Research press release


Nature Metabolism

Genetics: Mutation associated with childhood obesity uncovered

小児の重度肥満に関連する新しい遺伝的機構について報告した論文が、Nature Metabolismに掲載される。遺伝子の再編成の結果、空腹感の制御に関わる1個の遺伝子の発現に異常が生じるが、この再編成は肥満の定型的な遺伝子検査では検出されない。


Antje Körnerたちは、重度肥満の10代女性の組織サンプルを調べて、アグーチシグナルタンパク質(ASIP)遺伝子という1個の遺伝子が、その個体の細胞の再プログラム化によって生成された、脂肪細胞、白血球細胞、視床下部類似ニューロンなどの正常ならASIP遺伝子が存在しないはずの細胞において、高いレベルで発現されていることを発見した。遺伝子解析によって、ASIP遺伝子の1コピーが、活性なプロモーター(遺伝子発現を引き起こすDNA領域)の隣に配置されるという再編成が明らかになり、これによって、この遺伝子があらゆる組織において常に高レベルで発現していることが説明される。ここで見つかった染色体再編成の性質から、この再編成は、遺伝性の肥満を調べるほとんどの定型的遺伝子検査では検出できないことも分かった。ASIPはMC4Rの活性化を阻害するので、視床下部細胞での異常なASIP発現が、この女性に見られる肥満の説明になる可能性が高い。



A new genetic mechanism associated with severe childhood obesity is reported in a study published this week in Nature Metabolism. The genetic rearrangement results in abnormal expression of a gene associated with hunger control and is not detected by most routine genetic tests for obesity.

Activation of the melanocortin 4 receptor (MC4R) gene in a brain region called the hypothalamus triggers the sensation of satiety, or not feeling hungry. Mutations that interfere with MC4R activation or function have been linked to persistent hunger and to childhood obesity.

Studying tissue samples from a teenage girl with severe obesity, Antje Körner and colleagues found that a particular gene, the agouti-signaling protein (ASIP) gene, was expressed at high levels in cells where it is not normally present—such as in fat cells, white blood cells and hypothalamic-like neurons—generated by reprogramming cells from the individual. A genetic analysis revealed a rearrangement that placed a copy of the ASIP gene next to an active promoter, a region of DNA that drives gene expression, thereby explaining why the gene was constantly expressed in high levels in every tissue. The nature of the identified chromosomal rearrangement also meant that most routine tests for genetic forms of obesity would not detect it. ASIP inhibits MC4R activation, and the abnormal ASIP expression in hypothalamic cells thus provides a potential explanation for the observed obesity.

The team then searched specifically for this rearrangement in a cohort of over 1,700 children with obesity and identified 4 additional carriers (3 girls, 1 boy), and confirmed ASIP overexpression in 3 of these. This observation is in line with a genetic mouse model of obesity, the agouti mouse, in which obesity is due to abnormal expression of the mouse version of ASIP; however, no similar mutations involving ASIP associated with obesity had been found in humans until now.

The authors argue that the comparatively high frequency of the genetic rearrangement in the tested cohort calls for additional targeted screenings in other patient cohorts. Although the experiments in isolated cells support their model, the authors note that they have not confirmed ASIP expression and MC4R inhibition in the patients’ brains. Definitively linking the genetic rearrangement with obesity in humans would require further studies in human and animal models.

doi: 10.1038/s42255-022-00703-9


メールマガジンリストの「Nature 関連誌今週のハイライト」にチェックをいれていただきますと、毎週各ジャーナルからの最新の「注目のハイライト」をまとめて皆様にお届けいたします。