PEPITEM modulates leukocyte trafficking to reduce obesity-induced inflammation

Abstract

Dysregulation of leukocyte trafficking, lipid metabolism, and other metabolic processes are the hallmarks that underpin and drive pathology in obesity. Current clinical management targets alternations in lifestyle choices (e.g. exercise, weight loss) to limit the impact of the disease. Crucially, re-gaining control over the pathogenic cellular and molecular processes may offer an alternative, complementary strategy for obese patients. Here we investigate the impact of the immunopeptide, PEPITEM, on pancreas homeostasis and leukocyte trafficking in mice on high-fed obesogenic diet (HFD). Both prophylactic and therapeutic treatment with PEPITEM alleviated the effects of HFD on the pancreas, reducing pancreatic beta cell size. Moreover, PEPITEM treatment also limited T-cell trafficking (CD4+ T-cells and KLRG1+ CD3+ T-cells) to obese visceral, but not subcutaneous, adipose tissue. Similarly, PEPITEM treatment reduced macrophage numbers within the peritoneal cavity of mice on HFD diet at both 6 and 12 weeks. By contrast, PEPITEM therapy elevated numbers of T and B cells were observed in the secondary lymphoid tissues (e.g. spleen and inguinal lymph node) when compared to the untreated HFD controls. Collectively our data highlights the potential for PEPITEM as a novel therapy to combat the systemic low-grade inflammation experienced in obesity and minimize the impact of obesity on pancreatic homeostasis. Thus, offering an alternative strategy to reduce the risk of developing obesity-related co-morbidities, such as type 2 diabetes mellitus, in individuals at high risk and struggling to control their weight through lifestyle modifications.

PEPITEM Treatment Ameliorates EAE in Mice by Reducing CNS Inflammation, Leukocyte Infiltration, Demyelination, and Proinflammatory Cytokine Production

“…The PEPITEM treatment had an anti-inflammatory effect in the EAE model and improved the symptoms. The findings of this study are similar to a recent study by Pezhman et al The authors examined the effect of PEPITEM on leukocyte trafficking in a high-fed obesogenic diet and concluded that PEPITEM reduced the inflammation caused by obesity via restraining leukocyte trafficking [10]. Another study reported that PEPITEM inhibited T-cell trafficking and glomerulonephritis in a mouse model of SLE and preserved the structure of the kidney [21].…”

“…It plays a role in the adiponectin-PEPITEM pathway, which regulates the immune responses and inflammation in the body [9]. More recently, research suggested that PEPITEM may have potential benefits for obesity-related diseases and type 2 diabetes, as it reduces inflammation and improves glucose metabolism [10]. PEPITEM also reduces the recruitment of T cells into the inflamed tissues in peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis, and Sjögren's syndrome [9].…”

Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss

“… 14 We have previously identified a bioactive 14-amino acid peptide (PEPITEM) cleaved from 14-3-3ξ 15 , which regulates the migration of monocytes (osteoclast precursors) into non-bone tissues during inflammation. 16 , 17 Here we investigated the ability of PEPITEM to directly influence bone remodeling under homeostatic conditions and subsequently the therapeutic efficacy of PEPITEM in models of excessive bone loss.…”