The Potential Role of Activating the ATP-Sensitive Potassium Channel in the Treatment of Hyperphagic Obesity.

Neil Cowen,Anish Bhatnagar

doi:10.3390/genes11040450

Abstract

To evaluate the potential role of ATP-sensitive potassium (KATP) channel activation in the treatment of hyperphagic obesity, a PubMed search was conducted focused on the expression of genes encoding the KATP channel, the response to activating the KATP channel in tissues regulating appetite and the establishment and maintenance of obesity, the evaluation of KATP activators in obese hyperphagic animal models, and clinical studies on syndromic obesity. KATP channel activation is mechanistically involved in the regulation of appetite in the arcuate nucleus; the regulation of hyperinsulinemia, glycemic control, appetite and satiety in the dorsal motor nucleus of vagus; insulin secretion by β-cells; and the synthesis and β-oxidation of fatty acids in adipocytes. KATP channel activators have been evaluated in hyperphagic obese animal models and were shown to reduce hyperphagia, induce fat loss and weight loss in older animals, reduce the accumulation of excess body fat in growing animals, reduce circulating and hepatic lipids, and improve glycemic control. Recent experience with a KATP channel activator in Prader–Willi syndrome is consistent with the therapeutic responses observed in animal models. KATP channel activation, given the breadth of impact and animal model and clinical results, is a viable target in hyperphagic obesity.

Highlights

Hyperphagic obesity is characterized by a markedly increased appetite and aggressive food-seeking behavior, often associated with a lack of satiety, and the accumulation of excess body fat, frequently resulting in morbid obesity and obesity-associated comorbidities
The underlying basis for hyperphagic obesity is frequently genetic, involving biallelic-inactivating mutations in known genes, as is the case of leptin receptor deficiency [1], or the deletion or lack of expression of a chromosomal segment containing a number of genes, which is characteristic of Prader–Willi syndrome [2]
This review focuses on a single potential therapeutic target, the adenosine triphosphate (ATP)-sensitive potassium (KATP ) channel, which may have utility in various forms of hyperphagic obesity

Summary

Introduction

Hyperphagic obesity is characterized by a markedly increased appetite and aggressive food-seeking behavior, often associated with a lack of satiety, and the accumulation of excess body fat, frequently resulting in morbid obesity and obesity-associated comorbidities. Hyperphagic obesity is frequently associated with both elevated morbidity and mortality and reduced quality of life [2,3]. There are very few approved treatments for any form of hyperphagic obesity and, there is a need to identify effective therapeutic targets to address the unmet medical need in these conditions. This review focuses on a single potential therapeutic target, the ATP-sensitive potassium (KATP ) channel, which may have utility in various forms of hyperphagic obesity

Methods

Results

Discussion

Conclusion