Composition and methods for the prevention and treatment of diet-induced obesity
Inventors
Kishore, Bellamkonda K. • Zhang, Yue • Ecelbarger, Carolyn M.
Assignees
US Department of Veterans Affairs
Publication Number
US-10107795-B2
Publication Date
2018-10-23
Expiration Date
2033-10-25
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Abstract
Blunting the activity of the P2Y2 receptor results in a resistance to diet-induced obesity, an increased metabolic rate, and a better glucose tolerance. Compounds that inhibit the puringeric P2Y2 receptor are useful for treating disorders associated with diabetes, treating obesity, and increasing metabolism (e.g., fatty acid metabolism).
Core Innovation
The invention provides methods for preventing and treating diet-induced overweight or obesity by selectively blocking the activity of the P2Y2 purinergic receptor. It was discovered that genetic deletion of the P2Y2 receptor in mice leads to resistance to high-fat diet-induced obesity, increased metabolic rate, and improved glucose tolerance. This resistance is not due to reduced food consumption or impaired fat absorption but is attributed to an enhanced ability to metabolize excess calories more efficiently. The invention proposes targeting the P2Y2 receptor with specific pharmacological agents or drugs, such as selective P2Y2 receptor antagonists or oligonucleotides, to safely prevent or treat diet-induced obesity.
The background identifies obesity, particularly diet-induced obesity resulting from an energy imbalance between calories consumed and expended, as a major global health problem with serious consequences including cardiovascular diseases, diabetes, and certain cancers. Current anti-obesity drugs have significant safety and efficacy limitations, such as neurological side effects from appetite suppressants, inconsistent metabolic effects, or gastrointestinal issues from fat absorption inhibitors. The invention addresses this unmet need by focusing on increasing metabolism of excess calories via inhibition of the P2Y2 receptor, offering a potentially safer and more tolerable alternative to existing therapies.
Experimental evidence from studies on genetically modified mice deficient in the P2Y2 receptor demonstrates these mice do not gain weight despite consuming the same amount of high-fat diet and do not exhibit fat malabsorption. The knockout mice show higher expression of energy metabolism-related genes, including peroxisome proliferator-activated receptors and mitochondrial uncoupling proteins, contributing to increased calorie burning. Additionally, these mice exhibit lower inflammation markers and better insulin signaling in adipose tissue, linking P2Y2 receptor activity to metabolic regulation. These findings support the novel approach of targeting the P2Y2 receptor to treat diet-induced obesity and related metabolic disorders.
Claims Coverage
The patent includes one independent claim focusing on a method to treat diet-induced obesity by modulating the P2Y2 receptor. This claim covers the use of agents that blunt the receptor's expression or activity.
Method of treating diet-induced obesity by blunting P2Y2 receptor expression or activity
Administration of an agent to a subject that inhibits or reduces the expression or activity of the P2Y2 receptor to treat diet-induced obesity.
Use of selective P2Y2 receptor antagonists as therapeutic agents
The agent can be a selective antagonist of the P2Y2 receptor, specifically a small non-nucleic acid organic molecule that inhibits receptor activity.
Use of oligonucleotide agents targeting P2Y2 receptor RNA
The agent can be an oligonucleotide capable of hybridizing to RNA encoding the P2Y2 receptor under physiological conditions, including antisense oligonucleotides, ribozymes, inhibitory RNAs, and small inhibitory RNAs (siRNAs).
The claims focus on treating diet-induced obesity by administering agents that inhibit or reduce the activity or expression of the P2Y2 receptor, encompassing selective antagonists and various oligonucleotide-based inhibitors.
Stated Advantages
Resistance to diet-induced obesity without reducing food intake or causing fat malabsorption.
Increased metabolic rate allowing more efficient metabolism of excess calories.
Improved glucose tolerance and reduced markers of inflammation associated with obesity.
Potentially safer and better tolerated alternative to existing anti-obesity drugs that suppress appetite or block fat absorption.
Genetic deletion of P2Y2 receptor does not cause major adverse health effects, indicating a safe therapeutic target.
Documented Applications
Treatment and prevention of diet-induced obesity in subjects.
Treatment of metabolic disorders associated with obesity, such as diabetes mellitus.
Increasing energy metabolism in adipocyte cells for improved metabolic health.
Identification of candidate agents that modulate P2Y2 receptor expression or activity for therapeutic intervention.
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