Abstract

Consumption of high fat, high sugar (western) diets is a major contributor to the current high levels of obesity. Here, we used a multidisciplinary approach to gain insight into the molecular mechanisms underlying susceptibility to diet-induced obesity (DIO). Using positron emission tomography (PET), we identified the dorsal striatum as the brain area most altered in DIO-susceptible rats and molecular studies within this region highlighted regulator of G-protein signaling 4 (Rgs4) within laser-capture micro-dissected striatonigral (SN) and striatopallidal (SP) medium spiny neurons (MSNs) as playing a key role. Rgs4 is a GTPase accelerating enzyme implicated in plasticity mechanisms of SP MSNs, which are known to regulate feeding and disturbances of which are associated with obesity. Compared to DIO-resistant rats, DIO-susceptible rats exhibited increased striatal Rgs4 with mRNA expression levels enriched in SP MSNs. siRNA-mediated knockdown of striatal Rgs4 in DIO-susceptible rats decreased food intake to levels comparable to DIO-resistant animals. Finally, we demonstrated that the human Rgs4 gene locus is associated with increased body weight and obesity susceptibility phenotypes, and that overweight humans exhibit increased striatal Rgs4 protein. Our findings highlight a novel role for involvement of Rgs4 in SP MSNs in feeding and DIO-susceptibility.

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Acknowledgements

This work was supported by the NIAAA (AA11034, AA07574, AA07611, Y1AA3309), the NIDA (DA006278, DA015446, DA023214, DA030359, ZIA000069) and the NINDS (NS086444, NS093537). MM was supported by DA007135. MLM was supported by GM007280 and DA038954. MM is a cofounder and owns stock in Metis Laboratories.

Author information

Author notes

    • Michael Michaelides

    Present address: Biobehavioral Imaging & Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA

Affiliations

  1. Departments of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    • Michael Michaelides
    • , Michael L. Miller
    • , Gabor Egervari
    • , Joseph A. Landry
    • , Henrietta Szutorisz
    •  & Yasmin L. Hurd
  2. Departments of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    • Michael Michaelides
    • , Michael L. Miller
    • , Gabor Egervari
    • , Joseph A. Landry
    • , Henrietta Szutorisz
    • , Venetia Zachariou
    •  & Yasmin L. Hurd
  3. Biobehavioral Imaging & Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA

    • Michael Michaelides
    • , Juan L. Gomez
    •  & Randall J. Ellis
  4. Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    • Michael Michaelides
  5. Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA

    • Stefany D. Primeaux
  6. Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA

    • Stefany D. Primeaux
    •  & George A. Bray
  7. Electrophysiology Research Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA

    • Alexander F. Hoffman
    •  & Carl R. Lupica
  8. The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    • Ruth J. F. Loos
  9. Research Institute on Addictions, University at Buffalo, Buffalo, NY, 14203, USA

    • Panayotis K. Thanos
  10. Departments of Psychiatry and Pharmacology, University of Washington, Seattle, WA, 98195, USA

    • John F. Neumaier
  11. Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA

    • Gene-Jack Wang
    •  & Nora D. Volkow

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The authors declare that they have no conflict of interest.

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Correspondence to Yasmin L. Hurd.

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DOI

https://doi.org/10.1038/s41380-018-0120-7