Genetic disruption of protein phosphatase 5 in mice prevents high‐fat diet feeding‐induced weight gain

Grankvist, Nina; Honkanen, Richard E.; Sjöholm, Åke; Ortsäter, Henrik

doi:10.1016/j.febslet.2013.10.022

Cited by 15 publications

(18 citation statements)

References 31 publications

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“…During the course of our studies, it was reported that PP5KO mice showed improved GTT but no increase in insulin sensitivity [48]. Recent studies from the same group report that PP5KO mice fed a control diet exhibit decreased kidney, epididymal and subcutaneous fat depots [49], consistent with our analyses of Ppp5KI mice by weighing and MRI of kidney and gonadal fat depots. Feeding a HFD (45%) for 20 weeks increased weight gain, lowered GTT and led to insulin resistance in Ppp5KI mice and controls.…”

Section: Discussionsupporting

confidence: 89%

Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5

Jacob

Rosenzweig

Vázquez-Martin

et al. 2015

Biochemical Journal

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Glucocorticoids play an important role in the treatment of inflammation and immune disorders, despite side effects, which include metabolic derangements such as central adiposity. These studies examine the role of protein phosphatase 5 (Ppp5) in glucocorticoid receptor (GR) complexes which mediate response to glucocorticoids. Mice homozygous for inactivated Ppp5 (Ppp5 D274A/D274A ) exhibit decreased adipose tissue surrounding the gonads and kidneys compared with wild-type mice. Adipocyte size is smaller, more preadipocytes/stromal cell are present in their gonadal fat tissue and differentiation of preadipocytes to adipocytes is retarded. Glucocorticoid levels are raised and the GR is hyperphosphorylated in adipose tissue of Ppp5 D274A/D274A mice at Ser212 and Ser220 (orthologous to human Ser203 and Ser211) in the absence of glucocorticoids. Preadipocyte cultures from Ppp5 D274A/D274A mice show decreased down regulation of Delta-like protein-1/preadipocyte factor-1, hyperphosphorylation of extra-cellular signal regulated kinase 2 (ERK2) and increased concentration of (sex determining region Y)-box 9 (SOX9), changes in a pathway essential for preadipocyte differentiation, which leads to decreased concentrations of the transcription factors CEBPβ and CEBPα necessary for the later stages of adipogenesis. The data indicate that Ppp5 plays a crucial role in modifying GR-mediated initiation of adipose tissue differentiation, suggesting that inhibition of Ppp5 may potentially be beneficial to prevent obesity during glucocorticoid treatment.

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Section: Discussionsupporting

confidence: 89%

Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5

Jacob

Rosenzweig

Vázquez-Martin

et al. 2015

Biochemical Journal

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“…PP5 belongs to the PPP-family consisting of serine/threonine protein phosphatases [88, 89]. Evidence has indicated that PP5 activation requires the binding of its tetratricopeptide repeat (TPR) domain to the heat shock protein 90 (Hsp90) chaperone complex [26, 89] (Figure 2).…”

Section: Pp5 a Positive Modulator Of Pparγmentioning

confidence: 99%

Deciphering the Roles of Thiazolidinediones and PPARγin Bladder Cancer

et al. 2017

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The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγ may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγ in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.

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“…Deletion of serine/threonine phosphatases [25] and in particular protein tyrosine phosphatases [13,14,26] has earlier been shown to result in an improved metabolic phenotype in insulin resistance and diabetes. Moreover, elevated expression and activity of PTPs was detected in metabolic tissues in HFD-induced insulin-resistant mice earlier [8,15,27], including SHP-1 [8].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Src homology 2 domain‐containing phosphatase 1 increases insulin sensitivity in high‐fat diet‐induced insulin‐resistant mice

et al. 2016

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Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain‐containing phosphatase 1 (SHP‐1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high‐fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low‐fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD‐fed mice were pharmacologically treated with the SHP‐1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan‐PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA‐mediated SHP‐1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP‐1 was capable of dephosphorylating the ligand‐induced tyrosine‐phosphorylated insulin receptor. These results indicate a central role of SHP‐1 in insulin signalling during obesity, and SHP‐1 inhibition as a potential therapeutic approach in metabolic diseases.

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Genetic disruption of protein phosphatase 5 in mice prevents high‐fat diet feeding‐induced weight gain

Cited by 15 publications

References 31 publications

Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5

Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5

Deciphering the Roles of Thiazolidinediones and PPARγin Bladder Cancer

Inhibition of Src homology 2 domain‐containing phosphatase 1 increases insulin sensitivity in high‐fat diet‐induced insulin‐resistant mice

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