title: Adipocyte arrestin domain-containing 3 protein (Arrdc3) regulates uncoupling protein 1 (Ucp1) expression in white adipose independently of canonical changes in β-adrenergic receptor signaling.
abstract: Adaptive thermogenesis and cold-induced activation of uncoupling protein 1 (Ucp1) in brown adipose tissue in rodents is well-described and attributed to sympathetic activation of β-adrenergic signaling. The arrestin domain containing protein Arrdc3 is a regulator of obesity in mice and also appears linked to obesity in humans. We generated a mouse with conditional deletion of Arrdc3, and here we present evidence that genetic ablation of Arrdc3 specifically in adipocytes results in increased Ucp1 expression in subcutaneous and parametrial adipose tissue. Although this increase in expression did not correspond with significant changes in body weight or energy expenditure, adipocyte-specific Arrdc3-null mice had improved glucose tolerance. It was previously hypothesized that Arrdc3 ablation leads to increased β-adrenergic receptor sensitivity; however, in vitro experiments show that Arrdc3-null adipocytes responded to β-adrenergic receptor agonist with decreased Ucp1 levels. Additionally, canonical β-adrenergic receptor signaling was not different in Arrdc3-null adipocytes. These data reveal a role for Arrdc3 in the regulation of Ucp1 expression in adipocytes. However, this adipocyte effect is insufficient to generate the obesity-resistant phenotype of mice with ubiquitous deletion of Arrdc3, indicating a likely role for Arrdc3 in cells other than adipocytes.
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Shannon H
authors.initials: SH
authors.lastname: Carroll
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Ellen
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Bing F
authors.initials: BF
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: LeClair
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Arifeen
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Parth
authors.initials: P
authors.lastname: Patwari
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America.|Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Richard T
authors.identifier: http://orcid.org/0000-0003-4687-1381
authors.initials: RT
authors.lastname: Lee
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000502:physiology*; D001823:Body Composition; D051379:Mice; D018345:Mice, Knockout; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D000071256:Uncoupling Protein 1 / Q000378:metabolism*
chemical_list: C570236:ARRDC3 protein, mouse; D019390:Arrestins; D011943:Receptors, Adrenergic, beta; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1