Liver circadian clock disruption alters perivascular adipose tissue gene expression and aortic function in mice

Abstract

The liver plays a central role that influences cardiovascular disease outcomes through regulation of glucose and lipid metabolism. It is recognized that the local liver molecular clock regulates some liver-derived metabolites. However, it is unknown whether the liver clock may impact cardiovascular function. Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue surrounding blood vessels. Importantly, cross talk between the endothelium and PVAT via vasoactive factors is critical for vascular function. Therefore, we designed studies to test the hypothesis that cardiovascular function, including PVAT function, is impaired in mice with liver-specific circadian clock disruption. Bmal1 is a core circadian clock gene, thus studies were undertaken in male hepatocyte-specific Bmal1 knockout (HBK) mice and littermate controls (i.e., flox mice). HBK mice showed significantly elevated plasma levels of β-hydroxybutyrate, nonesterified fatty acids/free fatty acids, triglycerides, and insulin-like growth factor 1 compared with flox mice. Thoracic aorta PVAT in HBK mice had increased mRNA expression of several key regulatory and metabolic genes, Ppargc1a, Pparg, Adipoq, Lpl, and Ucp1, suggesting altered PVAT energy metabolism and thermogenesis. Sensitivity to acetylcholine-induced vasorelaxation was significantly decreased in the aortae of HBK mice with PVAT attached compared with aortae of HBK mice with PVAT removed, however, aortic vasorelaxation in flox mice showed no differences with or without attached PVAT. HBK mice had a significantly lower systolic blood pressure during the inactive period of the day. These new findings establish a novel role of the liver circadian clock in regulating PVAT metabolic gene expression and PVAT-mediated aortic vascular function.

Circadian clock core component Bmal1 dictates cell cycle rhythm of proliferating hepatocytes during liver regeneration

“…The liver-to-body weight ratios were not significantly different between Bmal1 +/+ and Bmal1 hep-/mice pre-PH (Fig. 8A), consistent with other's report (26). Bmal1 hep-/mice regained more liver mass than Bmal1 +/+ mice by day 5.5 post-PH.…”

PPARγ (Peroxisome Proliferator-Activated Receptor γ) Deacetylation Suppresses Aging-Associated Atherosclerosis and Hypercholesterolemia

“…Bmal1 ablation in mice present with increased inflammation, 69 vascular endothelial dysfunction, and atherogenesis 70 and affect lipoproteins. 71 In the liver, hepatocyte-specific Bmal1 knockout mice confer an alteration in metabolic and lipid profile, promoting hyperlipidemia and enhancing atherosclerosis, 72,73 whereas an increase in Bmal1 attenuated liver steatosis, 74 and promoted the upregulation of anti-inflammatory markers Arg1 and IL-10. 75 Gain-of-function studies in mouse endothelial cells and observations in human carotid plaques show that Bmal1 can inhibit atherosclerosis and promote plaque stability by suppressing oxLDL (oxidized-LDL) and ROS accumulation, 76 and in one study, treatment with recombinant Bmal1 decreased total cholesterol in mice.…”

Circadian clock disruptions link oxidative stress and systemic inflammation to metabolic syndrome in obstructive sleep apnea patients

“…On the other hand, disrupted circadian clocks are also closely correlated with MetS components and glucose homeostasis. Recent in vivo studies indicate that peripheral clocks dysregulations in the liver, adipose, kidney, and smooth muscles are involved in the development of hypertension, diabetes, and obesity ( Chang et al, 2018 ; Nakashima et al, 2018 ; Hou et al, 2019 ; Murata et al, 2020 ; Pati et al, 2021 ). In Dec1-deficient mice models, expression of Atp1b1, a negative transcriptional target of Dec1 and anti‐phase regulator of blood pressure rhythm, was upregulated in the kidney, aorta, and heart tissues, and in turn reduced blood pressure ( Nakashima et al, 2018 ).…”