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

Background The circadian clock is involved in lipid metabolism in adipocytes. The impairment of circadian clocks is a major cause of metabolic diseases, but the pathophysiological role of the circadian clock in adipose tissue depletion, in cachexia, remains unclear. To address this issue, we investigated the effects of circadian clock misalignment on adipose tissue metabolism in cardiac cachexia. Methods We produced cardiac cachexia rat models through injection of monocrotaline (MCT), which caused pulmonary hypertension-induced heart failure (HF). Cardiac function was measured by echocardiography. The histological features in fat and liver tissue were observed by H&E staining, Oil Red O staining and Picrosirius red staining. Immunohistochemical staining, Western blotting and RT‒qPCR were used to detect markers of lipolysis, lipogenesis and beiging of adipose tissue in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Results We found that rats with MCT injection exhibited right and left ventricular dysfunction. Compared with rats in the control group, rats housed in the light: dark cycle (LD group) exhibited disrupted circadian rhythm reflected by increased BMAL1 protein and decreased REV-ERBα. Meanwhile, these rats displayed decreased adipose mass and increased ectopic lipid deposition; moreover, smaller adipocytes and reduced lipid contents as well as increased extracellular matrix were found. In WAT, rats in the LD group exhibited elevated PKA-mediated lipolysis and WAT browning, while lipid storage was decreased as lipogenesis was inhibited. Meanwhile, in BAT, PKA-mediated thermogenesis was increased. NT-proBNP levels in blood and NE and IL-6 contents in adipose tissue were higher in the LD group than in the control group. Remarkably, compared with rats in the LD group, rats with circadian misalignment in the DL group and LV-Bmal1 shRNA group exhibited aggravated lipolysis and WAT browning, inhibited lipid storage in WAT, and elevated PKA-mediated thermogenesis in BAT. Moreover, rats in the DL group and LV-Bmal1 shRNA group showed higher levels of NT-proBNP in blood and NE and IL-6 contents in adipose tissue than rats in the LD group. Conclusion Our study suggested that a disrupted circadian rhythm aggravated fat wasting in patients with HF-induced cachexia by increasing lipolysis, preventing lipid storage in WAT and promoting beiging/brown adipocyte thermogenesis. This result indicated that stabilizing adipose tissue rhythms may help to combat disrupted energy homeostasis and alleviate excessive adipose tissue expenditure in HF-induced cachexia.