Reduced expression of mitochondrial frataxin in mice exacerbates diet-induced obesity

Abstract

Published evidence suggests that adiposity in humans may be linked to impaired energy expenditure for reasons widely unresolved. We have generated mice with a systemic impairment of oxidative phosphorylation (OXPHOS) due to aP2 cre-mediated targeted disruption, and unexpectedly ubiquitous reduction of mitochondrial frataxin protein expression. Only when maintained on a high-calorie diet resembling Westernized eating habits, these animals accumulate additional body fat, leading to increased body mass, and develop diabetes mellitus, despite the fact that both calorie uptake and physical activity were identical to that in control animals. This phenotype is caused by a mild but significant reduction in total energy expenditure paralleled by increased expression of ATP citrate lyase, a rate-limiting step in de novo synthesis of fatty acids and triglycerides. Taken together, these findings indicate that a limited impairment in oxidative metabolism within the mitochondria directly predisposes mammals to excessive body weight gain.metabolism ͉ mitochondria ͉ oxidative phosphorylation

Adipose tissue transcriptome reflects variations between subjects with continued weight loss and subjects regaining weight 6 mo after caloric restriction independent of energy intake

“…Mitochondrial dysfunction could result in cellular disruptions that could be related to complications associated with obesity via modifications of lipid metabolism and energy partitioning. Mice with systemic impairment of oxidative phosphorylation are more sensitive to obesity and to diabetes mellitus than control mice when fed a high-calorie diet under the same conditions of energy intake and physical activity (33). In humans, it has been shown that oxidative phosphorylation genes are also down-regulated in white adipose tissue of morbidly obese subjects compared with lean subjects, whereas after surgery-induced weight loss, an up-regulation of these genes was observed (34).…”

Modelo de obesidade induzida por dieta hiperlipídica e associada à resistência à ação da insulina e intolerância à glicose

“…O aumento de peso e tecido adiposo pode ser resultado da alteração na modulação hipotalâmica da sinalização da leptina em função da hiperleptinemia. Além disso, redução da massa e capacidade oxidativa mitocondrial também podem ser observadas em roedores alimentados com dieta hiperlipídica, favorecendo maior acúmulo de gordura (11,12).…”

Obesity: considerations about etiology, metabolism, and the use of experimental models

“…Some studies indicate that impairment on mitochondrial metabolism may lead to excessive body weight gain when the subjects are fed with high-calorie western diets 44. The study of Townsend et al45 offered two different diets (hyperlipidic and hypolipidic) to rats, both diets predominant in saturated fat.…”