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Obesity is increasing at epidemic rates across the US and worldwide, as are its co-morbidities, including type-2 diabetes and cardiovascular disease. Thus, targeted interventions to reduce the prevalence of obesity are of the utmost importance. The sigma-1 receptor (S1R) and sigma-2 receptor (S2R; encoded by Tmem97) belong to the same class of drug-binding sites, yet they are genetically distinct. There are multiple ongoing clinical trials focused on sigma receptors, targeting diseases ranging from Alzheimer’s disease through chronic pain to COVID-19. However, little is known regarding their gene-specific role in obesity. In this study, we measured body composition, used a comprehensive laboratory-animal monitoring system, and determined the glucose and insulin tolerance in mice fed a high-fat diet. Compared to Sigmar1+/+ mice of the same sex, the male and female Sigmar1−/− mice had lower fat mass (17% and 12% lower, respectively), and elevated lean mass (16% and 10% higher, respectively), but S1R ablation had no effect on their metabolism. The male Tmem97−/− mice exhibited 7% lower fat mass, 8% higher lean mass, increased volumes of O2 and CO2, a decreased respiratory exchange ratio indicating elevated fatty-acid oxidation, and improved insulin tolerance, compared to the male Tmem97+/+ mice. There were no changes in any of these parameters in the female Tmem97−/− mice. Together, these data indicate that the S1R ablation in male and female mice or the S2R ablation in male mice protects against diet-induced adiposity, and that S2R ablation, but not S1R deletion, improves insulin tolerance and enhances fatty-acid oxidation in male mice. Further mechanistic investigations may lead to translational strategies to target differential S1R/S2R regulations and sexual dimorphism for precision treatments of obesity.

The structurally and genetically distinct sigma-1 receptor (S1R) and sigma-2 receptor (S2R) comprise a unique class of drug binding sites. Their alleles are associated with human diseases involving neuronal systems, such as age-related macular degeneration (AMD) characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. Previous studies have suggested neuroprotective benefits for the brain and retina from pharmacological modulation of S1R and/or S2R. However, the effect of such modulation on AMD pathology remains underexplored. Here, we evaluated S1R- or S2R-selective modulation in an AMD-related model of Abca4−/−Rdh8−/− mice with a disrupted visual cycle that predisposes RPE and photoreceptors to illumination-induced damage. For S1R modulation, we used (+)-pentazocine, which is a high-affinity S1R-selective drug. For S2R modulation, we chose CM398, a high-affinity and highly S2R-selective ligand with drug-like properties. Abca4−/−Rdh8−/− mice received a single i.p. injection of (+)-pentazocine or CM398 or vehicle 30 min before illumination. Pretreatment with (+)-pentazocine improved electroretinogram a- and b-waves compared to that with vehicle. Consistently, in another AMD-related mouse model induced by tail-vein injected NaIO3, S1R genetic ablation aggravated photoreceptor loss. In Abca4−/−Rdh8−/− mice, pretreatment with CM398 appeared to partially avert illumination-induced photoreceptor loss and autofluorescent granule formation that signals RPE damage, as revealed by optical coherence tomography. Thus, this study using AMD-related models provides evidence of photoreceptor protection afforded by selective modulation of S1R or S2R.

Introduction: Pharmacological studies have identified two subtypes of sigma receptors, which are now known to be encoded by different genes. Activation of the sigma-1 receptor (S1R) is reported to protect the heart against myocardial ischemia-reperfusion injury (IRI). The role of sigma-2 receptors (S2R) in myocardial IRI remains unknown. Hypothesis: We hypothesize that inhibition of S2R attenuates myocardial IRI. Methods: C57BL/6 (WT) and congenic S2R knockout (KO) mice underwent 40 minutes of left coronary artery (LCA) occlusion followed by 60 minutes of reperfusion (40’/60’ IR). At the end of reperfusion, the hearts were harvested for TTC-Phthalo-blue staining to calculate infarct size (IS), denoted as a percentage of the ischemic risk region (RR). S1R agonist, PRE-084, and S2R antagonist, CM-398, were administered before LCA occlusion. Two other groups of WT mice underwent 30 minutes of LCA occlusion followed by 60 minutes of reperfusion (30’/60’ IR), with one control group and another treated with S2R agonist, Z485, prior to LCA occlusion. Results: In mice undergoing 40’/60’ IR, ischemic risk regions (RR, % of LV mass) were comparable among all groups. Infarct size (IS, % of RR) was 53±3% in control mice. Both the S1R agonist and S2R antagonist significantly reduced the IS to 37±4% and 38±2%, respectively ( p <0.05 vs. control). S2R KO mice had significantly smaller IS (32±4% vs. control, p <0.05. Figure Panel A). In mice undergoing 30’/60’ IR, ischemic risk regions were comparable among the 2 groups, but IS was significantly exacerbated in the S2R agonist-treated group (42±2% vs. control 25±4%, p <0.05. Figure Panel B). Conclusion: Contrary to the effect of S1R, activation of S2R during myocardial IRI aggravated infarct size. Inhibition of S2R exerts an infarct-sparing effect. This pathway presents a new potential therapeutic target to attenuate myocardial IRI.

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