Abstract
Although precisely controlled lipolysis is crucial for maintaining physiological levels of circulating free fatty acids in response to energetic stress, the underlying mechanisms by which this process is governed remain poorly understood. Survivin is a gene that has been found to be highly expressed in the most common human tumors, and it is considered to be associated with tumorigenesis. Survivin expression in normal tissue is developmentally downregulated and is undetectable in most terminally differentiated adult tissues. Here, we report that Survivin expression in mature adipocytes from murine white adipose tissue can be highly induced under high-fat diet feeding conditions. During the adipocyte differentiation of 3T3-L1 preadipocytes and mesenchymal C3H10T1/2 cells, Survivin expression is gradually decreased and almost undetectable in fully differentiated adipocytes. However, it can be expressed again upon insulin exposure, through the PI3K/mTOR signaling pathway. Nevertheless, Survivin overexpression is sensitive to nutritional deprivation, and expression markedly decreases in response to starvation with Hank’s buffered salt solution challenge. The ectopic expression of Survivin downregulates expression of Adrb3 and then decreases the production of cAMP, while Fsp27 protein levels are upregulated as a result of reduced protein degradation. This in turn inhibits isoproterenol-stimulated adipocyte lipolysis. Survivin also attenuates DNA damage related to PARP activation and inhibits TNFα-induced lipolysis, suggesting that Survivin may facilitate adipocyte maintenance in response to inflammatory stimuli. Further studies will be undertaken to determine whether Survivin is critical for lipid storage to maintain metabolic homeostasis in vivo.
Highlights
Adipose tissue is the primary fat storage depot and a major source of metabolic fuel, whose dysfunction is closely associated with obesity and related metabolic phenotypes
The results indicated that stimulation with insulin promoted a robust increase in Survivin in both 3T3L1 adipocytes and primary adipocytes, this effect was almost completely blocked by rapamycin and LY294002 (Figure 2i), suggesting that the expression of Survivin might be regulated by the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway
We have shown that Survivin is expressed both in separated murine white adipocytes upon high-fat feeding and in differentiated adipocytes after incubation with insulin
Summary
Adipose tissue is the primary fat storage depot and a major source of metabolic fuel, whose dysfunction is closely associated with obesity and related metabolic phenotypes. The stored triacylglycerols are hydrolyzed to glycerol, and fatty acids via β-adrenergic receptors (β-AR) signaling. These receptors in turn activate adenylyl cyclase to generate cAMP. Excessive lipolysis contributes to high circulating levels of fatty acids and causes deleterious effects on insulin signaling in peripheral tissues. Overnutrition causes hyper-activation of mTOR in adipocytes to maintain low circulating levels of free fatty acids, primarily by antilipolytic action, which preserves normal lipid partitioning and overall metabolic fitness. We show that Survivin expression in white adipose tissue is low but can be highly induced in response to a high-fat diet (HFD). Survivin expression increases upon insulin exposure through phosphatidylinositol 3-kinase (PI3K)/mTOR signaling.
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