title: Glucose intolerance and pancreatic β-cell dysfunction in the anorectic anx/anx mouse.
abstract: Inflammation and impaired mitochondrial oxidative phosphorylation are considered key players in the development of several metabolic disorders, including diabetes. We have previously shown inflammation and mitochondrial dysfunction in the hypothalamus of an animal model for anorexia, the anx/anx mouse. Moreover, increased incidence of eating disorders, e.g., anorexia nervosa, has been observed in diabetic individuals. In the present investigation we evaluated whether impaired mitochondrial phosphorylation and inflammation also occur in endocrine pancreas of anorectic mice, and if glucose homeostasis is disturbed. We show that anx/anx mice exhibit marked glucose intolerance associated with reduced insulin release following an intraperitoneal injection of glucose. In contrast, insulin release from isolated anx/anx islets is increased after stimulation with glucose or KCl. In isolated anx/anx islets there is a strong downregulation of the mitochondrial complex I (CI) assembly factor, NADH dehydrogenase (ubiquinone) 1α subcomplex, assembly factor 1 (Ndufaf1), and a reduced CI activity. In addition, we show elevated concentrations of free fatty acids (FFAs) in anx/anx serum and increased macrophage infiltration (indicative of inflammation) in anx/anx islets. However, isolated islets from anx/anx mice cultured in the absence of FFAs do not exhibit increased inflammation. We conclude that the phenotype of the endocrine pancreas of the anx/anx mouse is characterized by increased levels of circulating FFAs, as well as inflammation, which can inhibit insulin secretion in vivo. The anx/anx mouse may represent a useful tool for studying molecular mechanisms underlying the association between diabetes and eating disorders.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lindfors
authors.affiliation: Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden; Ariel University, Department of Physical Therapy, Ariel, Israel.
authors.forename: Abram
authors.initials: A
authors.lastname: Katz
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Lars
authors.initials: L
authors.lastname: Selander
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Johansen
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Giulia
authors.initials: G
authors.lastname: Marconi
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Tomas
authors.initials: T
authors.lastname: Hökfelt
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Belozersky Institute of Physico-Chemical Biology and Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia;
authors.forename: Sergei
authors.initials: S
authors.lastname: Zaitsev
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; ida.nilsson@ki.se.
authors.forename: Ida A K
authors.initials: IA
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D000855:Anorexia / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001786:Blood Glucose / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D018149:Glucose Intolerance / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D010179:Pancreas / Q000473:pathology
chemical_list: D001786:Blood Glucose; D007328:Insulin
keywords: anorexia; free fatty acids; insulin; macrophages; mitochondrial dysfunction