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

Mar 20, 2008American journal of physiology. Endocrinology and metabolism

Partial lack of leptin increases diet-related obesity and metabolic problems in mice

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Abstract

Mice with partial leptin deficiency showed significant metabolic abnormalities when fed a high-calorie diet.

Ob/+ mice did not exhibit major metabolic issues on a standard-calorie diet, except for elevated plasma adiponectin levels.
High-calorie feeding led to increased body fat, liver fat accumulation, high plasma cholesterol, and glucose intolerance in both ob/+ and +/+ mice, with more severe effects in ob/+ mice.
Ob/+ mice on a high-calorie diet showed reduced leptin and adiponectin levels, decreased expression of a key fat-burning protein, and increased liver enzymes, triglycerides, and signs of insulin resistance.
While fatty acid production in the liver decreased in +/+ mice on a high-calorie diet, it was increased in ob/+ mice, along with the reactivation of genes responsible for fat production.
Leptin treatment in ob/+ mice on a high-calorie diet alleviated most of the observed metabolic issues.

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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, beta-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.

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

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