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Genetic mutation linked to childhood obesity
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Pediatric patients with mutations in the KSR2 gene demonstrated an increase in appetite and slower metabolism compared with patients who carry a normal copy of the gene, suggesting new evidence as to how early-onset obesity may develop in some patients, according to data published in the journal Cell.
Sadaf Farooqi, MD, of the University of Cambridge, and colleagues carried out genetic sequencing in 2,101 patients with severe early-onset obesity and 1,536 controls from the Genetics of Obesity Study.
”Changes in diet and levels of physical activity underlie the recent increase in obesity; however, some people gain weight more easily than others,” Farooqi said in a press release. “This variation between people is largely influenced by genetic factors. The discovery of a new obesity gene, KSR2, demonstrates that genes can contribute to obesity by reducing metabolic rate.”
The researchers found several rare variants in KSR2 that interrupt a pathway known to regulate weight cellular fatty acid oxidation and glucose oxidation in transfected cells, according to data. Patients with the mutation tended to exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance, researchers wrote.
Drugs such as metformin may correct the low levels of fatty acid oxidation observed in cells expressing the KSR2 mutations, according to Farooqi.
To determine this potential strategy, researchers examined the ability of wild-type and mutant forms of KSR2 to affect AMP-activated protein kinase (AMPK) phosphorylation in the presence or absence of 1 mM metformin.
Metformin led to phosphorylation of AMPK phosphate/AMPK-alpha2 (Thr172) equally in cells transfected with wild-type and mutant forms of KSR2, the researchers wrote.
“This work adds to a growing body of evidence that genes play a major role in influencing a person’s weight and may be useful for developing new ways to treat people who are heavy and develop diabetes,” Farooqi said.
Further studies are warranted to determine the impact metformin may have on KSR2 mutations, researchers wrote.
Disclosure: The researchers report no relevant financial disclosures.
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