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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.</jats:p>","journal":"International Journal of Molecular Sciences","year":2022,"id":628860,"datarank":0.3958585994422889,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.0,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":973767,"name":"Elisa Félix‐Soriano","orcid":"0000-0003-4633-1289","position":1,"is_corresponding":false},{"id":852360,"name":"Katherine R. 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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.</jats:p>","is_dataset_classified":null,"base_score":2.639057329615259,"endowment":2.639057329615259,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36142759","pmcid":"PMC9506228","openalex_id":"https://openalex.org/W4296449581","authors":[],"funders":[{"funder_name":"NIH R01","grant_id":"EY022678","title":null},{"funder_name":"NIH R01","grant_id":"HL133665","title":null},{"funder_name":"NIH R01","grant_id":"HL138738","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"P30 DK020572","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL133665","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL138738","title":null},{"funder_name":"NEI NIH HHS","grant_id":"R01 EY022678","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01HL138738-05","title":"A Novel Role for Brown Adipose Tissue Enhance Heart Function and Metabolism"},{"funder_name":"National Institutes of Health","grant_id":"5R01EY022678-04","title":"Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina"},{"funder_name":"National Institutes of Health","grant_id":"5R01HL133665-03","title":"BET Bromodomain proteins as Novel Epigenetic Targets for prevention of Intimal Hyperplasia after Vascular Surgery"}],"total_grants":10,"fwci":0.7843,"citation_percentile":0.68410356,"influential_citations":0,"citation_trend":[{"year":2022,"count":1},{"year":2023,"count":2},{"year":2024,"count":4},{"year":2025,"count":3},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/23/18/10846/pdf?version=1663337727","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/23/18/10846/pdf?version=1663337727","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/23/18/10846/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms231810846","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36142759","host_type":"repository"},{"url":"https://doaj.org/article/943a3e6ff5584312bf4f3983c39b811f","host_type":"repository"},{"url":"https://dx.doi.org/10.3390/ijms231810846","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9506228","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9506228","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9506228?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.3390/ijms231810846","host_type":""}],"fields_of_study":["Pharmacological Receptor Mechanisms and Effects","Receptor Mechanisms and Signaling","Neuropeptides and Animal Physiology","0301 basic medicine","03 medical and health sciences","0303 health sciences"],"mesh_terms":["COVID-19","Sigma-1 Receptor","Animals","Carbon Dioxide","Female","Glucose","Male","Mice, Inbred C57BL","Obesity","Sex Characteristics","Receptors, sigma","Adiposity","Mice","Diet, High-Fat","Insulins"],"keywords":["Obesity","Sigma-1 receptor","Biology","Endocrinology","Disease","Internal medicine","Sexual dimorphism","Receptor","Pharmacology","Medicine","Agonist","Fatty Acid Oxidation","Sigma Receptors","Insulin Tolerance","Fat Mass And Lean Mass","Male","Insulins","Diet, High-Fat","Article","Mice","Animals","Receptors, sigma","Adiposity","Sex Characteristics","COVID-19","Carbon Dioxide","Mice, Inbred C57BL","Glucose","Female"],"sdg_mappings":[{"sdg_number":2,"sdg_label":"2. 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