Regulation of Brown Fat Adipogenesis by Protein Tyrosine Phosphatase 1B

Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of insulin signaling and energy balance, but its role in brown fat adipogenesis requires additional investigation.To precisely determine the role of PTP1B in adipogenesis, we established preadipocyte cell lines from wild type and PTP1B knockout (KO) mice. In addition, we reconstituted KO cells with wild type, substrate-trapping (D/A) and sumoylation-resistant (K/R) PTP1B mutants, then characterized differentiation and signaling in these cells. KO, D/A- and WT-reconstituted cells fully differentiated into mature adipocytes with KO and D/A cells exhibiting a trend for enhanced differentiation. In contrast, K/R cells exhibited marked attenuation in differentiation and lipid accumulation compared with WT cells. Expression of adipogenic markers PPARγ, C/EBPα, C/EBPδ, and PGC1α mirrored the differentiation pattern. In addition, the differentiation deficit in K/R cells could be reversed completely by the PPARγ activator troglitazone. PTP1B deficiency enhanced insulin receptor (IR) and insulin receptor substrate 1 (IRS1) tyrosyl phosphorylation, while K/R cells exhibited attenuated insulin-induced IR and IRS1 phosphorylation and glucose uptake compared with WT cells. In addition, substrate-trapping studies revealed that IRS1 is a substrate for PTP1B in brown adipocytes. Moreover, KO, D/A and K/R cells exhibited elevated AMPK and ACC phosphorylation compared with WT cells.These data indicate that PTP1B is a modulator of brown fat adipogenesis and suggest that adipocyte differentiation requires regulated expression of PTP1B

Protein tyrosine phosphatase 1B : a novel molecular target for retinal degenerative diseases

Protein tyrosine phosphatase 1B (PTP1B) is considered as a major negative regulator of insulin receptor (IR) signaling. IR signaling in retina has been demonstrated to be neuroprotective. Photoreceptor-specific deletion of PTP1B results in enhanced retinal IR-mediated neuroprotection indicating the importance of PTP1B as a negative regulator in the retina. Elevated levels of retinal PTP1B activity have been observed in mice lacking retinal pigment epithelium (Rpe65 -/-), a mouse model of leber congenital amaurosis (LCA-type 2), retinitis pigmentosa and diabetic retinopathy animal models. This enhanced PTP1B activity could downregulate the IR signaling which may contribute to the death of photoreceptor neurons and ultimately lead to retinal degenerations. The potential therapeutic agents that specifically reduce or inhibit the PTP1B activity could be beneficial in protecting or delaying the photoreceptor cell death in the retinal degenerative diseases.6 page(s