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Emerging evidence suggests that hepatocyte intracellular Ca<jats:sup>2+<\/jats:sup> signaling is altered in lipid-loaded liver cells isolated from obese rodent models. The mechanisms of altered Ca<jats:sup>2+<\/jats:sup>-insulin and insulin-Ca<jats:sup>2+<\/jats:sup> signaling pathways in obesity remain poorly understood. Here, we show that the kinetics of insulin-initiated intracellular (initial) Ca<jats:sup>2+<\/jats:sup> release from endoplasmic reticulum is significantly impaired in steatotic hepatocytes from obese Alstr\u00f6m syndrome mice. Furthermore, exenatide, a glucagon-like peptide-1 (GLP-1) analog, reversed lipid-induced inhibition of intracellular Ca<jats:sup>2+<\/jats:sup> release kinetics in steatotic hepatocytes, without affecting the total content of intracellular Ca<jats:sup>2+<\/jats:sup> released. Exenatide reversed the lipid-induced inhibition of intracellular Ca<jats:sup>2+<\/jats:sup> release, at least partially, via lipid reduction in hepatocytes, which then restored hormone-regulated cytoplasmic Ca<jats:sup>2+<\/jats:sup> signaling and insulin sensitivity. This data provides additional evidence for the important role of Ca<jats:sup>2+<\/jats:sup> signaling pathways in obesity-associated impaired hepatic lipid homeostasis and insulin signaling. It also highlights a potential advantage of GLP-1 analogs when used to treat type 2 diabetes associated with hepatic steatosis. <\/jats:p>","DOI":"10.1152\/ajpcell.00020.2021","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T18:59:23Z","timestamp":1623265163000},"page":"C187-C198","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Impaired Ca<sup>2<b>+<\/b><\/sup> signaling due to hepatic steatosis mediates hepatic insulin resistance in Alstr\u00f6m syndrome mice that is reversed by GLP-1 analog treatment"],"prefix":"10.1152","volume":"321","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9477-3500","authenticated-orcid":true,"given":"Eunus S.","family":"Ali","sequence":"first","affiliation":[{"name":"College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doroth\u00e9e","family":"Girard","sequence":"additional","affiliation":[{"name":"Vaxine Pty Ltd, Adelaide, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1580-5245","authenticated-orcid":true,"given":"Nikolai","family":"Petrovsky","sequence":"additional","affiliation":[{"name":"College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia"},{"name":"Vaxine Pty Ltd, Adelaide, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(16)30011-5"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.21037\/hbsn.2016.09.11"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgw060"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nature09968"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20140881"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.03.007"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1155\/2000\/574820"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1293"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2019.02.005"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.02.032"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/me.2005-0494"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2010.210"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2337\/db20-0647"},{"key":"B14","unstructured":"Marion V, Petrovsky N. 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