| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Kazuma Tohoku University, Hosipital, Research Associate, 病院・助手 (60292215)
ISHIHARA Hisamitsu Tohoku University, Hospital, Research Associate, 病院・助手 (60361086)
ISHIGAKI Yasushi Tohoku University, Hospital, Research Associate, 病院・助手 (50375002)
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| Research Abstract |
An explosive increase in the number of diabetic patients, which has become a major public health concern in most industrialized countries in recent decades, is mainly the result of excess energy intake and physical inactivity. Excess energy intake results in obesity, a common condition associated with diabetes, hyperlipidemia and premature heart disease. However, the major treatment modalities for diabetes, including insulin injection and oral sulfonylureas, aim at lowering blood glucose levels by driving glucose into cells in peripheral tissues such as muscle and fat. This further exacerbates insulin resistance when energy intake is in excess, resulting in a vicious cycle. Therefore, novel therapies which promote increased energy expenditure are needed.
Inefficient metabolism, such as the generation of heat instead of ATP, is a potential treatment strategy for type 2 diabetes associated with obesity. Therefore, to examine whether dissipating excess energy in the liver is a possible the
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rapeutic approach to high fat diet-induced metabolic disorders, we attempted to express uncoupling protein-1 (UCP1) ectopically in murine liver using adenoviral vectors. Once diabetes with obesity developed, hepatic UCP1 expression increased energy expenditure, decreased body weight, and reduced fat in the liver and adipose tissues, resulting in markedly improved insulin resistance, and thus, diabetes and dyslipidemia. Hepatic UCP1 expression also reversed high fat diet-induced hyperphagia and hypothalamic leptin resistance, as well as insulin resistance in muscle. In contrast, intriguingly, in standard chow-fed lean mice, hepatic UCP1 expression did not significantly affect energy expenditure or hepatic ATP contents. Furthermore, no alterations in blood glucose levels, body weight, or adiposity were observed. These findings suggest that ectopic UCP1 in the liver dissipates surplus energy without affecting required energy and exerts minimal metabolic effects in lean mice. Thus, this gene therapy is a new potential therapeutic strategy for the metabolic syndrome. Less
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