Leptin’s Effects in Weight Control May Fade With Age, Study Contends

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by Marta Figueiredo |

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Two mutations in or near the LEP gene resulting in lower levels of the hunger-reducing hormone leptin are associated significantly with a higher body mass index (BMI) in early childhood, but not in adulthood, according to a large, international genetic study.

These results suggest an age-dependent link between leptin and BMI, and may explain why giving leptin to obese adults is ineffective at controlling their weight.

“Our findings suggest that young children might be particularly sensitive to the effect of leptin in controlling their body weight,” Tuomas Kilpeläinen, PhD, of the University of Copenhagen’s Novo Nordisk Foundation Center for Basic Metabolic Research, said in a university press release. Kilpeläinen is the study’s co-senior author.

“This new knowledge on the impact of leptin in the weight control of young people now needs to be followed up with further studies to uncover the molecular mechanisms that underlie this age-dependent relationship between leptin and BMI,” Kilpeläinen said.

The study, “Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity,” was published in the journal Diabetes.

Leptin is released from fat cells to send signals to the brain that suppress hunger and regulate energy balance. While leptin levels generally are linked to body fat mass, this association seems to vary between individuals and across ethnicities, likely due to genetic factors.

“Identification of genetic variants associated with circulating leptin may shed new light on the role of variability in leptin levels in the general population,” the researchers wrote.

Now, an international team looked for genetic variants that influence leptin levels in 57,232 individuals with European, African, East Asian, or Hispanic ancestry.

The analysis identified five new genetic variants associated with leptin levels, independent of BMI. These included mutations in the LEP, ZNF800, KLHL31, and ACTL9 genes and one near the KLF14 gene. The data also confirmed similar associations with five previously established variants.

Among these 10 mutations, the most strongly associated with leptin levels were located in and near the LEP gene, which provides the information needed to produce the leptin hormone.

Notably, the newly identified LEP mutation (Val94Met) was linked with lower leptin levels in adults of African ancestry only. Additional analysis using human cells grown in the lab showed this variant reduced leptin secretion from cells.

Based on previous findings revealing that a mutation (rs10487505) in a region shown to regulate LEP activity was associated significantly with an increased risk of obesity in children, but not in adults, the team evaluated the influence of age in the link between the Val94Met mutation and leptin levels.

They conducted an age-stratified analysis of data from more than 2,700 children (ages 2 to 18 years) with African-ancestry followed at the Children’s Hospital of Philadelphia.

Results showed that the Val94Met mutation was associated with a higher BMI in these children between ages 3 and 7, with a more pronounced effect at age 6. Notably, no such association was found in children older than 8, “suggesting that the BMI-increasing effect of the [Val94Met variation] wanes shortly before puberty,” the team wrote.

These findings suggest that children of African ancestry carrying this genetic variant, which drops their leptin levels, are more at risk of developing obesity during childhood, but such obesity will not continue into adulthood.

Additional analyses highlighted that the rs10487575 variant near the LEP gene showed a similar age-dependent association with increased BMI.

“The pronounced association of these variants with BMI in early childhood implicates genetic regulation of LEP in early growth and suggests that young children may be particularly sensitive to the metabolic/behavioral effects of leptin,” the researchers wrote.

The Val94Met and rs10487505 mutations in and near LEP are likely to drop circulating leptin levels “by different molecular mechanisms,” the team wrote, adding that Val94Met variant lowers leptin secretion from cells, while rs10487505 may lower the activity of the LEP gene.

More studies are needed to “uncover the molecular mechanisms that underlie this age-dependent relationship between leptin and BMI,” the scientists wrote.

Also, sex-specific effects on leptin levels were found for the KLHL31 and ACTL9 variants, as well as for two genes identified in additional analysis — DNAJC18 and CNTD1. KLHL31 and DNAJC18 were linked to leptin levels in women only, while ACTL9 and CNTD1 in men only. Additional research also is needed to confirm these associations, the team added.

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