Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding
DOI is broken and has been reported
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2013
|
| Online Access: | http://hdl.handle.net/1721.1/79107 https://orcid.org/0000-0002-3854-5968 |
| _version_ | 1811093979639316480 |
|---|---|
| author | Speed, Nicole Saunders, Christine Davis, Adeola R. Owens, W. Anthony Matthies, Heinrich J. G. Saadat, Sanaz Kennedy, Jack P. Vaughan, Roxanne A. Neve, Rachael L. Lindsley, Craig W. Russo, Scott J. Daws, Lynette C. Niswender, Kevin D. Galli, Aurelio |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Speed, Nicole Saunders, Christine Davis, Adeola R. Owens, W. Anthony Matthies, Heinrich J. G. Saadat, Sanaz Kennedy, Jack P. Vaughan, Roxanne A. Neve, Rachael L. Lindsley, Craig W. Russo, Scott J. Daws, Lynette C. Niswender, Kevin D. Galli, Aurelio |
| author_sort | Speed, Nicole |
| collection | MIT |
| description | DOI is broken and has been reported |
| first_indexed | 2024-09-23T15:53:41Z |
| format | Article |
| id | mit-1721.1/79107 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:53:41Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/791072022-09-29T16:52:13Z Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding Speed, Nicole Saunders, Christine Davis, Adeola R. Owens, W. Anthony Matthies, Heinrich J. G. Saadat, Sanaz Kennedy, Jack P. Vaughan, Roxanne A. Neve, Rachael L. Lindsley, Craig W. Russo, Scott J. Daws, Lynette C. Niswender, Kevin D. Galli, Aurelio Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Neve, Rachael L. DOI is broken and has been reported 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. National Institutes of Health (U.S.) (grant DA14684) National Institutes of Health (U.S.) (grant DK085712) 2013-06-14T14:58:31Z 2013-06-14T14:58:31Z 2011-09 2011-05 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/79107 Speed, N, Saunders, C, Davis, AR, Owens, WA, Matthies, HJG, et al. (2011) Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding. PLoS ONE 6(9): e25169. https://orcid.org/0000-0002-3854-5968 en_US http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0025169;jsessionid=DB6638FB5993E73D1782E249CF913EBA PLoS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Speed, Nicole Saunders, Christine Davis, Adeola R. Owens, W. Anthony Matthies, Heinrich J. G. Saadat, Sanaz Kennedy, Jack P. Vaughan, Roxanne A. Neve, Rachael L. Lindsley, Craig W. Russo, Scott J. Daws, Lynette C. Niswender, Kevin D. Galli, Aurelio Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding |
| title | Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding |
| title_full | Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding |
| title_fullStr | Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding |
| title_full_unstemmed | Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding |
| title_short | Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding |
| title_sort | impaired striatal akt signaling disrupts dopamine homeostasis and increases feeding |
| url | http://hdl.handle.net/1721.1/79107 https://orcid.org/0000-0002-3854-5968 |
| work_keys_str_mv | AT speednicole impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT saunderschristine impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT davisadeolar impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT owenswanthony impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT matthiesheinrichjg impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT saadatsanaz impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT kennedyjackp impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT vaughanroxannea impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT neverachaell impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT lindsleycraigw impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT russoscottj impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT dawslynettec impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT niswenderkevind impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding AT galliaurelio impairedstriatalaktsignalingdisruptsdopaminehomeostasisandincreasesfeeding |