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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/E939    most recent 00379.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Begriche, K. Articles by Fromenty, B. PubMed PubMed Citation Articles by Begriche, K. Articles by Fromenty, B.

Partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice

¹Institut National de la Santé et de la Recherche Médicale, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Université Paris 7 Denis Diderot, site Bichat, F-75018, Paris; and ²AP-HP, Service Central d'Anatomie et de Cytologie Pathologiques, Hôpital Beaujon, Clichy, France

Submitted 18 June 2007 ; accepted in final form 5 March 2008

Partial leptin deficiency is not uncommon in the general population. We hypothesized that leptin insufficiency could favor obesity, nonalcoholic steatohepatitis (NASH), and other metabolic abnormalities, particularly under high calorie intake. Thus, mice partially deficient in leptin (ob/+) and their wild-type (+/+) littermates were fed for 4 mo with a standard-calorie (SC) or a high-calorie (HC) diet. Some ob/+ mice fed the HC diet were also treated weekly with leptin. Our results showed that, when fed the SC diet, ob/+ mice did not present significant metabolic abnormalities except for elevated levels of plasma adiponectin. Under high-fat feeding, increased body fat mass, hepatic steatosis, higher plasma total cholesterol, and glucose intolerance were observed in +/+ mice, and these abnormalities were further enhanced in ob/+ mice. Furthermore, some metabolic disturbances, such as blunted plasma levels of leptin and adiponectin, reduced UCP1 expression in brown adipose tissue, increased plasma liver enzymes, β-hydroxybutyrate and triglycerides, and slight insulin resistance, were observed only in ob/+ mice fed the HC diet. Whereas de novo fatty acid synthesis in liver was decreased in +/+ mice fed the HC diet, it was disinhibited in ob/+ mice along with the restoration of the expression of several lipogenic genes. Enhanced expression of several genes involved in fatty acid oxidation was also observed only in ob/+ animals. Leptin supplementation alleviated most of the metabolic abnormalities observed in ob/+ fed the HC diet. Hence, leptin insufficiency could increase the risk of obesity, NASH, glucose intolerance, and hyperlipidemia in a context of calorie overconsumption.

fatty liver; nonalcoholic steatohepatitis; mitochondria; hyperlipidemia; adiponectin