Abstract
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.
Highlights
Obesity is regarded as one of the main medical problem of the XXI century: according to WHO data (2014), more than 1.9 billion people are overweight, and 600 million are affected by obesity
Considering beneficial effects of the p62 plasmid on ovariectomy-induced chronic inflammation [27], we explored whether this vaccine can alleviate inflammation in diet-induced obesity (DIO) model which is a common model for study of metabolic diseases
Obesity leads to many dysfunctions: the imbalance in glucose metabolism observed in patients with obesity can provoke the development of type 2 diabetes (T2D), whereas the imbalance in the protein and lipid metabolism can lead to cardiovascular diseases
Summary
Obesity is regarded as one of the main medical problem of the XXI century: according to WHO data (2014), more than 1.9 billion people are overweight, and 600 million are affected by obesity. (MF) and chronic inflammation of adipose tissue (AT) which affects its metabolic and secretory functions and plays a key role in obesity-related pathology [2, 3]. We have recently developed p62 (SQSTM1)encoding plasmid (DNA vaccine) which demonstrated anti-cancer activity in animals models [13,14,15] and in the phase I/IIa clinical trial in patients with solid tumors [16]. Since chronic inflammation is believed to contribute to the development of obesity, we hypothesized that the p62 plasmid can alleviate it as well as related systemic and brain metabolic impairments. We tested this hypothesis using a rat model of the diet-induced obesity
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