Investigating the Effect of PTP1B Inhibitor on Leptin Signaling Pathway in High-Fat-Diet and Low Dose Streptozotocin-Induced Type II Diabetic Mice Model

Abstract

Obesity and diabetes are complex metabolic disorders characterized by elevated levels of fats and glucose, respectively. Currently, Protein Tyrosine Phosphatase 1B (PTP1B) is known for its negative regulation of insulin and leptin signaling. A low dose of streptozotocin (STZ) combined with a High Fat Diet (HFD) results in endoplasmic reticulum stress that results in the cleavage of PTP1B which increases the level of active PTP1B in the cytosol, causing the dephosphorylation of tyrosine mediated receptors. Shred of evidence showed that PTP1B is overexpressed in both hypothalamus and adipocytes, disrupting the leptin signaling pathways in both organs. Hence, we predict that the inhibition of PTP1B might be a potential therapeutic target in the relieving of leptin resistance. Numerous studies have reported that Dodonaea Viscosa extract has hypoglycemic, anti-inflammatory, and anti-PTP1B properties. Compound 5, 7-dihydroxy-3, 6- dimethoxy-2- (4-methoxy-3- (3-methyl-2-enyl) phenyl)-4H -chromen-4- one extracted from the Dodonaea Viscosa was analyzed and showed anti-diabetic and anti-leptin resistant properties. We have divided our experimental animals into three groups named Group I, (Normal), Group II, (STZ HFD induced diabetic group), and Group III, (STZ-HFD-compound treated group). Real-time PCR data showed that leptin lipolytic (PPARα, HSL, and MGL), and energy homeostasis markers (STAT3 and POMC) are found downregulated in both adipose and hypothalamus, respectively followed by their upregulation in the compound-treated group. We explored the downstream cascade of leptin signaling and its role in anorexic signaling in the hypothalamus and lipolysis in adipose tissue. Interestingly, we observed that both activities were dysregulated in the STZ-HFD model and were potentially reverted in the compound-treated group. Likewise, PTP1B and inflammatory markers (IL-6 and IL-1β) expression was significantly reduced in Group III. Collectively, the inhibitory effect of our compound helps to determine that, our compound not only inhibits the activity of PTP1B but also affects its regulated pathways same as our target leptin signaling pathway. Taken together, our compound ameliorates the diabetic condition by targeting insulin signaling mediators and our study demonstrates that by targeting PTP1B we might also encounter leptin signaling. Key words: Leptin resistance, PTP1B, streptozotocin, HFD, Dodonaea Viscosa, Viscosol