A genetic rearrangement, undetectable by most routine genetic tests, that leads to high levels of the agouti-signaling protein (ASIP), has been detected in five children with obesity. Abnormal expression of the mouse homolog of the ASIP gene is found in a commonly used mouse model of obesity—the agouti mouse—but until now ASIP mutations had not been linked to obesity in humans.

The study that resulted in the identification of the potential new mechanism underlying childhood obesity was led by Antje Körner, MD, and colleagues at the University of Leipzig, Germany, and published in the journal Nature Metabolism on December 19, 2022 “Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity.”

“This is a very nice contribution. Their conclusion that genomic alterations resulting in the ubiquitous expression of ASIP causes obesity phenotypes is well supported by their observational and experimental data,” said Claude Bouchard, PhD, emeritus professor at Pennington Biomedical Research Center in Baton Rouge, LA, whose own work focuses on the genetics of obesity. (Bouchard was not involved in the current study).

The sensation of feeling full (satiety) depends on the activation of a gene called melanocortin 4 receptor (MC4R) in the hypothalamus. Alterations in the genome that prevent the physiological activation of MC4R, therefore result in a lack of satiety and constant pangs of hunger. Such mutations have been linked to childhood obesity.

The proband in Körner’s study was a teenage European girl who first presented with severe obesity and overgrowth when she was less than two years old. She was diagnosed with the first signs of severe hyperinsulinemia and hepatic steatosis in early childhood. Tissue analysis revealed mutations in ASIP accompanied by high expression of the gene in cells where ASIP is not normally expressed—fat cells, white blood cells and hypothalamic-like neurons. These cell types were generated by reprogramming cells from the patient (iPSC, induced pluripotent stem cells).

The researchers found a genetic rearrangement in the proband’s genome that placed a copy of the ASIP gene directly under a ubiquitously active E3 ligase promoter, resulting in its constant expression at high levels in every tissue in the body. Genetic rearrangements are harder to identify than point mutations, deletion or insertions and are not detected by routine tests for genetic forms of obesity.

ASIP’s biological function is to repress MC4R activation, thereby affecting eating behavior, energy expenditure, adipocyte differentiation and pigmentation, as observed in the proband. Abnormal and ectopic ASIP overexpression in hypothalamic cells will therefore continuously prevent MC4R activation leading to sensations of constant hunger.

Körner’s team screened a cohort of 1,700 children for the presence of the ASIP genetic rearrangement and identified three girls and one boy with the same mutation. The researchers confirmed ASIP overexpression in three of the four children. This high frequency of genetic rearrangement in the tested cohort warrants targeted screenings in other patient cohorts, the investigators emphasized.

“It is noteworthy that the ubiquitous expression of ASIP interferes with normal signaling at the melanocortin receptor pathway, a key regulator of energy balance,” said Bouchard. “Of particular interest is their observation that four children of the Leipzig Childhood Obesity carry the same mutation as their proband.”

“Our data indicate that ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity,” the authors concluded.

To definitively link the ASIP genetic rearrangement with obesity in humans, the experiments conducted in this study on native cells and iPSCs from patients must be confirmed through the analysis of ASIP expression and MC4R inhibition in patient brain tissue samples as well as animal model studies.

“This contribution along with others over the last few years strongly suggest that low frequency or rare mutations are very important components of the Human Obesity Genome. We can undoubtedly expect that many more such mutations will be identified in the coming years,” Bouchard added.

Despite the established genetic contribution to obesity, monogenic forms of human obesity are rare. Detection of such monogenic forms of obesity will improve understanding of the pathophysiological mechanisms underlying obesity and bolter precision medicine approaches.

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