Insulin stimulates hormone‐sensitive cyclic GMP‐inhibited cyclic nucleotide phosphodiesterase in rat brown adipose cells

Omatsu‐Kanbe, Mariko; Cushman, Samuel W.; Manganiello, Vincent C.; Taira, Masato

doi:10.1016/0014-5793(95)01112-r

Cited by 6 publications

(6 citation statements)

References 37 publications

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“…PKA phosphorylation of PDE3B is activating, which serves as a negative-feedback loop; interruption of this circuit would be expected to potentiate isoproterenolstimulated glycerol release, as found in our experiments (34,36). Importantly, this provides strong support for the notion that, had activation of PDE3B by Akt been important for antilipolysis, the experimental system would have had the sensitivity to detect this, since the magnitudes of PDE3B activation by Akt and PKA are similar (34,35,50,51). Furthermore, we have shown that no other residue previously identified as a potential target of phosphorylation is important in this process.…”

Section: Discussionsupporting

confidence: 75%

The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin

DiPilato

Ahmad

Harms

et al. 2015

Molecular and Cellular Biology

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c Inhibition of adipocyte lipolysis by insulin is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance and type 2 diabetes mellitus. The main target of the antilipolytic action of insulin is believed to be phosphodiesterase 3B (PDE3B), whose phosphorylation by Akt leads to accelerated degradation of the prolipolytic second messenger cyclic AMP (cAMP). To test this hypothesis genetically, brown adipocytes lacking PDE3B were examined for their regulation of lipolysis. In Pde3b knockout (KO) adipocytes, insulin was unable to suppress ␤-adrenergic receptor-stimulated glycerol release. Reexpressing wild-type PDE3B in KO adipocytes fully rescued the action of insulin against lipolysis. Surprisingly, a mutant form of PDE3B that ablates the major Akt phosphorylation site, murine S273, also restored the ability of insulin to suppress lipolysis. Taken together, these data suggest that phosphorylation of PDE3B by Akt is not required for insulin to suppress adipocyte lipolysis.A dipose tissue serves the highly specialized function of storing excess energy in the form of triglycerides (TG) until a time of caloric need. These lipid stores are then hydrolyzed into glycerol and free fatty acids (FFAs), a process termed lipolysis, and released into circulation to provide energy to other tissues. The intricate balance maintained by adipose tissue in response to nutritional status is essential for whole-body energy homeostasis. The importance of the control of lipid storage is illustrated by the consequences of an excess of dietary lipids, which leads to inappropriate deposition of neutral lipid in nonadipose cell types and insulin (Ins) resistance (1). While much is known about the regulatory mechanisms that govern lipid metabolism, there are questions that remain unresolved, such as how lipolysis is suppressed following nutrient intake.Adipocytes are specifically poised to respond to lipolytic stimulation in a dynamic fashion. During fasting, catecholamines initiate the canonical ␤-adrenergic receptor (␤-AR) signaling cascade, leading to the generation of the second messenger cyclic AMP (cAMP) and subsequent activation of protein kinase A (PKA). Two key protein targets of PKA, perilipin 1 (PLIN1) and hormone-sensitive lipase (HSL), help facilitate the robust lipolytic response resulting in the sequential hydrolysis of TG first to diacylglycerol (DG), then to monoacylglycerol (MG), and finally to glycerol and FFA (2). PLIN1 associates with and protects the neutral lipid droplet from lipases in the unstimulated (basal) state to maintain lipid storage (3). However, phosphorylation of PLIN1 by PKA leads to the release of comparative gene identification-58 (CGI-58), allowing it to associate with and activate adipose triglyceride lipase (ATGL), the first enzyme in the lipolytic cascade (4, 5). In addition, upon PKA phosphorylation, HSL translocates from the cytosol to the surface of the lipid droplet, where it hydrolyzes DG to MG (6, 7). The final hydr...

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Section: Discussionsupporting

confidence: 75%

The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin

DiPilato

Ahmad

Harms

et al. 2015

Molecular and Cellular Biology

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“…The expression of PDE(s) has been poorly investigated in BAT. However, the presence of PDE3 mRNA in this tissue was first demonstrated by in situ hybridisation [22] and the regulation of this isoform is thought to be similar to that in white adipose cells [14]. The data provided in this study confirm that PDE3 is present in BAT but they also show that activity of this isoform represents only half of the total PDE activity, thus suggesting that other PDE(s) play a role in the degradation of cAMP.…”

