6 Myeloid cell protein tyrosine phosphatase 1B prevents development of retinopathy in mice in states of overnutrition

<h3></h3> Western diet contributes to the growing rate of obesity. Over half of the global population are overweight or obese and prevalence in children has risen by 50% over the last 30 years. Childhood obesity poses a major health risk and is correlated with persistence into adulthood, where it is often co-morbid with chronic inflammatory disease. Diabetic retinopathy (DR) is a chronic inflammatory process often presenting as a late event; however, retinopathy has been linked to obesity where there is proposed early-onset. Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin/leptin signaling. Myeloid-PTP1B promotes high-fat (HF) diet-associated inflammation in mice, rendering it an attractive therapeutic target. We are assessing the role of myeloid-PTP1B in retinopathy at different timepoints using atherosclerosis-prone (ApoE-B/-) mice. We created myeloid-PTP1B knockout mice on the ApoE-/- background (ApoE-/-/LysMPTP1B-/-). At 10 weeks of age, ApoE-/- and ApoE-/-/LysMPTP1B-/- mice were fed HF diet for 5, 10 or 20 weeks, prior to analysing body composition, serum, retinal thickness and bone marrow (BM) and spleen inflammatory cells by flow cytometry. Fasted glycemia was reduced in ApoE-/-/LysMPTP1B-/- mice from 5-10 weeks of diet, despite increased fat mass. While serum IL-10 was unaltered, TNF-α was increased at 20 weeks of diet in both groups. ApoE-/-/LysMPTP1B-/- mice had higher BM CCR2+ than ApoE-/- mice, however this was reduced in the spleen. ApoE-/- mice had increased CCR2+ splenocytes as diet duration increased. ApoE-/-/LysMPTP1B-/- mice were protected from retinal degeneration, while ApoE-/- mice had retinal thinning at the far periphery as diet duration increased. These data suggest overnutrition, and duration of, generate activation of BM cells which populate peripheral tissues and potentially induce damage i.e., retinopathy. This process is regulated by myeloid-PTP1B. We suggest myeloid-PTP1B inhibition is valuable to prevent diet-induced disease.