Childhood Obesity: Researchers Discover a New Causal Mutation

Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity. Nature Metabolism 2022

Excerpt of graphic below. © Prof. Antje Körner, University of Leipzig

Monogenetic forms of obesity are very rare. Researchers have now discovered a new mechanism linked to severe obesity: overexpression of the ASIP protein. They published details of their findings in Nature Metabolism.

One two-year-old girl was already receiving medical treatment for severe obesity and gigantism. She also showed signs of insulin resistance and hepatic steatosis.

Both parents suffer from obesity. The father has type 2 diabetes, high blood pressure, and gout. The girl shares certain external characteristics (e.g., red hair, pale skin and freckles) with her father. Clinically relevant genetic variants linked to monogenic obesity or other genetic disorders were ruled out via exome sequencing.

However, the phenotype of severe childhood obesity with excessive longitudinal growth, hypopigmentation, and changes to the appetite point to a genetic cause.

© Prof. Antje Körner, University of Leipzig

Molecular Biological Testing of the Stromal Vascular Fraction
The researchers collected a sample of subcutaneous fatty tissue from the patient during bariatric surgery. They looked for differentially expressed genes in cells of the stromal vascular fraction (SVF) using transcriptome analysis and compared the findings with SVF cells from healthy control subjects. A single gene responsible for Agouti-signaling protein (ASIP) coding showed severe overexpression in the patient’s cells.

The researchers found a heterozygous tandem duplication on the ASIP genomic locus. The mutation places ASIP under the control of a ubiquitously active promoter, causing increased and ubiquitous synthesis of the Agouti-signaling protein, which they were able to demonstrate under experimental conditions.

A Phenotype Observed in Mouse Models
The patient’s phenotype is extremely similar to that seen in the Agouti mouse model. Acting as an antagonist, ASIP suppresses the activation of melanocortin receptors (MCRs), such as MC4R, which can affect eating behavior, energy use, adipocyte differentiation, and pigmentation. The working group confirmed the aberrant ASIP expression in various types of cells from the patient, including induced stem cells, which they were able to differentiate in hypothalamic-like neurons, among others.

Because this mutation is not identified in standard human genetic screening, researchers re-examined the Leipzig Adipose Cohort of 1,745 patients and identified 4 patients with an identical mutation and similar phenotype – a high rate considering the rarity of monogenic obesity. 

Thus, for the first time, a genetic form of obesity has been discovered in humans that corresponds to the findings of one of the oldest mouse models. This discovery is not only relevant for the research of pathophysiological correlations and biological feedback loops associated with obesity in humans, but also because genetic diagnostic algorithms will have to be reconsidered, and there may be potential treatment options available for these patients.


Original publication:
Elena Kempf, Kathrin Landgraf, ..., Matthias Blüher & Antje Körner: Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity. Nature Metabolism, 2022. DOI: 10.1038/s42255-022-00703-9