P62 plasmid can alleviate diet-induced obesity and metabolic dysfunctions
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Tatiana Halenova1, Oleksii Savchuk1, Ludmila Ostapchenko1, Andrey Chursov2, Nathan Fridlyand3, Andrey B. Komissarov4, Franco Venanzi3, Sergey I. Kolesnikov5,6,7, Albert A. Sufianov8,9, Michael Y. Sherman10, Vladimir L. Gabai2,10 and Alexander M. Shneider2,9,11
1Educational and Scientific Center ‘Institute of Biology and Medicine’, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
2Curelab Oncology Inc, Dedham, MA, USA
3School of Biosciences, University of Camerino, Camerino, Italy
4Research Institute of Influenza, St-Petersburg, Russia
5Russian Academy of Sciences, Moscow, Russia
6Lomonosov Moscow State University, Moscow, Russia
7Research Center of Family Health and Reproduction Problems, Irkutsk, Russia
8Federal Center of Neurosurgery, Tyumen, Russia
9Sechenov First Moscow State Medical University, Moscow, Russia
10Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
11Department of Molecular Biology, Ariel University, Ariel, Israel
Vladimir L. Gabai, email: [email protected]
Alexander M. Shneider, email: [email protected]
Keywords: diabetes, high-calorie diet, inflammation, cytokines, serotonin
Received: May 23, 2017 Accepted: June 26, 2017 Published: August 03, 2017
A high-calorie diet (HCD) induces two mutually exacerbating effects contributing to diet-induced obesity (DIO): impaired glucose metabolism and increased food consumption. A link between the metabolic and behavioral manifestations is not well understood yet. We hypothesized that chronic inflammation induced by HCD plays a key role in linking together the two components of diet-induced pathology. Based on this hypothesis, we tested if a plasmid (DNA vaccine) encoding p62 (SQSTM1) would alleviate DIO including its metabolic and/or food consumption abnormalities. Previously we reported that injections of the p62 plasmid reduce chronic inflammation during ovariectomy-induced osteoporosis. Here we found that the p62 plasmid reduced levels of pro-inflammatory cytokines IL-1β, IL-12, and INFγ and increased levels of anti-inflammatory cytokines IL-4, IL-10 and TGFβ in HCD-fed animals. Due to this anti-inflammatory response, we further tested whether the plasmid can alleviate HCD-induced obesity and associated metabolic and feeding impairments. Indeed, p62 plasmid significantly reversed effects of HCD on the body mass index (BMI), levels of glucose, insulin and glycosylated hemoglobin (HbA1c). Furthermore, p62 plasmid partially restored levels of the satiety hormone, serotonin, and tryptophan, simultaneously reducing activity of monoamine oxidase (MAO) in the brain affected by the HCD. Finally, the plasmid partially reversed increased food consumption caused by HCD. Therefore, the administering of p62 plasmid alleviates both metabolic and behavioral components of HCD-induced obesity.
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