title: Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels.
abstract: Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes.
  
  
  
  We examined whether APP/PS1 mice exhibit increased susceptibility to aging or high-fat diet (HFD)-induced metabolic impairment using metabolic phenotyping and insulin-signaling studies.
  
  
  
  APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling.
  
  
  
  Our data suggest that AD pathology increases susceptibility to diabetes due to impaired hypothalamic insulin signaling, and that plasma BCAA levels could serve as a biomarker of hypothalamic insulin action in patients with AD.
authors.affiliation: Department of Medicine, Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Henry H
authors.initials: HH
authors.lastname: Ruiz
authors.affiliation: Department of Medicine, Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Chi
authors.affiliation: Department of Medicine, Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Shin
authors.affiliation: Department of Medicine, Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lindtner
authors.affiliation: Department of Medicine, Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Wilson
authors.initials: W
authors.lastname: Hsieh
authors.affiliation: Department of Neurology and Pediatrics, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Ehrlich
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY, USA; Department of Psychiatry, Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.affiliation: Department of Medicine, Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: christoph.buettner@mssm.edu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D000597:Amino Acids, Branched-Chain / Q000097:blood / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004435:Eating / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D008659:Metabolic Diseases / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; D016564:Amyloid beta-Protein Precursor; D007328:Insulin; D053764:Presenilin-1; D014280:Triglycerides
keywords: Alzheimer disease; Branched chain amino acids; Diabetes; Glucose; Insulin signaling