Methods for treating diet-induced obesity by decreasing or inhibiting P2Y2 purinergic receptor expression or activity
Inventors
Kishore, Bellamkonda K. • Zhang, Yue • Ecelbarger, Carolyn M.
Assignees
US Department of Veterans Affairs • Government of the United States of America
Publication Number
US-10024846-B2
Publication Date
2018-07-17
Expiration Date
2033-10-25
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Abstract
The invention provides a method for treating or preventing diet-induced obesity in a subject comprising administering an agent in an effective amount so that expression or activity of the P2Y2 receptor is decreased or inhibited in the subject thereby treating or preventing diet-induced obesity in the subject.
Core Innovation
The invention provides a method for treating or preventing diet-induced obesity in a subject by administering an agent in an effective amount that decreases or inhibits expression or activity of the P2Y2 purinergic receptor, thereby treating or preventing diet-induced obesity in the subject. It was discovered that genetic deletion of the P2Y2 receptor results in resistance to high-fat diet-induced obesity, increased metabolic activity, and better glucose tolerance, suggesting targeting the P2Y2 receptor is a safe and effective approach for treatment or prevention of diet-induced obesity and associated metabolic disorders such as diabetes mellitus.
The problem being solved is the need for safe and efficacious medications for prevention or treatment of obesity, especially diet-induced obesity, which is a major public health problem worldwide. Existing anti-obesity drugs have significant limitations, including safety or efficacy concerns, with side effects ranging from neurological to gastrointestinal issues. The invention addresses these limitations by providing a new therapeutic target, the P2Y2 receptor, involved in energy metabolism, which when inhibited increases metabolism of excess calories without affecting appetite suppression or fat absorption.
Claims Coverage
The patent contains one independent claim focused on methods to treat diet-induced obesity by modulating expression or activity of the P2Y2 purinergic receptor, which is further specified by various embodiments covering different types of agents and biological effects.
Method for treating diet-induced obesity by decreasing or inhibiting P2Y2 receptor expression or activity
A method for treating diet-induced obesity in a subject by administering an agent in an effective amount so that expression or activity of the P2Y2 purinergic receptor is decreased or inhibited in the subject, thereby treating the obesity.
Use of P2Y2 receptor antagonists of varying selectivity and source
Agents comprising P2Y2 receptor antagonists, including non-selective, slightly selective, selective, or specific antagonists, such as isolated organic molecules (e.g., flavonoids like strobopinin, kaempferol, tangeretin), isolated inorganic molecules, and synthetic or biochemically produced molecules with defined IC50 values.
Use of polypeptides including antibodies to inhibit P2Y2 receptor activity
Agents including fusion proteins, antibodies (polyclonal, monoclonal), antigen-binding fragments, and various antibody formats that inhibit P2Y2 receptor activity.
Use of nucleic acid-based agents and gene disruption systems
Agents comprising nucleic acids or systems capable of targeted disruption or knockdown of the P2Y2 receptor gene, including antisense oligonucleotides, ribozymes, inhibitory RNAs such as siRNA, shRNA, and miRNA, and gene editing systems like CRISPR/Cas9.
Methods modulating expression or activity of metabolic and inflammatory genes
Agents that increase expression or activity of peroxisome proliferator-activated receptor (PPAR) genes (PPAR-δ and PPAR-γ) and uncoupling protein (UCP) genes (UCP-1, UCP-2, UCP-3) in brown fat, decrease expression or activity of pro-inflammatory genes (IL-6, MCP-1/CCL-2, CCR2, CD68, F4/80) in white adipose tissue, and increase or maintain expression or activity of insulin receptor substrate-1 (IRS1), insulin receptor, and glucose transporter type 4 (GLUT4) in white fat.
The independent claim broadly covers methods to treat diet-induced obesity by administering agents that reduce P2Y2 receptor expression or activity, with inventive features encompassing diverse classes of antagonists, biological molecules, nucleic acid-based therapies, and modulation of metabolic and inflammatory gene expressions, providing a comprehensive approach targeting P2Y2 receptor for obesity and related metabolic disorders.
Stated Advantages
Compounds that inhibit P2Y2 receptor provide resistance to diet-induced obesity along with increased metabolic activity and improved glucose tolerance.
Targeting P2Y2 receptor offers a safer and possibly more tolerable approach compared to existing obesity treatments that suppress appetite or interfere with fat absorption.
Blocking P2Y2 receptor does not reduce food consumption or fat absorption but increases energy metabolism to burn excess calories effectively.
The invention enables development of selective pharmacological agents or gene-silencing therapies with potential for efficacious and safe anti-obesity drug development.
Documented Applications
Treatment or prevention of diet-induced obesity in subjects with administration of agents that decrease or inhibit P2Y2 receptor expression or activity.
Increasing energy metabolism in adipocyte cells or other cells by contacting them with agents that blunt P2Y2 receptor expression or activity, particularly in subjects at risk for or suffering from glucose metabolism disorders.
Use of gene editing, antisense oligonucleotides, ribozymes, siRNA, or shRNA to knockdown P2Y2 receptor expression as therapeutic approaches.
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