Abstract
Liver X receptors (LXRs) are transcription factors known for their role in hepatic cholesterol and lipid metabolism. Though highly expressed in fat, the role of LXR in this tissue is not well characterized. We generated adipose tissue LXRα knockout (ATaKO) mice and showed that these mice gain more weight and fat mass on a high-fat diet compared with wild-type controls. White adipose tissue (WAT) accretion in ATaKO mice results from both a decrease in WAT lipolytic and oxidative capacities. This was demonstrated by decreased expression of the β2- and β3-adrenergic receptors, reduced level of phosphorylated hormone-sensitive lipase, and lower oxygen consumption rates (OCRs) in WAT of ATaKO mice. Furthermore, LXR activation in vivo and in vitro led to decreased adipocyte size in WAT and increased glycerol release from primary adipocytes, respectively, with a concomitant increase in OCR in both models. Our findings show that absence of LXRα in adipose tissue results in elevated adiposity through a decrease in WAT oxidation, secondary to attenuated FA availability.
Highlights
Liver X receptors (LXRs) are transcription factors known for their role in hepatic cholesterol and lipid metabolism
While other studies of LXR in White adipose tissue (WAT) have pointed to LXR␣ as playing a greater role than the LXR isoform [40, 43], the degree to which LXR␣ regulates lipid metabolism in adipose tissue and how it contributes to energy homeostasis has not been determined
To study the role of LXR␣ in the regulation of lipid metabolism in adipose tissue in vivo and understand how it contributes to energy homeostasis, we generated adipose tissue LXR␣ knockout (ATaKO) mice
Summary
Liver X receptors (LXRs) are transcription factors known for their role in hepatic cholesterol and lipid metabolism. In cases of excess energy intake, adipose tissue engages in lipogenesis to store this energy as triglyceride (TG), while in times of inadequate dietary sources, it breaks down its reserves through lipolysis to provide substrate for oxidation and ATP synthesis within other tissues [4] Both lipogenesis and lipolysis are tightly controlled in adipocytes [5]. Obese individuals are less sensitive to the antilipolytic actions of insulin and display an increase in basal lipolytic activity in their white adipose tissue (WAT), which results in high circulating levels of FFAs [6]. These chronically elevated FFAs have been implicated in the pathogenesis of insulin resistance and type 2 diabetes [7]. In addition to being released into the circulation and, to a much lesser extent, being reesterified in situ [20], a portion of the liberated FFA undergoes mitochondrial oxidation within WAT itself [18, 21, 22]
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