Document Detail


Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding.
MedLine Citation:
PMID:  21969871     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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:
Nicole Speed; Christine Saunders; Adeola R Davis; W Anthony Owens; Heinrich J G Matthies; Sanaz Saadat; Jack P Kennedy; Roxanne A Vaughan; Rachael L Neve; Craig W Lindsley; Scott J Russo; Lynette C Daws; Kevin D Niswender; Aurelio Galli
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-09-28
Journal Detail:
Title:  PloS one     Volume:  6     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2011  
Date Detail:
Created Date:  2011-10-04     Completed Date:  2012-04-13     Revised Date:  2014-10-17    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e25169     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Biological Transport
Biotinylation
Brain / metabolism
Cell Membrane / metabolism
Corpus Striatum / metabolism
Diet, High-Fat
Dopamine / metabolism*
Homeostasis
Insulin / metabolism
Locomotion
Male
Obesity / metabolism
Proto-Oncogene Proteins c-akt / metabolism*
Rats
Rats, Sprague-Dawley
Signal Transduction
Substantia Nigra / metabolism
Grant Support
ID/Acronym/Agency:
DA14684/DA/NIDA NIH HHS; DK085712/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Insulin; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; VTD58H1Z2X/Dopamine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Enrollment characteristics and risk behaviors of injection drug users participating in the Bangkok T...
Next Document:  Cranial growth and variation in edmontosaurs (Dinosauria: Hadrosauridae): implications for latest Cr...