Protein tyrosine phosphatase 1B inhibits adipocyte differentiation and mediates TNFα action in obesity

• Published in: Biochimica et biophysica acta Vol. 1831; no. 8; pp. 1368 - 1376
• Main Authors: Song, Dan-Dan, Chen, Yue, Li, Zhi-Yong, Guan, Yun-Feng, Zou, Da-Jin, Miao, Chao-Yu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2013
• Subjects: 3T3-L1 Cells; Adipocyte differentiation; adipocytes; Adipocytes - metabolism; Adipocytes - pathology; Adipogenesis; adipose tissue; animal disease models; Animals; Antigens, Differentiation - metabolism; Cell Differentiation; Gene Expression Regulation, Enzymologic - drug effects; Gene Knockdown Techniques; gene overexpression; glucose; homeostasis; insulin; Male; Mice; Mice, Obese; mutants; Obesity; Obesity - metabolism; Obesity - pathology; Protein tyrosine phosphatase 1B; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; protein-tyrosine-phosphatase; recombinant proteins; Tumor necrosis factor alpha; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; white adipose tissue; Protein tyrosine phosphatase 1B; Obesity; Tumor necrosis factor alpha; Adipocyte differentiation; Adipogenesis
• ISSN: 1388-1981; 0006-3002; 1879-2618; 1878-2434
• DOI: 10.1016/j.bbalip.2013.05.006

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of systemic glucose and insulin homeostasis; however, its exact role in adipocytes is poorly understood. This study was to elucidate the role of PTP1B in adipocyte differentiation and its implication in obesity. During differentiation of 3T3-L1 white preadipocytes, PTP1B decreased progressively with adipocyte maturation. Lentivirus-mediated PTP1B overexpression in preadipocytes delayed adipocyte differentiation, shown as lack of mature adipocytes, low level of lipid accumulation, and down-regulation of main markers (PPARγ2, SREBP-1c, FAS and LPL). In contrast, lentivirus-mediated PTP1B knockdown accelerated adipocyte differentiation, demonstrated as full of mature adipocytes, high level of lipid accumulation, and up-regulation of main markers. Dominant-negative inhibition on endogenous PTP1B by lentivirus-mediated overexpression of PTP1B double mutant in Tyr-46 and Asp-181 residues (LV-D/A-Y/F) also stimulated adipogenesis, more efficient than PTP1B knockdown. Diet-induced obesity mice exhibited an up-regulation of PTP1B and TNFα accompanied by a down-regulation of PPARγ2 in white adipose tissue. TNFα recombinant protein impeded PTP1B reduction and inhibited adipocyte differentiation in vitro; this inhibitory effect was prevented by LV-D/A-Y/F. Moreover, PTP1B inhibitor treatment improved adipogenesis and suppressed TNFα in adipose tissue of obese mice. All together, PTP1B negatively regulates adipocyte development and may mediate TNFα action to impair adipocyte differentiation in obesity. Our study provides novel evidence for the importance of PTP1B in obesity and for the potential application of PTP1B inhibitors. •PTP1B acted as a critical negative regulator in adipocyte differentiation.•PTP1B mediated the inhibitory effect of TNFα on adipocyte differentiation.•PTP1B inhibitor improves adipogenesis and down-regulates TNFα in obesity.