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

Apr 21, 2021American journal of physiology. Regulatory, integrative and comparative physiology

Disrupting the liver’s daily rhythm changes nearby fat tissue genes and aorta function in mice

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Abstract

Mice with liver-specific circadian clock disruption showed significantly elevated plasma levels of β-hydroxybutyrate and triglycerides.

Liver clock disruption may influence cardiovascular function and perivascular adipose tissue (PVAT) function.
HBK mice exhibited altered energy metabolism and thermogenesis in PVAT, indicated by increased expression of regulatory genes.
Sensitivity to acetylcholine-induced vasorelaxation was significantly reduced in aortae with attached PVAT from HBK mice.
In contrast, flox mice showed no differences in aortic vasorelaxation with or without PVAT.
HBK mice had significantly lower systolic blood pressure during their inactive period.

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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.is a core circadian clock gene, thus studies were undertaken in male hepatocyte-specificknockout (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,,,,, and, 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. Bmal1Bmal1Ppargc1a Pparg Adipoq Lpl Ucp1

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

Abstract

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