{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T15:30:00Z","timestamp":1767713400633,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Swedish Research Council","award":["2016-01088"],"award-info":[{"award-number":["2016-01088"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The statin drug target, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is strongly linked to body mass index (BMI), yet how HMGCR influences BMI is not understood. In mammals, studies of peripheral HMGCR have not clearly identified a role in BMI maintenance and, despite considerable central nervous system expression, a function for central HMGCR has not been determined. Similar to mammals, Hmgcr is highly expressed in the Drosophila melanogaster brain. Therefore, genetic and pharmacological studies were performed to identify how central Hmgcr regulates Drosophila energy metabolism and feeding behavior. We found that inhibiting Hmgcr, in insulin-producing cells of the Drosophila pars intercerebralis (PI), the fly hypothalamic equivalent, significantly reduces the expression of insulin-like peptides, severely decreasing insulin signaling. In fact, reducing Hmgcr expression throughout development causes decreased body size, increased lipid storage, hyperglycemia, and hyperphagia. Furthermore, the Hmgcr induced hyperphagia phenotype requires a conserved insulin-regulated \u03b1-glucosidase, target of brain insulin (tobi). In rats and mice, acute inhibition of hypothalamic Hmgcr activity stimulates food intake. This study presents evidence of how central Hmgcr regulation of metabolism and food intake could influence BMI.<\/jats:p>","DOI":"10.3390\/cells11060970","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T12:58:36Z","timestamp":1647003516000},"page":"970","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Statin Target Hmgcr Regulates Energy Metabolism and Food Intake through Central Mechanisms"],"prefix":"10.3390","volume":"11","author":[{"given":"Michael J.","family":"Williams","sequence":"first","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"given":"Ahmed M.","family":"Alsehli","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"},{"name":"Faculty of Medicine, King Abdulaziz University and Hospital, Al Ehtifalat St., Jeddah 21589, Saudi Arabia"}]},{"given":"Sarah N.","family":"Gartner","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6875-3928","authenticated-orcid":false,"given":"Laura E.","family":"Clemensson","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"given":"Sifang","family":"Liao","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"given":"Anders","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"given":"Kiriana","family":"Isgrove","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand"}]},{"given":"Lina","family":"Thelander","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"given":"Zaid","family":"Khan","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"},{"name":"Department of Plant Protection Biology, Swedish University of Agricultural Sciences (SLU), Sundsv\u00e4gen 14, 230 53 Alnarp, Sweden"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2191-7083","authenticated-orcid":false,"given":"Pavel M.","family":"Itskov","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7811-5383","authenticated-orcid":false,"given":"Thiago C.","family":"Moulin","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"given":"Valerie","family":"Ambrosi","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9542-8653","authenticated-orcid":false,"given":"Mohamed H.","family":"Al-Sabri","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7730-6452","authenticated-orcid":false,"given":"Francisco Alejandro","family":"Lagunas-Rangel","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]},{"given":"Pawel K.","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand"}]},{"given":"Helgi B.","family":"Schi\u00f6th","sequence":"additional","affiliation":[{"name":"Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala University, 751 24 Uppsala, Sweden"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41574-019-0176-8","article-title":"Obesity: Global epidemiology and pathogenesis","volume":"15","year":"2019","journal-title":"Nat. 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