Double Leptin and Melanocortin-4 Receptor Gene Mutations Have an Additive Effect on Fat Mass and Are Associated with Reduced Effects of Leptin on Weight Loss and Food Intake

Jul 5, 2005Endocrinology

Combined mutations in leptin and melanocortin-4 receptor genes increase body fat and reduce leptin's effects on weight loss and appetite

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Abstract

A 2-fold increase in body weight was observed in Lep(ob)/Lep(ob) mice associated with severe obesity.

Double heterozygous and homozygous mutants showed an additive effect on fat mass.
Lep(ob)/Lep(ob) mice demonstrated significantly higher 24-hour total and resting energy expenditure.
Obesity's impact on energy expenditure was reduced by 50% in Lep(ob)/Lep(ob) Mc4r+/- and Mc4r-/- mice.
Loss of MC4Rs did not change the basal food intake of Lep(ob)/Lep(ob) mice but led to partial leptin resistance regarding food intake and weight loss.
Leptin's suppression of insulin and corticosterone levels in Lep(ob)/Lep(ob) mice was not significantly influenced by Mc4r genotype.

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Melanocortin-4 receptors (MC4Rs) are involved in the regulation of food intake, sympathetic nervous activity, and adrenal and thyroid function by leptin. The role of MC4Rs in regulating energy balance by leptin was investigated using double heterozygote or homozygous leptin (Lep(ob)) and Mc4r gene mutant mice. Double heterozygous or homozygous mutants were generated by crossing MC4R knockout (Mc4r-/-) mice, backcrossed onto C57BL/6J, with B6.V-Lep(ob) mice. Energy expenditure was measured using indirect calorimetry. The effect of leptin on food intake, weight loss, insulin, and corticosterone was compared for Lep(ob)/Lep(ob)Mc4r-/- mice and Lep(ob)/Lep(ob) mice. Double heterozygous and homozygous mutants exhibited an additive effect on fat mass. The 2-fold increase in body weight associated with severe obesity of Lep(ob)/Lep(ob) mice was associated with a significantly higher 24 h total and resting energy expenditure. The effect of obesity on energy expenditure was attenuated by 50% in Lep(ob)/Lep(ob) Mc4r+/- and Lep(ob)/Lep(ob) Mc4r-/- mice. Loss of MC4Rs did not affect basal food intake of Lep(ob)/Lep(ob) mice but was associated with partial leptin resistance in terms of food intake and weight loss. Leptin suppression of insulin and corticosterone in Lep(ob)/Lep(ob) mice were not significantly affected by Mc4r genotype. These results suggest a complex interaction between the Lep and Mc4r genes in energy homeostasis and suggest that MC4Rs retain significant anti-obesity function in the obese leptin-deficient state. Increased adiposity with double mutations may involve a reduction in energy expenditure. MC4Rs might have a modest role in the regulation of energy balance by exogenously administered leptin, primarily effecting food intake.

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Double Leptin and Melanocortin-4 Receptor Gene Mutations Have an Additive Effect on Fat Mass and Are Associated with Reduced Effects of Leptin on Weight Loss and Food Intake

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