GPR37 modulates body weight and insulin sensitivity in a sex-biased manner

RESEARCH ARTICLE GPR37 modulates body weight and insulin sensitivity in a sex-biased manner Mariam Ahmed1☯, Mariela Nunez Santos1☯, Karen Abdelsayed1, Corrine Liu1, Nimco Xuseen1, Pokuaa Adwoa Boakye1, Sharon Owino 1,2* 1 Neuroscience Program, Smith College, Northampton, Massachusetts, United States of America, 2 Department of Pharmacology and Toxicology, Morehouse School of Medicine‌‌, Atlanta, Georgia, United States of America ☯ These authors contributed equally to this work. * Abstract OPEN ACCESS Citation: Ahmed M, Santos MN, Abdelsayed K, Liu C, Xuseen N, Boakye PA, et al. (2026) GPR37 modulates body weight and insulin sensitivity in a sex-biased manner. PLoS One 21(5): e0349406. https://doi.org/10.1371/ journal.pone.0349406 Editor: Rajakumar Anbazhagan, National Institute of Child Health and Human Development (NICHD), NIH, UNITED STATES OF AMERICA Received: September 16, 2025 Metabolic disorders are a growing public health concern in the United States, with approximately 40% of the population living with obesity. The urgent need for novel therapeutic targets has driven interest in G protein–coupled receptors (GPCRs), a diverse group of seven-transmembrane receptors that regulate various physiological processes and represent a significant portion of current drug targets. In this study, we investigated the role of GPR37, a brain-enriched orphan GPCR, in systemic glucose regulation. Using heterozygous Gpr37 + /- mice, we assessed body weight, glucose tolerance, and insulin sensitivity. Male Gpr37 + /- mice exhibited significantly reduced body weight, an enhanced metabolic response to fasting, and increased insulin sensitivity compared to wild-type controls. These findings indicate that reduced Gpr37 gene dosage is associated with metabolic efficiency, particularly in the regulation of glucose metabolism, and reveal a previously unrecognized sex-biased role for GPR37 in systemic energy homeostasis. Taken together, these data suggest that GPR37 contributes to metabolic regulation and represents a candidate pathway for further pharmacological and tissue-specific study. Accepted: April 29, 2026 Published: May 28, 2026 Copyright: © 2026 Ahmed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data availability statement: All relevant data are within the manuscript and its Supporting Information files. Funding: This work was supported by the American Heart Association [Grant Number Introduction Metabolic disorders involving glucose metabolism, such as obesity and diabetes, are rising at an alarming rate in the United States, posing significant public health challenges. A recent study found that only 12% of American adults are metabolically healthy, even among individuals of normal weight [1]. Currently, approximately 40% of Americans live with obesity [2], while globally, an estimated 589 million adults aged 20–79 are affected by diabetes [3]. The increasing incidence and reduced quality of life associated with these disorders underscore the urgent need for new therapeutic targets. PLOS One | https://doi.org/10.1371/journal.pone.0349406 May 28, 2026 1/7 AHA-23AIREA961441 to SO]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors declare no conflicts of interest relevant to the content of this manuscript. The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. G protein–coupled receptors (GPCRs), which account for over thirty percent of approved drug targets, are increasingly recognized as promising therapeutic candidates for metabolic diseases, due to their critical roles in regulating fat storage, glucose homeostasis, insulin sensitivity, nutrient metabolism, and overall energy balance [4–6]. GPR37, a brain-enriched GPCR, primarily expressed in oligodendrocytes, is also detected in ghrelin-producing cells of the gut and in the liver, suggesting a potential role in regulating systemic metabolic regulation [7]. Unlike its homolog GPR37L1, whose metabolic role appears minor [8], GPR37’s role in glucose metabolism and insulin sensitivity remains unknown. To examine how glucose metabolism is affected in GPR37 heterozygous mice (Gpr37 + /-), we compared metabolic outcomes between wild-type (WT), and Gpr37 + /- mice. Glucose and insulin tolerance tests were performed to evaluate metabolic responses in both male and female mice. Gpr37 + /- mice exhibited increased insulin sensitivity, reduced body weight, and a more pronounced fastinginduced decrease in blood glucose levels. Notably, these effects were more evident in male mice, suggesting a potential sex-biased contribution of GPR37 to metabolic homeostasis. Materials and methods All animal procedures were conducted in accordance with the guidelines established by the Smith College Institutional Animal Care and Use Committee (IACUC). The protocol was reviewed and approved by Smith College IACUC (Protocol Number: ASAF#22R-SO-301). All animal procedures were approved by the Institutional Animal Care and Use Committee and conducted in accordance with NIH guidelines. Animals were handled by trained personnel, and all procedures were performed to minimize discomfort and stress; mice were euthanized by CO2 inhalation followed by cervical dislocation as a secondary method consistent with AVMA guidelines, and no surgical procedures requiring anesthesia or analgesia were performed in this study. GPR37 knock-out mice (Gpr37 -/-) were generously donated by Dr. Randy Hall (Emory University) and backcrossed with wild-type mice (Jackson Laboratory) to generate WT and Gpr37 + /- mice. Six-month-old male and female Gpr37 + /- mice and their WT littermates were used for all metabolic assessments. Mice were group-housed in a temperature- and humidity-controlled facility under a 10-hour light/14-hour dark cycle, with ad libitum access to standard chow and water. Following a 6-hour fast, glucose and insulin tolerance were evaluated using an intraperitoneal (i.p.) glucose tolerance test (GTT) or an i.p. insulin tolerance test (ITT). During the GTT, mice were administered a bolus of 20% D-glucose solution (1.5 g/kg body weight) following which a calibrated glucometer was used to measure blood glucose levels via the tail vein at 0, 30, 60, 90, and 120 minutes post-injection. During the ITT, mice received an i.p. injection of insulin (0.5 U/kg body weight), and blood glucose levels were measured at 0, 15, 30, 60, and 120 minutes post-injection. All data were analyzed using two-way ANOVA or unpaired two-tailed t-tests where appropriate, with statistical significance defined as p < 0.05. Two-way ANOVA models included Sex, Genotype, and Sex × PLOS One | h (...truncated)