Section: Discussionsupporting

confidence: 66%

“…10 Tissues were minced and digested at 37°C with the combination of collagenase and DNAse I as described by Omatsu‐Kanbe et al [14]. The floating fractions containing brown adipose cells were washed three times in Krebs Ringer bicarbonate HEPES buffer (120 mM NaCl, 4 mM KH 2 PO 4 , 1 mM MgSO 4 , 1 mM CaCl 2 , 10 mM NaHCO 3 , 30 mM HEPES, pH 7.4) containing 2.5 mM glucose and 200 nM adenosine and then homogenised and processed as described above.…”

Section: Methodsmentioning

confidence: 99%

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Evidence for the presence of several phosphodiesterase isoforms in brown adipose tissue of Zucker rats: modulation of PDE2 by the fa gene expression

et al. 1999

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The present study was undertaken to characterise the phosphodiesterases (PDEs) present in brown adipose tissue (BAT) of Zucker rat pups and to determine whether the capacity for degradation of cyclic nucleotides was affected by the fatty genotype. Regardless of the genotype, PDE2^4 contributed to total PDE activity, the PDE3 activity equalling the sum of PDE2 and 4 activities. In fa/fa compared to Fa/fa rats, (a) PDE2 activity was significantly increased, (b) Western blot analysis of PDE2 revealed two signals at 71 and 105 kDa, with changes in protein being in good parallelism with changes in activity, (c) the PDE2 mRNA concentration was also significantly increased. In good agreement, the cGMP concentration was decreased in BAT from fa/fa pups.z 1999 Federation of European Biochemical Societies.

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“…This indicates that while PDE3B mRNA levels are generally downregulated in fat tissues, the posttranscriptional regulation of PDE3 activity in brown fat may be different from that of white fat, which must have compensated for the reduced expression of the PDE3B gene. It has been demonstrated that the regulation of PDE3 activity in rat brown adipocytes by insulin and isoproterenol is similar to that in white adipocytes (46). It should be noted, however, that the increased lipolysis that is associated with diabetes can be explained by the reduced PDE3 activity in white adipose tissues, since the brown adipose mass in humans is very small compared with the white adipose mass.…”

Section: Discussionmentioning

confidence: 96%

Cyclic nucleotide phosphodiesterase 3 expression in vivo: evidence for tissue-specific expression of phosphodiesterase 3A or 3B mRNA and activity in the aorta and adipose tissue of atherosclerosis-prone insulin-resistant rats.

et al. 1998

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With a view of understanding the potential roles of phosphodiesterase (PDE)3 in the acceleration of atherosclerosis in diabetes, we have analyzed the in vivo levels of low Km cAMP PDE3 and PDE4 activities as well as PDE3A and PDE3B mRNA in a relevant animal model. The JCR:LA-cp rat is a unique strain that develops obesity, insulin resistance, and vasculopathy when homozygous for the autosomal recessive cp gene (cp/cp). Lean rats, bred (designated +/?) as a 2:1 mixture of animals that are heterozygous (cp/+) or homozygous normal (+/+), are metabolically normal. We find that PDE3 activity is the major low Km cAMP activity in the aorta of cp/cp rats and is approximately twofold higher than that in lean +/? rats. PDE3A mRNA levels in middle-aged cp/cp rats are also elevated, approximately threefold, compared with those of +/? rats or young 12-week-old cp/cp rats. Thus, in the aorta of atherosclerosis-prone insulin-resistant cp/cp rats, PDE3A gene expression is upregulated, resulting in significantly higher PDE3 activity. This upregulation of PDE3A mRNA levels was a rather unique phenomenon to the aorta of JCR:LA-cp rats compared with that in the aorta of other rat strains. This result is consistent with our hypothesis that an increased PDE3 activity in aortic smooth muscle cells may contribute to accelerated atherosclerosis in diabetes. Furthermore, determination of PDE3 activity and PDE3A and PDE3B mRNA levels in heart and white and brown fat tissues of JCR:LA-cp rats revealed that PDE3B mRNA and activity in white adipose tissue is downregulated in this diabetic animal model, and that PDE3A and PDE3B genes are tissue-specifically expressed and differentially regulated in aorta and adipose tissue, respectively, under hyperinsulinemic conditions.

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Insulin stimulates hormone‐sensitive cyclic GMP‐inhibited cyclic nucleotide phosphodiesterase in rat brown adipose cells

Cited by 6 publications

References 37 publications

The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin

The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin

Evidence for the presence of several phosphodiesterase isoforms in brown adipose tissue of Zucker rats: modulation of PDE2 by the fa gene expression

Cyclic nucleotide phosphodiesterase 3 expression in vivo: evidence for tissue-specific expression of phosphodiesterase 3A or 3B mRNA and activity in the aorta and adipose tissue of atherosclerosis-prone insulin-resistant rats.

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