title: Overexpression of FoxO1 in the hypothalamus and pancreas causes obesity and glucose intolerance.
abstract: Recent studies have revealed that insulin signaling in pancreatic β-cells and the hypothalamus is critical for maintaining nutrient and energy homeostasis, the failure of which are hallmarks of metabolic syndrome. We previously reported that forkhead transcription factor forkhead box-containing protein of the O subfamily (FoxO)1, a downstream effector of insulin signaling, plays important roles in β-cells and the hypothalamus when we investigated the roles of FoxO1 independently in the pancreas and hypothalamus. However, because metabolic syndrome is caused by the combined disorders in hypothalamus and pancreas, to elucidate the combined implications of FoxO1 in these organs, we generated constitutively active FoxO1 knockin (KI) mice with specific activation in both the hypothalamus and pancreas. The KI mice developed obesity, insulin resistance, glucose intolerance, and hypertriglyceridemia due to increased food intake, decreased energy expenditure, and impaired insulin secretion, which characterize metabolic syndrome. The KI mice also had increased hypothalamic Agouti-related protein and neuropeptide Y levels and decreased uncoupling protein 1 and peroxisome proliferator-activated receptor γ coactivator 1α levels in adipose tissue and skeletal muscle. Impaired insulin secretion was associated with decreased expression of pancreatic and duodenum homeobox 1 (Pdx1), muscyloaponeurotic fibrosarcoma oncogene homolog A (MafA), and neurogenic differentiation 1 (NeuroD) in islets, although β-cell mass was paradoxically increased in KI mice. Based on these results, we propose that uncontrolled FoxO1 activation in the hypothalamus and pancreas accounts for the development of obesity and glucose intolerance, hallmarks of metabolic syndrome.
authors.affiliation: Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Kikuchi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Amano
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kitazumi
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Lee
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yokota-Hashimoto
authors.forename: Vina Yanti
authors.initials: VY
authors.lastname: Susanti
authors.forename: Yukari Ido
authors.initials: YI
authors.lastname: Kitamura
authors.forename: Jun
authors.initials: J
authors.lastname: Nakae
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004435:Eating; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D010179:Pancreas / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin