissue were detected. Results Rats with HF exhibited decreased cardiac function and reduced adipose accumulation as well as adipocyte atrophy. In contrast, administration of APS not only improved cardiac function and increased adipose weight but also prevented adipose atrophy and FFA efflux in HF-induced cachexia. Moreover, APS inhibited HF-induced lipolysis and browning of white adipocytes since the expression levels of lipid droplet enzymes, including HSL and perilipin, and beige adipocyte markers, including UCP-1, Cd137 and Zic-1, were suppressed after administration of APS. In BAT, treatment with APS inhibited PKA-p38 MAPK signalling, and these effects were accompanied by decreased thermogenesis reflected by decreased expression of UCP-1, PPAR-γ and PGC-1α and reduced FFA β-oxidation in mitochondria reflected by decreased Cd36, Fatp-1 and Cpt1. Moreover, sympathetic nerve activity and interleukin-6 levels were abnormally elevated in HF rats, and astragalus polysaccharide could inhibit their activity. Conclusion APS prevented lipolysis and adipose browning in WAT and decreased BAT thermogenesis. These effects may be related to suppressed sympathetic activity and inflammation. This study provides a potential approach to treat HF-induced cardiac cachexia.

Circadian rhythm dysregulation aggravates adipose tissue depletion in heart failure-induced cachexia

“…Additionally, in our study, we found beiging markers, including Ucp-1, Cd137, Tbx-1 and Zic-1, indicating increased beiging of WAT in HF-induced cachexia by MCT injection. This was consistent with our previous study using a salt-sensitive hypertension-induced cardiac cachexia rat model [20]. Moreover, our study showed, for the rst time, that disrupted circadian rhythm aggravates beiging of WAT in HF-induced cachexia.…”

“…In the lipolysis process, TGs stored within lipid droplets are hydrolysed into FFAs and released as fuel in peripheral tissues according to metabolic demand. In the hypermetabolism state of cachexia, excessive TGs are hydrolysed, causing not only adipocyte atrophy but also increased FFA ectopic deposition in peripheral tissue [20]. As described previously, fatty liver and elevated blood levels of FFAs were found in cachexia caused by cancer and severe burn injury [36].…”

“…Rats in the LV-Control shRNA group were injected with empty lentiviral vehicle. Rats in the control group and DL group, LV-Bmal1 shRNA group and LV-Control shRNA group were fed in pairs to match the daily food intake of the LD group [20].…”

Astragalus polysaccharide: implication for intestinal barrier, anti-inflammation, and animal production

“…In addition, in ovo injection of 2 mg APS per egg significantly enhanced VH and the ratio of VH/CD and improved intestinal morphology and development of chicks, resulting in marked increase on average daily feed intake (ADFI), body weight (BW), and FCR of layer chicks ( 127 ). Interestingly, recent studies revealed that APS could regulate lipid metabolism and adipogenesis ( 128 ). A previous study reported that in ovo injection of 4.5 mg APS enhanced carcass percentage, reduced abdominal fat, as well as reduced educed triglycerides, total cholesterol, low-density lipoproteins, and very low-density lipoproteins in the plasma of broilers ( 129 ).…”

Mechanism of Astragalus membranaceus (Huangqi, HQ) for treatment of heart failure based on network pharmacology and molecular docking

“…reported that Astragalus polysaccharide, a key active ingredient isolated from HQ, prevents heart failure‐induced cachexia by alleviating excessive adipose expenditure in white and brown adipose tissue. 14 HQ injection, which is a formulation of an extract of HQ, is a most commonly used type of proprietary Chinese medicine for the clinical operation of treating chronic heart failure. There were 62 randomized controlled trials (RCTs) and quasi‐RCTs evaluated.…”