RETRACTED: A non‐erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet‐induced insulin resistance in mice

Abstract

BACKGROUND AND PURPOSEThe haematopoietic activity of erythropoietin (EPO) is mediated by the classic EPO receptor (EpoR) homodimer, whereas tissue-protective effects are mediated by a heterocomplex between EpoR and the β-common receptor (βcR). Here, we investigated the effects of a novel, selective ligand of this heterocomplex -pyroglutamate helix B surface peptide (pHBSP) -in mice fed a diet enriched in sugars and saturated fats. EXPERIMENTAL APPROACHMale C57BL/6J mice were fed a high-fat high-sucrose diet (HFHS) for 22 weeks. pHBSP (30 μg·kg −1 s.c.) was administered for the last 11 weeks. Biochemical assays, histopathological and immunohistochemical examinations and Western blotting were performed on serum and target organs (liver, kidney and skeletal muscle). KEY RESULTSMice fed with HFHS diet exhibited insulin resistance, hyperlipidaemia, hepatic lipid accumulation and kidney dysfunction. In gastrocnemius muscle, HFHS impaired the insulin signalling pathway and reduced membrane translocation of glucose transporter type 4 and glycogen content. Treatment with pHBSP ameliorated renal function, reduced hepatic lipid deposition, and normalized serum glucose and lipid profiles. These effects were associated with an improvement in insulin sensitivity and glucose uptake in skeletal muscle. Diet-induced overproduction of the myokines IL-6 and fibroblast growth factor-21 were attenuated by pHBSP and, most importantly, pHBSP markedly enhanced mitochondrial biogenesis in skeletal muscle. CONCLUSIONS AND IMPLICATIONSChronic treatment of mice with an EPO derivative, devoid of haematopoietic effects, improved metabolic abnormalities induced by a high-fat high-sucrose diet, by affecting several levels of the insulin signalling and inflammatory cascades within skeletal muscle, while enhancing mitochondrial biogenesis.

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

“…GLP-1 is a potent insulinotropic hormone, formed as a 30-amino acid peptide secreted from the L-cells of the intestinal epithelium in response to food. When GLP-1 is continuously infused to insulin resistant animals, blood glucose is normalized (Sreenan et al, 2000), with effects similar to those we recorded administering pHBSP in our mouse model of diet-induced insulin resistance (Collino et al, 2014). Notably, in an animal model of type 2 diabetes, the GLP-1-dependent amelioration in glucose tolerance was still detectable several days after the end of the infusion and the beneficial effect rather than declining, progressively increased, reaching a peak at day 9 (Hui et al, 2002).…”

“…A host of tissues and cells under stress have been shown to express and co-localize EPOR and βcR, including the central (Brines et al, 2004) and peripheral (Loesch et al, 2010) nervous systems, retina (Colella et al, 2011), heart (Xu et al, 2009), kidney (Kitamura et al, 2008), skeletal muscle (Collino et al, 2014), the endothelium (Su et al, 2011), as well as macrophages and bone marrow derived mesenchymal cells (Bohr et al, 2015).…”

“…Insulin receptor signaling through Akt promotes translocation of the glucose transporter type 4 by activation of AS160, resulting in increased glucose uptake. We recently demonstrated that pHBSP attenuated the impairment in insulin signaling, caused by a high fat, high sucrose (HFHS) diet in skeletal muscle (Collino et al, 2014). Specifically, pHBSP counteracted the HFHS-induced alterations in the phosphorylation of key insulin signaling molecules, Akt and its downstream substrate glycogen synthase kinase-3β.…”

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

“…histological Examination of the Kidney and Oil Red Staining of the Liver Dewaxed 5-μm sections of kidney were stained with hematoxylin and eosin and examined as previously described (17). Neutral lipids were assessed on sections of frozen liver embedded in OCT (10 μm in thickness) by oil red O staining.…”

Chronic Treatment With an Erythropoietin Receptor Ligand Prevents Chronic Kidney Disease–Induced Enlargement of Myocardial Infarct Size

“…18 Third, insulin resistance in skeletal muscle has been shown to be alleviated by activation of the heteromeric erythropoietin receptor. 19 To test the hypothesis, we used an established model of CKD, 5/6 nephrectomized rat, and epoetin β pegol, a continuous erythropoietin receptor activator (CERA). Cardiovascular effects of CKD are replicated in the rat 5/6 nephrectomy model of CKD, and we examined the myocardium 5 weeks after the first nephrectomy, when mild hypertension and mild proteinuria are known to be induced without cardiac hypertrophy, cardiac fibrosis, or vascular calcification.…”