Lipin1 Is a Key Factor for the Maturation and Maintenance of Adipocytes in the Regulatory Network with CCAAT/Enhancer-binding Protein α and Peroxisome Proliferator-activated Receptor γ2

Abstract

Lipin1 expression was induced at a late stage of differentiation of 3T3-L1 preadipocytes and maintained at high levels in mature adipocytes. Knockdown of expression of lipin1 by small interfering RNA in 3T3-L1 preadipocytes almost completely inhibited differentiation into adipocytes, whereas overexpression of lipin1 accelerated adipocyte differentiation, demonstrating that lipin1 is required for adipocyte differentiation. In mature adipocytes, transfection of lipin1-small interfering RNA decreased the expression of adipocyte functional genes, indicating the involvement of lipin1 in the maintenance of adipocyte function. Lipin1 increases the transcription-activating function of peroxisome proliferator-activated receptor ␥ 2 (PPAR␥ 2 ) via direct physical interaction, whereas lipin1 did not affect the function of other adipocyte-related transcription factors such as C/EBP␣, liver X-activated receptor ␣, or sterol regulatory element binding protein 1c. In mature adipocytes, lipin1 was specifically recruited to the PPAR␥-response elements of the phosphoenolpyruvate carboxykinase gene, an adipocyte-specific gene. C/EBP␣ up-regulates lipin1 transcription by directly binding to the lipin1 promoter. Based on the existence of a positive feedback loop between C/EBP␣ and PPAR␥ 2 , we propose that lipin1 functions as an amplifier of the network between these factors, resulting in the maintenance of high levels of the specific gene expression that are required for adipogenesis and mature adipocyte functions.Adipose tissue plays an essential role in maintaining metabolic homeostasis (1). White adipose tissue takes up fatty acids derived from the diet or the liver as well as increases the uptake of glucose in response to insulin by recruiting glucose transporter 4 (GLUT4) 2 to the plasma membrane. Then white adipose tissue stores the glucose or fatty acids as a form of triacylglyceride and releases free fatty acids during states of starvation. Recent studies have shown that adipose tissue secretes various humoral factors called adipocytokines which play numerous functions associated with food intake, insulin sensitivity, energy homeostasis, inflammatory responses, and atherogenesis (2). In obese subjects adipocytes cannot function adequately, thereby causing various metabolic syndromes including insulin resistance, dyslipidemia, and coronary-vascular disease (3-6). Lipodystrophy leads to the same condition as obesity due to lack of adipocyte function (7-9). Thus, studying the molecular mechanisms that control adipose tissue development and function is important for understanding the pathophysiology of metabolic syndromes.Adipogenesis is a process in which premature cells acquire adipocyte-specific functions. A complex network of transcription factors is developed during this process in response to extracellular adipogenic stimuli. In 3T3-L1 preadipocyte cells the CCAAT/enhancer-binding proteins ␤ and ␦ (C/EBP␤ and C/EBP␦) are induced immediately upon adipogenic hormonal stimuli, and they are expressed for approximately 2 days ...

Chronically increased glucose uptake by adipose tissue leads to lactate production and improved insulin sensitivity rather than obesity in the mouse

“…In contrast, a significant increase in the expression of both Lipin1 (also known as Lpin1) mRNA and protein, a factor specifically recruited to the PPARγ 2 -response element of the Pepck promoter, was observed in WAT from transgenic mice (Fig. 3d, e) [31]. However, despite an increase in both Pepck expression and in the glyceroneogenic rate observed in vitro, no change was observed in fat accumulation in these mice.…”

PPAR control: it's SIRTainly as easy as PGC

“…Thus, lipin-1 may be a promising target for therapeutic intervention for metabolic disorders such as fatty liver and resolution of insulin resistance. Lipin-1 is also required for the maintenance of the mature adipocyte phenotype both through its PAP activity in relation to TAG synthesis and via its action to amplify the transcriptional activity of PPARg and the expression of PPARg target genes, such as PEPCK and glycerol kinase (Koh et al 2008). Alterations in lipin-1 function in adipose tissue are therefore likely to impact the efficacy of the TZDs in the treatment of insulin resistance.…”

“…In contrast, lipin-1 promotes adipocyte TAG storage (see above). Lipin-1 physically interacts with PPARg and is recruited to PPARg response element upstream of the PEP carboxykinase (PEPCK) gene (Koh et al 2008). PEPCK is involved in glycerogenesis in white adipose tissue (Franckhauser et al 2002).…”

Hypoxia causes triglyceride accumulation via HIF-1-mediated stimulation of lipin 1 expression

“…Mutations in the lipin 1 gene (Lpin1), which is expressed predominantly in adipose tissue and skeletal muscle, are the cause of lipodystrophy in the fatty liver dystrophic (fld) mouse and, conversely, overexpression of lipin 1 in the adipose tissue of transgenic mice promotes obesity (Péterfy et al, 2001;Phan and Reue, 2005). Moreover, lipin 1 as well as lipin 2, a liver-enriched isoform, interact with and/or modulate the activity of several transcription factors, including members of the peroxisome proliferator-activated receptor (PPAR) family and SREBP that control the expression of genes involved in fatty acid and lipid metabolism (Donkor et al, 2009;Finck et al, 2006;Koh et al, 2008;Peterson et al, 2011). Apart of its apparently important role in adipogenesis, relatively little is known about the function of lipin 1 in cells other than adipocytes.…”