title: Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding.
abstract: BACKGROUND
  The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.
  
  
  RESULTS
  We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.
  
  
  CONCLUSIONS
  Acquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food lifestyle" creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.
authors.affiliation: Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Speed
authors.forename: Christine
authors.initials: C
authors.lastname: Saunders
authors.forename: Adeola R
authors.initials: AR
authors.lastname: Davis
authors.forename: W Anthony
authors.initials: WA
authors.lastname: Owens
authors.forename: Heinrich J G
authors.initials: HJ
authors.lastname: Matthies
authors.forename: Sanaz
authors.initials: S
authors.lastname: Saadat
authors.forename: Jack P
authors.initials: JP
authors.lastname: Kennedy
authors.forename: Roxanne A
authors.initials: RA
authors.lastname: Vaughan
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.forename: Lynette C
authors.initials: LC
authors.lastname: Daws
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Niswender
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
mesh_terms: D000818:Animals; D001692:Biological Transport; D019921:Biotinylation; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D059305:Diet, High-Fat; D004298:Dopamine / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D008124:Locomotion; D008297:Male; D009765:Obesity / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism
chemical_list: D007328:Insulin; D051057:Proto-Oncogene Proteins c-akt; D004298:Dopamine