7-BIA: A Small Molecule PTPRD Antagonist for Treatment of Metabolic Syndrome

Title: 7-BIA: A Small Molecule PTPRD Antagonist for Treatment of Metabolic Syndrome Abstract Diabetes is a global health crisis, affecting a staggering 530 million adults worldwide. Type 2 diabetes (T2DM) constitutes about 98 percent of all diabetes diagnosed globally. This challenge is compounded by a complex interplay of various metabolic syndrome (MS) factors, including obesity, insulin resistance, hypertension, and dyslipidemia, all contributing to the surge in T2DM cases. Asprosin, a recently discovered metabolic adipokine, emerges strongly associated with various conditions of MS, including T2DM, obesity, fatty liver, PCOS, and hypertension. Notably, two distinct functions of asprosin have been identified thus far. It triggers hepatic gluconeogenesis and stimulates feeding behavior through the activation of AgRP (Agouti-related peptide) neurons. Given the widespread distribution of asprosin''s receptor, Ptprd (Protein Tyrosine Phosphatase type δ), it is plausible that asprosin has additional non-canonical metabolic functions. Ptprd is highly expressed in pancreatic β cells. β cells when subjected to asprosin treatment show impaired insulin production, increased inflammation, and apoptosis. We hypothesize that the pathological rise in circulating asprosin in obesity detrimentally impacts β cell function and that countering asprosin-Ptprd signaling has the potential to proactively slow the progression of T2DM. Furthermore, our preliminary findings indicate that oxytocin neurons in the hypothalamus represent an additional direct target for asprosin. Notably, our research shows that asprosin-deficient mice (those with the Neonatal Progeroid syndrome (NPS) genetic mutation) and mice with genetic Ptprd loss in oxytocin neurons exhibit hypotension. Hence, asprosin-Ptprd signaling emerges as a common thread in the development and manifestation of three key components of MS: T2DM, obesity induced by overnutrition, and hypertension. While we have previously demonstrated that treatment with 7-BIA (7-butoxy illudalic acid analog), a small molecule Ptprd antagonist, significantly reduces appetite in mice, its effects on glucose homeostasis and hypertension have not been examined to date. We hypothesize that 7-BIA has the potential to serve as a unified treatment approach for all three elements of MS: obesity, T2DM, and hypertension, providing a promising "one remedy for three maladies." Our aim is to investigate the relationship between asprosin and MS, posing a pivotal question: Can 7-BIA, a Ptprd antagonist, offer a viable approach to simultaneously address three interrelated metabolic disorders— obesity, T2DM, and hypertension? We will tackle this inquiry by examining the impact of chronic 7-BIA treatment on glycemic state, insulin resistance, blood pressure, food intake and body weight in db/db mice. .